Immunology Test 3
Intrisically regulated
(Clonal anergy or tuning) Regulation by: - BCR/TCR downregulation - Induction of inhibitory receptors (CD5, CTLA4) - Phosphatases (SHP1, SHIP) - Ubiquitin ligases (CBL, GRAIL, ITCH, ROQUIN)
Major Basic protein
(Eosinophil toxic protein) Poisons parasites and mammalian cells. Triggers histamine release from mast cells.
Eosinophil cationic protein
(Eosinophil toxic protein) Poisons parasites. Neurotoxin.
Recombinant viruses in animals and humans mechanism
1. A pig is infected with human and avian strains of influenza virus 2. Recombination of avian and human RNA produces a virus that infects human cells and has a new form of hemagglutinin 3. No humans have antibodies that recognize the new hemagglutinin: the entire population is vulnerable to infection
two parts of antibody production
1. Activating and proliferation (speed) 2. Quality (somatic hypermutation and isotype switching) (*3. selection for the best ones*)
2 artificial methods of immunity
1. Active immunization 2. Passive immunization
Difference between IgE and IgG
1. IgE is not retained by the blood but instead concentrates in the tissues, where it binds to FcepsilonRI, the high-affinity IgE receptor on mast cells. 2. IgE's three-dimensional structure differes greatly from that of IgG. IgG has a symmetrical, extended Y-shaped structure, whereas IgE has a bent, asymmetrical 'shrimp-like' structure in which the amino and carboxy terminals of the heavy chain are half as far apart as expected for an extended Y-shaped structure. 3. Unlike other immunolglobulins, IgE binds to its high-affinity receptor in the absence of antigen, and in foing so the IgE molecule becomes even more bent. This conformation allows the antigen-binding sites to project out from the surface of the mast cells and be in advantageous positions for capturing antigens.
Adaptive immune responses to tumors
1. CD8 CTLs are the key players on the killing effect of tumors 2. CD4 T helper cells = cytokines = CTLs 3. Abs = activating complements or Ab-dep cell med toxicity (ADCC) = preventing oncogenic viruses
Strategies to regulate self-reactive receptors
1. Cell deleted 2. Receptor edited 3. Intrisically regulated 4. Extrinsically regulated
Antibody prevention against bacteria mechanism
1. Child with antibodies against S. pyogenes 2. Antibodies prevent the attachment of bacteria to the tissue: most bacteria are swept to the gut 3. Bacterial population is limited and kept at a steady state: child remains healthy
Purpose of Myeloablative therapy
1. Crippling of the recipient's immune system rules out the possibility that the grafted stem cells will be subject to immunological rejection 2. killing all the hematopoietic cells in the recipient's bone marrow provides necessary space for the transplanted stem cells to interact with stromal cells, flourish, and create a new immune system.
Steps of Cross-linking
1. Cross-linking of B-cell receptors by antigen 2. Clustering of antigen receptors allows receptor-associated kinases to phosphorylate the ITAMs (Signal transduction)
What is needed for B cell activation (2 things)?
1. Cross-linking of surface Ig 2. Signals from B cell co-receptor
Healthy newborn baby
1. First pregnancy of RhD- mother carrying a RhD+ fetus 2. Primary immune response, IgM plus low amounts of low-affinity IgG 3. Minor destruction of fetal erythrocytes by anti-RhD IgG 4. Healthy newborn baby
IgM, IgG, IgA(monomeric) mechanism
1. Fluid-phase endocytosis of IgG from the blood by endothelial cells of the blood vessel 2. Acidic pH of the endocytic vesicle causes the association of IgG with FcRn, protecting it from proteolysis 3. On reaching the basolateral face of the endothelial cell, the basic pH of the extracellular fluid dissociates IgG from FcRn.
Celiac disease mechanism
1. Gluten is degraded in the gut lumen to give a resistant fragment 2. Gluten fragment enters gut tissue and is deaminated by transglutaminase 3. Naive CD4 T cell responds to deaminated peptides presented by HLA-DQ 4. Inflammatory effector T cells cause villous atrophy
Hyperacute rejection mechanism
1. Healthy kidney grafted into patient with kidney failure and pre-existing antibodies against donor blood group antigens 2. Antibodies against donor blood group antigens bind vascular endothelium of graft, initiating an inflammatory response that occludes (obstructs) blood vessels 3. Graft becomes engorged and purple-colored because of hemorrhage 4.Graft failure
Proactive mechanism of mucosal tissues
1. Healthy tissue protected by mucosal immunity 2. Bacteria gain access to lamina propria by endocytosis, activate macrophages but do not cause inflammation 3. Local effector cells respond to limit infection, dendritic cells to mesenteric lymph node to activate adaptive immunity 4. Effector B cells and T cells that are highly specific for the invading bacteria colonize the infected area 5. Infection is terminated with either minor tissue damage or no need for repair
mechanism of Inflammation in normal tissue
1. Healthy tissue protected by systemic immunity 2. Surface wounds introduces bacteria that activate macrophages to make inflammatory cytokines 3. Cytokines released by macrophages produce an inflammatory immune response 4. Infection is terminated, leaving a damaged and distorted tissue for repair 5. Repaired and healthy tissue
What is the most common type of live-attenuated bacterial vaccines?
BCG vaccine derived from a bovine strain of TB that provides protection against some forms of TB
Mothers provide protective antibodies to their young
BOTH before and after birth (passive transfer of immunity - Ig isotypes are distributed selectively in the human body and so are passed by mothers to their young
BCG
Bacille Calmette-Guerin strain of tuberculosis used in the tuberculosis vaccine. Not pathogenic to humans. Live-attenuated bacterial vaccine whose efficacy varies with the human population. Never been used in the US.
Anthrax
Bacillus Anthracis; Anthrax Toxic Complex; Increases vascular permeability, leading to edema, hemorrhage, and circulatory collapse
Mantle Zone
Area surrounding the germinal center containing the naïve B cells that are passing through the lymph node in search of specific antigen and survival signals
vpr
Arrests cell cycle. Transports DNA to nucleus. Influences virion production.
What usually happens at the beginning stages of HIV infection (weeks up to months)?
Asymptomatic or flu like CD4 T cell levels drop Viremic HIV phase CD8 T cells and anti-HIV Ab fight off infection CD4 levels go back up and viremia goes down
Vaccines using recombinant gene technology
Attempts to make vaccines more effective, cheaper, and safer
Is the villous epithelium well protected?
Yes, they contain villi, enterocytes, paneath cells and goblet cells
How do mast cells differ from B cells?
B cells commit to making antibody of just one specificity. Mast cells acquire IgE with different specificities.
aside from crosslinking with the antigen to antibody, what else does the B-cell activation require
B-cell activation requires signals from the B-cell coreceptor.
Primary Lymphoid Follicle
B-cell area in secondary lymphoid tissue in the absence of an immune response; contains resting B cells
Secondary Lymphoid Follicle
B-cell area of a secondary lymphoid tissue that is responding to antigen; contains differentating and proliferating B cells; where somatic hypermutation and isotype switching occur
secondary follicle
B-cell area of a secondary lymphoid tissue that is responding to antigen. It contains proliferating and differentiation B cells and develops a germinal center in which B cells undergo somatic hypermutation and isotype switching. Also called secondary lymphoid follicle
Can vaccination cause disease?
Yes. Vaccination can inadvertently cause disease. For example, in 1955, a manufacturer of the vaccine did not properly inactivate the virus, causing a polio outbreak among 94 people who had received the vaccination and 166 of their friends and family.
Original antigenic sin
a bias seen in successive immune responses to structurally related antigens such as those on different strains of influenza virus. On infection for the secondary time with influenza, the antibody response is restricted to epitopes that the second strain shares with the first strain to which the person was exposed. Other highly immunogenic epitopes on the second and subsequent viruses are ignored.
Neutropenia
a condition of abnormally low number of neutrophils in the blood, which can be due to various causes such as genetic deficiencies in neutrophil production, or autoimmunity directed against surface antigens on white blood cells.
neutropenia
a condition of abnormally low numbers of neutrophils in the blood, which can be due to various causes such as genetic deficiencies in neutrophil production, or autoimmunity directed against surface antigens on white blood cells. Macrophage activation by effector CD4 T cells also depends on the interaction of CD40 on the macrophage with CD40 ligand on the T cell. In patients with X-linked hyper-IgM syndrome this interaction foes not occur, which impairs the macrophage production of granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that stimulates the development of neutrophils in the bone marrow and their release into the circulation. People lacking CD40 ligand can be profoundly deficient in neutrophils, a state called neutropenia that often leads to sever sores and blisters in the mouth and throat.
calcineurin
a cytosolic serine/ threonine phosphatase that contributes to T-cell activation. The immunosuppressive drug cyclosporin A and tacrolimus act by inhibiting calcineurin.
Type IV hypersensitivity
a delayed-type tissue-damaging immune reaction caused by the secondary response of T cells specific for peptides derived from human proteins that have been modified by small chemically reactive molecules from the environment
Systemic lupus erythematosus (SLE)
a disease in which IgG is made against a wide range of cell-surface and intracellular self antigens that are common to many cell types. The deposits of antibody and antigen that result in inflammatory reactions are deposited in tissues and can cause glomerulonephritis in the kidneys, arthritis in the joints, and a butterfly-shaped skin rash on the face. A systemic autoimmune disease in which autoantibodies made against DNA, RNA, and nucleoprotein particles form immune complexes that damage small blood vessels.
What happens to naive B cells in the B cell area?
antigen specific B cells process the endocytosed antigen and present antigen-derived peptides on MHC class II molecules
thymus-independent antigen (TI antigens)
antigen that can elicit antibody production in the absence of T cells. There are two types of TI antigens: TI-1 antigens: have intrinsic B-cell activating activity TI-2 antigens: have multiple identical epitopes that cross-link B-cell receptors
What drives affinity maturation of the B-cell response in the germinal center
antigen-mediated selection of centrocytes. Centrocytes express protein Bcl-xL when the T cell receptor interacts with the B cell MHC and CD40 CD40 ligand.
cryptic epitopes
antigenic determinant on a molecule that is normally hidden from the immune system but becomes revealed under conditions of infection of inflammation
Evolution of new influenza virus variants by
antigenic drift
molecular mimicry
antigenic similarity between between a pathogen antigen and a cellular antigen, which results in the induction of antibodies of T cells that act against the pathogen but also cross-react with the self antigen
allergens
any antigen that elicits hypersensitivity or allergic reaction. Allergens are usually innocuous proteins that do not in themselves threaten the integrity of the body
Immunosuppressive drugs and its purpose in this chapter
any drug that prevents an immune response, usually by interfering with T-cell activation, proliferation, and differentiation Immunosuppressive drugs are used before, during, and after transplantation.
mucins
any family of very large glycoproteins that are secreted by mucosal epithelia and are the main components of the mucus that protects these surfaces and helps keep the bacteria away from them. -negatively charged mucus to attract effector cells and immunoglobulins -cysteine residues that allow cross-linking and disulfide bonds -free cysteine is used for covalent bonds with IgA
cyclophilins
any member of a family of cytoplasmic proteins that bind to the immunosuppressive drugs cyclosporin A and tacrolimus. The complex of drug and cyclophilin binds calcineurin, and this prevents T-cell activation.
variable surface glycoproteins (VSG)
any of a family of glycoproteins that form the surface coat of African trypanosomes. The trypanosome can repeatedly change its glycoprotein coat by expressing different glycoprotein genes by a process akin to gene conversion.
adhesin
any of various molecules on the surface of bacteria that bind to epithelial cells, enabling the bacteria to colonize epithelial surfaces ex) S. pyogenes
Pathogen specific memory B cells
are abundant and make better antibodies than do naive B cells
In secondary immune response, memory B cells
are activated whereas naive B cells are inhibited
CTLs
are capable of directly lysing grafted cells as well as of releasing various toxic and chemotactic factors
Secondary Immune Responses
are faster and more effective than primary immune responses
Peyers Patches
are fundamental sites for the initiation of the immune response and form dome-like follicles organized into T and B cell areas
Adult parasitess
are the largest microorganisms. Diphyllobothrium latum. Ascaris lumbricoides
The alloantibodies that cause chronic rejection of organ transplants
are the result of stimulation by the indirect pathway of allorecognition
Bacterial diseases
are the result of toxins secreted by bacteria
High-affinity IgG and IgA antibodies
are used to neutralize microbial toxins and animal venoms
Self-reactive (naive) T cells that do not escape negative selection
are usually not activated by binding cells expressing specific peptide MHC complexes because these don't express B7 (needed for co-stimulatory signal by binding CD28). Induces anergy
Transplantation antigens
name historically given to the MHC molecules because they are the main antigens that provoke the rejection of transplanted organs.
B7
needed for co-stimulatory signal by binding CD28
Radiotherapy
non-selective, strong side effect
chemotherapy
non-selective, strong side effect
centrocytes
nondividing B cell in the germinal center. Centrocytes have undergone isotype switching and somatic hypermutation. Programmed to die within a short time unless their surface immunoglobin is bound by antigen and their CD40 is bound by the DC40 ligand of a helper T cell.
Endotoxins
nonsecreted toxins- usually only released when the bacterium dies. Important in the pathogenesis of disease. ex)LPS
Secondary immunodeficiency diseases
not due to defective genes but to environmental factors such as immunosuppressive drugs
anamnestic response
old name for "memory response"
MHC Class I deficiency
rare genetically determined immunodeficiency in which MHC class I molecules are not present on cell surfaces, as a result of nonfunctional TAP proteins. The result is a deficiency of CD8 T cell function. Also known as bare lymphocyte syndrome type I. Less severe than MHC Class II deficiency.
Basophils
rare granulocytes that initiate TH2 responses and the production of IgE Basophils have the unique ability to secrete the TH2 cytokines IL-4 and IL-13 at the beginning of an immune response
erythema
rash
IgG and protection against blood borne pathogens
-dominant class of Ig in plasma - actively transported from the blood into the extracellular spaces within tissues for better delivery to tissues
diagnostic tests available for type ____ hypersensitivity reactions
1
Production mechanism for effector T cells
1. A naive T cell is activated by the pathogen 2. A clone of pathogen-specific effector and memory T cells is produced 3. Effector T cells outnumber memory T cells
gnotobiotic
"germ-free" environment
When are Helper T cells not needed to activate a B cell?
"thymus independent antigens" Highly polyvalent Cause extensive cross linking of B cell receptors Coats the entire surface of B cell This is enough to cause B cell activation
Myasthenia gravis
(Autoimmune neuromuscular disease) - Antibody mediated neurological disease - Antibodies to AChR that interferes with neuromuscular signaling and subsequent muscle contraction -Muscle weakness and fatigue - Muscle lymphocyte infiltration
Eosinophil-derived neurotoxin
(Eosinophil toxic protein) Degradation of RNA. Antiviral effects.
CXCL8
(chemokine of eosinophil) Promotes influx of leukocytes.
Herd Immunity
(community immunity) Vaccination of the a significant portion of the population protects the minority that have not been vaccinated. low probability of finding susceptible individuals and creating a chain of infection
Eosinophil peroxidase
(enzyme produced by eosinophil) Poisons parasites and mammalian cells by catalyzing halogenation. Triggers histamine release from mast cells.
Naive B cell
+ MHC-II + Co-stimulation
Memory B cell
+++ MHC-II +++ Co-stimulation
X-linked Agammaglobulinemia (x-LA)
- Absence of Igs and B cells - Arrest at Pre-B cell stage (H-chain rearranged not L chain)
Why conjugate vaccines?
- Activates complement - Vaccines of purified capsular polysaccharides are effective in adults but not infants
Celiac Disease
- Adaptive immune response to gluten proteins - The immune response damages the intestinal epithelium and reduces nutrient uptake in gut - diarrhea, stomach pain
What happens in the lymph nodes?
- Afferent lymph brings in the pathogen - Subcapsular Sinus Macrophages and Follicular Dendritic Cells capture the antigen - Naive B cells enter through high endothelial vein (HEV) and look for antigen to bind to on Follicular Dendritic Cells - Myeloid macrophages activate antigen specific T-cells including CD4 T cells
MHC class I
- All cells - A, B, C - One attachment binding protein to cell membrane
Rheumatoid arthritis
- Antibody and T cell mediated autoimmune disease - Chronically inflamed joints infiltrated by multiple immune cells - TH1 cells recognizing a specific antigen present within the joint triggers them to release inflammatory cytokines to initiate local inflammation - Plasma cells make a IgM, IgG and IgA that binds to the Fc region of patient's own IgG. These are deposited in the joints and activate complement cascade to increase inflammatory response
Sensitization
- Antigen exposure - IgE antibody production - IgE bound to FCεR on mast cells, basophils, eosinophils
Mechanism of CD4 T cells and B cell Interaction to Thymus Dependent Antigens
- Antigen is processed and presented on B cell surface with MHC class II molecules - T cell and B cell interact via CD40L and CD40 - T cell produce cytokine (IL-4) which activates B cell - Cognate interaction
Precursor T cell Differentiation defect
- Athymic - DiGeorge Syndrome - Lack of T helper (Th) cells, Cytotoxic T cells (CTL), and T regulatory (Treg) cells - B cells are present but T-dependent B cell response are defective - Anti-viral and anti-fungal immunity impaired - Treated with thymic transplant - Autosomal dominant trait
How does mucosal immunity occur?
- Bacterial access to the lamina propria and macrophages are activated - No inflammation, effector cells travel to mesenteric lymph node - Highly specialized b and t cells for the infected
Presentation of Antigen by FDC's
- Bind antigen in form of immune complexes - Bound immune complexes are not internalized and become clustered as Icosomes
Dimeric IgA mechanism
- Binding of IgA to receptor on basolateral face of epithelial - Receptor-mediated endocytosis of IgA - Transport of IgA to apical face of epithelial cell - Receptor is cleaved, IgA is bound to mucus through the secretory piece
Mechanism of transcytosis
- Binding to poly-Ig receptor on basolateral epithelium - Endocytotic vesicle transport to apical epithelium - Protease cleavage of receptor to secretory piece
Result of inhibition of humoral immunity
- Block effector functions - Blocks complement mediated effector pathways - Inhibits complement activation of infected call
Sjogren's syndrome
- Chronic autoimmune disorders of exocrine glands (salivary and lacrimal) - Unknown etiology - Genetic susceptibility: MHC, STAT4, IRF5, CXCR5 - CNS complications in 25% of patients - Motor sensory loss, chronic progressive myelitis, lower motor neuron disease, cognitive decline
Highly Active Anti-Retroviral Therapy (HAART)
- Combination therapy reduces HIV in the blood below detectable levels - Retards disease progression - Prevents new cells becoming infected - Does not eliminated virus from already infected cells
Isolated Lymphoid Follicles
- Composed of single follicle - Consist of mainly B cells - Found in large intestine
Autoimmune Disorders
- Conditions that occur when the immune system attacks the body's own tissues as if they were foreign - NOT CAUSED IgE
Mucosal Immune Response
- Continously in contact with microorganisms which are potential pathogens so it is proactive - constantly has effector cells - Does not use inflammation
Viral Examples of Inhibitory infllamatory response
- Cytomegalovirus - Vaccinia - Epstein-Barr virus - Vaccinia
HIV
- Disease is characterized by a massive reduction in the number of CD4 T cells - Patients suffer severe infections (opportunistic) that rarely cause trouble in healthy individuals - The long-term consequence of HIV is AIDS
Systemic Immune Response
- Does not anticipate infection - Widespread inflammation because cytokines are used to recruit effector cells to the tissue
How is IgG transported into extracellular spaces?
- Endothelial cells of blood vessels perform pinocytosis - proteins taken up are generally degraded in lysosomes but IgG isn't degraded because it is protected by a membrane receptor called FcRn or the Brambell receptor - FcRn binds to the Fc protion of IgG and diverts it away from the lysosomes and takes it to the basolateral surface of the cell to be released
Tenets of the hygiene hypothesis
- Excessive hygiene reduces childhood exposure to commensal and pathogenic microorganisms as well as to other humans and to animals - Vaccination redues the developing immune system's experience in facing natural infections, fighting them to a successful conclusion and terminating them. - Overreliance on antibiotics to terminate infections reduces the use of the immune system and its education in the discrimination of self from foreign pathogenic microorganisms. Antibiotics also select for resistant superbacteria, which also perturb the immune system.
What happens in the secondary follicle?
- FDCs make cytokines that force the B cells to divide rapidly and to become large, metabolically active centroblasts - helper T cells also divide and make cytokines and continue to interact with B cells via their CD40 ligand - Induces the B cell to start somatic hypermutation and isotype switching
Hyper-IgM syndrome
- Genetic immunodeficiency from no CD40L - B cells cannot switch isotypes - No response to TD antigens
Celiac Disease
- Gluten: proteins rich in glutamine and proline (gluteins and gliadins) - Transglutaminase convert Glutamine into Glutamate: these allow the peptides to bind binding pockets in DQ2 and DQ8 allotypes - CD4 autoreactive T cells to glutein and gliadisn derived peptides - Immune system reacts by destroying small intestine
Naive B cell Inducible property
- Growth - Somatic hypermutation - Isotype Switching
Airway remodeling genes
- Growth factors - Proteolytic enzymes
Subcapsular Sinus Macrophages
- Have CR1 and CR2 to taking up antigens tagged with complement (not phagocytic) - Aid Follicular Dendritic cells by presenting intact antigens
Chronic Granulomatous Disease
- Have recurrent bacterial infections - Commensals become pathogenic - X-linked or autosomal recessive - Treated with IFN-γ against infections
Viral Examples of blocking antigen processing and presentation
- Herpes simplex, cytomegalovirus - Herpes simplex
Medullary Sinus Macrophages
- Highly phagocytic - They filter lymph before it leave to ensure all remaining pathogens are removed
What type of treatments are available for type I hypersensitivity reactions?
- Hyposensitization - Therapeutic anti-IgE
Mechanism of destruction of parasites
- IgE coating of parasites - Binding of mast cells, basophils, and activated eosinophils (release of granules contents onto surface)
2 primary antigens are recognized
- IgG response against Rh antigens - IgM response against I antigens present in glycophorin
Hyposensitization
- Immunotherapy - Repeated low-dose exposure may induce an increase in regulatory T cells and their cytokines - May also induce competitive IgG subtypes
Result of blocking antigen processing and presentation
- Impairs recognition of antigen- presenting cells by CD4 T cells - Blocks peptide association with MHC class I
What do Mucins do?
- Impedes the movement of microorganisms - Heavily hydrated and prevents dehydration of the surface - Polyanionic so it binds to positively charged effectors of innate and adaptive immunity
Major Histocompatibility Complex
- Increased "relative risk" to particular autoimmune diseases is associated with certain individuals that express certain MHC alleles
Tolerance
- Increased FoxP3+ Tregs - Increased IFN-γ, IL-10, TNF-α
Clinical latency period of active infection and renewal of CD4 T cells
- Indicates virus is being cleared - All the newly expanded CD4 T cells will be target for infection
Features of effective vaccines
- Induces neutralizing antibody - Induces protective T cells - Practical considerations
Blocking of antigen processing and presentation
- Inhibition of MHC class I upregulation by IFN-γ - Inhibition of peptide transport by TAP
Result of Immunosuppression of host
- Inhibits TH1 lymphocytes. Reduces IFN-γ production.
Proteins involved in generation and regulation of immune responsiveness
- Innate immune receptors - Cytokines/chemokines and their receptors - MHC proteins
What causes dysregulated cell growth and proliferation?
- Intrinsic factors - Environmental factors - Microbial infections
Germinal Center
- Known as a seconday follicle formed by B lymphoblasts that leave the primary follicle while still attached to cognate pairs (composed of all antigen specific B cells) - Appears a week after infection starts and causes lymph node swelling
Symptoms of systemic anaphylaxis
- Labored respiration - Precipitous drop in blood pressure leading to anaphylactic shock - Contraction of smooth muscles leading to defecation, urination, and bronchiolar constriction (May lead to death by asphyxiation)
Digeorge Syndrome
- Lack thymus - Lack T cells - Normal B cell numbers - Lack effective antibody responses against most antigens - Affected individuals suffer from opportunistic infections and usually die from infection within the first 2 years of life - B cells are activated to make low-affinity IgM (which do not require T cell help) - B-cells do not undergo isotype switching and affinity maturation
Secondary Response
- Large number of pathogen-specific cells - Antibodies are already present - Lower threshold of activation - Enter infected tissue immediately - Close interaction between innate and adaptive immunity
Why are Follicular Dendritic Cells well suited for their function?
- Large surface area the B cells can react on - Not phagocytic so the antigen is not degraded - Use receptors to uptake an antigen
Live-attenuated Virus Vaccine
- Live virus has been mutated so that it has a reduced ability to grow in human cells and is no longer pathogenic to human - Most viral vaccines
Environment factor MS
- Low Vitamin D - EBV infection
Genetics factor MS
- MHC class II - IL-7R - CD58 - IRF8
Genetic Risk Factors of developing autoimmune disease
- MHC genotype - Genetic associations are modest and not mendelian. Gene linkage studies are not likely to directly point to the cause of MS - Molecular mimicry has little direct support despite decades of searching for the initiating environmental agent - In order to develop new effective therapies for CNS autoimmune conditions, we need to elucidate and understand the cause of the disease
M Cells
- Microfold Cells - Variety of cell-surface receptors and adhesion molecules that recognize microorganisms - Internalize organism through endocytic vesicles that cross the cell and go out the other side - The antigen can the encounter dendritic cells
Problems associated with immunization
- Mild toxicity most common - Risk of anaphylactic shock - Residual virulence from attenuated viruses - Allegations that certain vaccines cause autism, diabetes, and asthma ( research not proven yet)
Prevention of Graft Rejection
- Minimize antigenic (HLA) differences - Minimize rejection responses (i.e. immunosuppression)
IgA transfer
- Mother transfer - Until recently mothers used to breast feed longer than1 year - Modern society: hygiene, nutrition, vaccination - Compensatory mechanisms
What happens to centrocytes?
- Move closer to follicular dendritic cells - Undergo apoptosis if their Ig-receptor does not bind to an antigen and their CD40 receptor binds with a t-cell's
Acute responses
- Mucosal mast cell captures antigen - Inflammatory mediators contract smooth muscle, increase mucus secretion by airway epithelium, and increase blood vessel permeability
Plasma cell Intrinsic property
- NO surface Ig - No surface MHC class II - High-rate Ig Secretion
Plasma cell Inducible property
- No growth - No somatic hypermutation - No isotype switching
Memory cells
- Outnumber naive lymphocytes - Can be activated quickly - Present in lymphoid and non-lymphoid tissues - Antibodies are synthesized faster able to be directed to specific anatomical locations. Compete more efficiently for antigen and inactivate naive lymphocytes
TH2 Effector Functions
- Produce IL-13 that increases the production of epithelial cells in infected tissue (higher number of mucus secreting goblet cells) - IL-5 increase the number of eosinophils who have IgE granules that can bind to FCER1 (kill helminthes) - Produce B cells that are IgE - Produce IL-3 and IL-9 which recruits mast cells to release granules. Diarrhea is used to expel helminths
MHC Class II
- Professional APCs - DP, DQ, DR - Double attachment binding proteins to cell membrane
Myeloid Dendritic Cells
- Professional antigen presenting cells that come from hematopoietic cells - Branched - Immature can take antigens but not active T cells - Mature/Activated are in secondary lymphoid tissue and stimulate T cells via B7 receptor
Dimeric IgA and protection against blood borne pathogens
- Protects the surfaces of the mucosal epithelia -Made in patches of mucosal-associated lymphoid tissue -Transport across epithelia is mediated by the poly-Ig receptor -Once receptor is used and cleaved, IgA retains fragment of the receptor called the secretory piece (binds Ab to mucus so not washed away)
Vaccine Requirements
- Purified antigens are not usually strongly immunogenic - The state of inflammation and immunogenicity of the antigen can be enhanced by using adjuvant
Acute Allograft Rejection
- Recognition/sensitization - Proliferation and Differentation - Destruction = effector response mostly T cells (CD4 and CD8) (Development of memory T cells with amplification)
Antibody-dependent cell-mediated cytotoxicity (ADCC)
- Requires presence of preformed antibodies - Fc receptor that binds IgG1 and IgG3
Desensitization
- Result of treatment - Increased IgG4 - Decreased IgE - Decreased basophil reactivity - Decreased mast cell reactivity
Defect in Lymphoid Progenitor
- Results in Severe Combined Immunodeficiency (SCID) - Lack T, B, and/or NK cells - Thymus does not develop - Myeloid and erythroid cells are normal - Generally lethal - Susceptible to bacterial, viral, and fungal infections - In infants, passively transferred maternal Abs are present - Live attenuated vaccines (e.g. Sabin polio) can cause disease
Leukotrienes and prostaglandins
- Secondary mediators - Active at nanomole levels (1000x more effect than histamine at inducing brochoconstriction!). Also more potent stimulators of vascular permeability and mucous secretion. ***Considered to be a major cause of asthma symptoms.
Mucins
- Secreted by goblet cells - Polypeptide chains over 10,000 amino acids - Serine and threonine residues glycosylated with glycans - Disulfide bonds between different polypeptides to make polymers and intertwining networks
Result of Inhibitory inflammatory response
- Sensitizes infected cells to effects of some chemokines; advantage to virus unknown - Blocks effects of cytokines by inhibiting their interaction with host receptors - Blocks adhesion of lymphocytes to infected cells - Blocks inflammatory responses elicited by IL-1 or bacterial pathogens
Primary Response
- Small number of pathogen-specific cells - Delay before pathogen-specific antibodies - High threshold of activation - Delay before antibodies enter the tissue - innate and adaptive have a delay
Plasmacytoid dentritic cells (PDCs)
- Specialize Interferon Type 1 secreting cells, 1000x more than normal cells - Found in blood and lymphoid tissues (small numbers) but not in other tissues - Uses TLR7 and TLR9 to detect viral infections - Interferon produced prevent systemic infection from occuring
Follicular Dendritic Cells
- Stromal cells that develop from fibroblasts cell in bone marrow - Found in follicles of lymphoid tissues - Long branching for B cell activation - Select B cells for antibody production - Serve as an area to store non-degraded antigens to be presented to B cells for antibody production
Naive B cell Intrinsic property
- Surface Ig - Surface MHC class II - NO high-rate Ig secretion
MS - IL12
- TH1 cells - IFNy, STAT4, T-bet
MS- TGFB and IL6 (IL-1 and IL-23)
- TH17 cells - IL17, STAT3, RORyt
Why are viruses one of the most adept at immune evasion?
- Take over host cell machinery - Can pick up host genes, interfere with host cell mechanisms - Can hide (latency)
In order to prevent acute rejection
- The recipient can be tested for T cell reactivity against the donor cells (both CD4 and CD8 T lymphocytes) - Direct pathway declines as dendritic cells in graft are replaced by immature donor dendritic cells
HIV Drugs
- Treating HIV-infect pregnant women with zidovudine an inhibitor of the reverse transcriptase to prevent transmission to the baby - Combination therapy = highly active anti-retroviral therapy (HAART)
Cause of Autoimmune diseases
- UNKNOWN - some may be triggered by an infectious agent or environment exposure - genetic factors play a major role in susceptibility - Auto-reactive cells are present in healthy individuals
Attenuated live vaccines
- Use pathogens with reduced virulence - Can result in mild infections - Active microbes stimulate a strong immune response - Can provide contact immunity - Modified microbes may retain enough residual virulence to cause disease
Effect of experimental Anti-IgE
- Used in lab, compare binding sites. Anti-IgE cross-links IgE bound to FcεRI and activates mast-cell deregulation. Inflammatory response.
Other examples of Latency
- Varicella-zoster (from DRG to epithelial cells) - Epstein-Barr virus or acute infectious mononucleosis (B cells)
Inhibition of inflammatory response
- Virally encoded chemokine receptor homolog - Virally encoded soluble cytokine receptor, e.g., IL-1 receptor homolog, TNF receptor homolog, IFN-γ receptor homolog - Viral inhibition of adhesion molecule expression, e.g. LFA-3, ICAM-1 - Protection from NFkB activation by short sequences that mimic TLRs
How does HIV work?
- Virus enters host cells using viral spike envelope gp120 and gp41 which interacts with CD4 as a its receptor (co-receptor is needed) - Virus infects CD4+ cells which includes CD4+ T cells, macrophages and dendritic cells
What cells does chronic rejection involve?
- alloreactive effector T cells - antibody against MHC (HLA) molecules of donor - memory T lymphocytes
Acute rejection
- begins 7-10 days post-transplant T cell activation and effector function
Food allergies
- common type of allergy on the rise - Food allergens are often water-soluble glycoproteins stable to heat, acid, and proteases - can cause vomiting and diarrhea due to smooth muscle contraction and gut vasodilation
Skin Testing
- commonly used - cheap, safe - injects small quantities of known allergens under skin - swelling and redness (resulting from local mast cell degranulation) indicate allergic response
autoimmune disorders lead to
- destruction of healthy cells - changes in organ function
Characteristics of IgM
- first antibody produced - Secreted form is pentamer with 10 binding sites - Penetration of tissue fluids is limited - Phagocytic cells have no IgM Fc receptors - Fc region can bind complement
Viral examples of inhibition of humoral immunity
- herpes simplex cytomegalovirus -Herpes simplex - Vaccinia
Hyperacute rejection
- immediate - pre-existing antibodies
IgE
- less made of this than others - doesn't circulate as a soluble antibody that will bind antigen - cell surface receptor for antigen - Fc region is bound by FcERI, found on mast cells, basophils, and active eosinophils - cannot dissociate from FcERI receptor - When a pathogen binds to IgE on a mast cell and cross-links 2 or more FcERI, it releases mediators to force out parasites from the respiratory and GI tract - Each cell ends up coated with IgE where a single mast cell can carry many molecule-specific IgE
For localized hypersensitivity reactions
- patholog is limited to a specific tissue or organ - Includes allergic rhinitis (hay fever), asthma, atopic dermatitis (eczema), and food allergies - Symptoms result from release of mediators in immediate exposure area
Defective neutrophils
- patients have neutrophils that are defective in production of reactive oxygen species that is responsible for killing of phagocytosed microorganisms - Accumulation of granulocytes, Mo and T cells forming granulomas
B cells (centrocytes) which undergo somatic hypermutation
- produce receptor with range of affinities - highest affinity receptors are selected - must bind antigen or face apoptosis
Tumor-suppressor proteins
- repair damaged DNA - Control cell adhesion - Inhibit the cell cycle in the cell-signaling pathway
Necessary characteristics of cancer cells
- stimulate their own growth - ignore growth-inhibiting signals - avoid death by apoptosis - develop a blood supply: angiogenesis - leave their site of origin to invade other tissues - replicate constantly to expand their numbers - evade and outrun immune response
Autologous Bone Marrow transplants
- used in cancer patients where a matched donor is not available
Transmission of HIV
- via bodily fluids: blood, semen, vaginal fluid, or mother's milk - IV drug administration with contaminated needles - Transfusion of human blood or blood components from HIV-infected donors
Symptoms of Celiac Disease
- villous atrophy - anemia - diarrhea - malabsorption - increased susceptibility to intestinal cancer
Inhibition of humoral immunity
- virally encoded Fc receptor - virally encoded complement receptor - virally encoded complement control protein
Toxoid vaccines
-Chemically or thermally modified toxins used to stimulate immunity - Useful for some bacterial diseases - Stimulate antibody mediated immunity - Require multiple doses because they possess few antigenic determinants
Sabine Polio Vaccine Problems
-Induces polio in 3 people per million vaccinated (mutation of live strand)
Production mechanism for effector B cells
1. A naive B cell is activated by the pathogen and a Tfh cell 2. A clone of pathogen-specific B cells is produced 3. Effector B cells outnumber memory B cells
Centrocytes with identical B cell receptors
1. Antigen-selected centrocytes mature under the influence of an IL-10 secreting OR IL-4 secreting helper Tfh cell 2. Centrocytes differentiate into plasma cells OR memory B cells 3. Make antibodies that fight and terminate the current infection
Conjugate vaccines mechanism
1. B cell binds bacterial polysaccharide component of vaccine conjugate 2. Conjugate is internalized and degraded 3. Peptides from the toxoid are presented to the T cell, which activates the B cell 4. Activated B cell differentiates into a plasma cell producing anti-polysaccharide antibodies that bind to bacteria
Super antigens mechanism
1. Bacterial superantigen binds to MHC class II 2. Superantigen binds T-cell receptor and CD28 3. Leads to activation -Polyclonal activation of 2-25% of CD4+ T cells -Unusual presentation and recognition
3 proteins of B cell co-receptor
1. CD21 (complement receptor 2 (CR2)) = binds to complement on pathogen 2. CD19 3. CD81
Methods pathogens escape or subvert immune system
1. Evasion by genetic variation 2. Evasion by hiding 3. Use body's own immune mechanism for their survival
Healthy newborn babies (2)
1. First and subsequent pregnancies of RhD- mother carrying a RhD+ fetus and infused with anti-Rh IgG 2. Primary immune response to RhD is inhibited by the presence of RhD-specific IgG 3. Fetal erythrocytes are not destroyed 4. Healthy newborn babies
Chronic rejection mechanism
1. Immune complexes deposited in the blood vessel walls of the transplanted kidney recruit inflammatory cells 2. Increasing damage enables immune effectors to enter the tissue of the blood vessel wall and to inflict increasing damage
Food allergy mechanism
1. Ingestion of antigen activates mucosal mast cells 2. Activated mast cells release histamine, which acts on epithelium, blood vessels, and smooth muscle 3. Antigen diffuses into blood vessels and is widely disseminated causing urticaria. Smooth muscle contraction induces vomitting and diarrhea. Fluid outflow into gut lumen.
What mechanisms does herpeviruses and poxviruses use to subvert the immune response?
1. Inhibition of humoral immunity 2. Inhibition of inflammatory response 3. Blocking of antigen processing and presentation 4. Immunosuppression of host
When successful, what three purposes does the primary immune response serve?
1. It clears the infection 2. Temporarily strengthens defenses to prevent reinfection 3. Establishes a long-lasting immunological memory of the pathogen.
Direct pathway of allorecognition
1. Kidney graft with dendritic cells 2. Dendritic cells migrate to the spleen, where they activate effector T cells 3. Effector T cells migrate to graft via blood 4. Graft destroyed by effector T cells
Secondary response mechanism (2)
1. Memory B cell binds pathogen 2. Memory B cell is activated and becomes an antibody-producing plasma cell 3. Production of high-affinity IgG
Temporary symptoms of Ab-mediated autoimmune disease on newborn babies
1. Mother's with Grave's disease makes anti-TSHR antibodies 2. During pregnancy, antibodies cross the placenta into the fetus 3. Newborn infant also suffers from Grave's disease 4. Plasmapheresis removes maternal anti-TSHR antibodies and cures the infant's disease
Epithelium
1. Mucus formation (goblet cells) 2. Physical barrier (EC Tight junctions) 3. Defensins and cathelicidins (ECs and Paneth Cells) Bridge between innate and adaptive 4. Anti-microbial enzymes (paneth cells)
Innate immune responses to tumors
1. NK cells kill many types of tumor cells that have reduced class I, but express ligands for activating NK cells 2. Macrophages = Ab-med phagocytosis = cytokines (TNF-a), ROS and NO
Primary response mechanism
1. Naive B cell binds pathogen 2. Naive B cell is activated and becomes an antibody-producing plasma cell 3. Production of low-affinity IgM antibodies
Secondary response mechanism (1)
1. Naive B cell binds pathogen coated with specific antibody 2. A negative signal is given to the naive B cell to prevent its activation 3. No production of low-affinity IgM antibodies
Steps of Mechanism for B-cell mediated immunity
1. Naive B cells search for specific antigen displayed by FDC in the B-cell area; naive T cells search for specific antigen presented by dendritic cells in the T-cell area. 2. Antigen-activated T cells proliferate and differentiate; antigen-activated B cells move to the boundary region 3. Antigen-activated B cells present antigen to effector Tfh cells, forming cognate interactions and cognate pairs
Anemic newborn babies
1. Second and subsequent pregnancies of RhD- mother carrying a RhD+ fetus 2. Secondary immune response, abundant, high-affinity IgG transcytosed to fetal circulation 3. Massive destruction of fetal erythrocytes triggered by anti-RhD IgG 4. Anemic newborn babies
What two tactics improve success of transplantation
1. Selection of a transplant donor who has an HLA type as similar as possible to that of the recipient. This reduces the number of alloreactive T cells that become activated by the transplant 2. Administration of immunosuppresive drugs that interfere with the activation of alloreactive T cells.
What are the two semiautonomous parts of the human immune system
1. Systemic immune system: defends against pathogens penetrating the skin 2. mucosal immune system: defends against pathogens breaching mucosal surfaces
Two Steps for Activation
1. The activation, proliferation, and differentiation of naive, CD4 positive T cells into effector T cells of the Th2 type (T helper) 2. the activation of B cells specific for the same antigen by effector Th2 cells
What two distinct types of alloreaction can occur in clinical transplantation.
1. Transplant rejection 2. Graft- versus- host reaction (GVHR)
Transport of IgG from blood to mucosal secretions
1. Transport of IgG from the blood to the lamina propria and on to the gut lumen with recycling of FcRn
Sympathetic opthalmia
1. Trauma to one eye results in the release of sequestered intraocular protein antigens 2. Released intraocular antigens are carried to lymph nodes and activate Tcells 3. Effector T cells return via bloodstream and attack antigen in both eyes
Without Antibodies mechanisms against viruses
1. Twin sister without anti-influenza virus antibodies 2. Virus infects cells and replicates 3. Twin sister gets severely sick for 2 weeks
Autoimmune disease is the result of
1. a loss of tolerance to self antigen(s) followed by: 2. immunopathological damage or dysfunction
What 4 properties have aided in blood's extensive use as a transplanted tissue?
1. blood is readily donated by healthy individuals, at regular intervals, without compromising their health 2. The procedure of blood transfusion is simple and inexpensive compared with solid organ transplant 3. blood components are usually required to function for only a limited time, because within weeks a patient's bone marrow will make up the loss. 4. erythrocytes, the beneficial cells in a blood transfusion, do not express polymorphic major histocompatibility complex (MHC) class I or class II molecules, the major genetic barrier to the transplantation of other tissues and organs.
What are the advantages of memory cells during a secondary response.
1. pathogen-specific memory cells far outnumber their naive counterparts 2. memory cells, like effector cells, are more readily activated than naive lymphocytes. 3. memory B cells have undergone isotype switching, somatic hypermutation, and affinity maturation. So, upon activation by the pathogen, the memory B cells make better IgG, IgA, or IgE antibodies that are inherently better at binding the pathogen and delivering it for disposal than the antibodies made in the primary response, especially IgM.
Which immunosuppressive drugs are used before transplantation
1. rATG 2. Alemtuzumab or anti-CD52 3. Prednisone (--> prednisolone)
What are the three signals that are necessary to activate naive alloreative T cells and drive them to become effector T cells?
1. the T cell receptor on recognizing antigen presented by allogeneic HLA class I or II molecules. 2. co-stimulatory signal generated by CD28 when it engages a B7 co-stimulatory molecule. 3. generated by the T cell's IL-2 receptor when it binds to IL-2
Rotavirus
1973; major cause of severe childhood diarrhea - Neutralizing antibodies target viral coat proteins VP4 and VP7 -42 different variants and account for 90% of disease
What is a Type 2 response caused by?
A B cell response with Ab's reactive to altered/self epitopes
anemia
A deficiency in red blood cells.
Where do most lymphomas originate?
A germinal center cell
What is the universal blood recipient type?
AB RhD+
What are the antigens important in blood transfusion
ABO and Rhesus D blood group antigens of the erythrocyte surface
Before blood transfusion, donors and recipients are matches for what two factors?
ABO and the Rhesus D antigens
What must be controlled for during blood transfusions?
ABO blood type and Rhesus antigens
FcgammaRIIA
Activating receptor that promotes the internalization of bound antigen:antibody complexes and destruction on a wide variety of myeloid cells.
Somatic mutation stimulation requires
Activation - Induced Deaminase (AID)
What was the originally the only type of adjuvant approved for humans?
Alum (aluminum hydroxide gel)
What increases after each immunization?
Amount and affinity of antibodies
How do cytotoxic drugs act as immunosuppressives?
Analogues of nucleic acids to kill proliferating cells
What is a chronic rejection of solid organ transplant?
Antibodies that are formed AFTER transplant that are against HLA 1 T cells that react to fragments of transplant cells found on MHC II of dendritic cells Takes months to years
Autoimmune diseases arise when what is lost?
Autoimmune diseases arise when tolerance to self antigens is lost
What is the name of the Type II autoimmune disease that causes a loss of platelet function and abnormal bleeding?
Autoimmune thrombocytopenia purpura Platelet integrin gpIIb:IIIa is the target (same as Plavix)
Antigen-Dependent B cell differentiation
B cell activation and the germinal Center response
Additional signals are required and provided by
B cell co-receptors CD4 Th2 lymphocytes
Centrocytes
B cells that divide more slowly and give rise to fully mutated cell surface receptors
Centroblasts
B-cells that are more larger and more metabolically active than others
What are the benefits and challenges of using pigs for xenotransplantation
Benefits 1. Pigs have similar sized organs 2. Pigs are already farmed, slaughtered, and consumed by humans in large numbers Challenges 1. Humans have circulating antibodies that bind to pig endothelial cells and would cause hyperacute rejection. 2. Complement regulatory proteins on the surface of pig cells do not inhibit human complement
What does the B-cell co-receptor (CR2) recognize?
C3d (on pathogen surface) Breakdown product of C3b complement fragment (mediated by CR1 on B cell)
What is the target of gp-120 for binding?
CD4
What are prostaglandins?
Cause vasodialation, vascular permeability and neutrophil recruitment
Hepatitis C Virus (HCV)
Causes both acute and chronic infections. Some suffer mild symtpms of disease and make a primary immune response that clears the infection and bestows immunological memory of the virus. The majority of people infected with HCV make a suboptimal immune response that results in a chronic infection and persisting disease in which the infected liver goes through cycles of cellular destruction followed by tissue regeneration. This situation can lead to cancer, liver failure, and the need for a liver transplant. Resolution of acute HCV infection correlated with an ealry-acting and robust innare immune response, followed by a delayed but forceful adaptive immune response, involving strong effector CD4 and CD8 T-cell responses, and neutralizing antibodies that prevent the virus from infecting hepatocytes.
Which type of rejection takes the longest time to develop?
Chronic: Months to years Acute: Days Hyperacute: Immediate
Botulism
Clostridium Botulinum; Botulinum Toxin; Blocks release of acetylcholine leading to paralysis
Tetanus
Clostridium Tetani; Tetanus Toxin; blocks inhibitory neuron action leading to chronic muscle contraction
Microbial Evasion of Host Defenses
Co-evolution of our defenses against microbial infection and the microbial pathogens that cause those infections. As our defenses against infection improve, so do the mechanisms expressed by the pathogens for evading those defenses.
How does syphilis avoid destruction?
Coats itself with human proteins: Immune system sees pathogen as self
Synthesize essential metaboiltes
Cofactor for synthesis of clotting factors in the liver
Isotype switching in B cells determined by
Cognate interaction with CD4 T cells and T cell cytokines
Combinations of HLA Class II allotypes confer susceptibility and resistance to what?
Combinations of HLA Class II allotypes confer susceptibility and resistance to type 1 diabetes. Polymorphisms of HLA-DQ and HLA-DR are associated with susceptibility and resistance to type 1 diabetes. Common Causcasian HLA haplotypes that encode either the DQ2 or the DQ8 allotypes confer susceptibility to type 1 diabetes.
Subunit viral vaccines?
Consists of only the antigenic components of virus
Signal 2
Costimulatory molecules CD40 on B cell CD40L induced on activated Th2 T cells
Why does an cowpox inoculation provide protective immunity from the smallpox virus?
Cowpox and smallpox have similar surface antigens Mount antibody defense against cowpox. Contract small pox and these antibodies can fight it too
Hypersensitivity IV
DTH is Tcell/APC mediated
Example of Combination Vaccines
DTP-diphtheria and tetanus toxins combined w/ killed Bordetellapertussis
hypothyroid
Describes an abnormally low production of thyroid hormone by the thyroid gland.
Type II hypersensitivity
Drug allergies
Example of Immunosuppression of host
Epstein-barr virus
Hypersensitivity
Exaggerated immune responses to harmless environment antigens that can lead to significant pathology
T/F: Plasma cells have MHC and surface Ig.
False Only secretes Ig, no surface Does not present MHC on surface anymore
Chemical innate defenses of skin
Fatty Acids Antibacterial peptides
What happens when CD4 T cell count drops to <500 per microliter?
Greater susceptibility to opportunistic infections Symptomatic phase
How are Live-attenuated Virus Vaccines made?
Growing the virus in cell of a non-human species
HLA-DR2
HLA-DR2 patients make antibodies against double-stranded DNA
HLA-DR3
HLA-DR3 patients make antibodies against proteins of a small cytoplasmic ribonucleoprotein complex.
IL-5 augments production of
IgA
IgA protease in Neisseria meningitis
IgA prominently produced at mucosal boundaries. IgA protease interferes with mucosal immunity.
What is the source of type I hypersensitivity reactions?
IgE
Antibodies against helminth worms
IgE, IgG1, IgG4
Immunosuppression
Immune evasion mechanism; other mechanisms beside HIV
How to prevent chronic rejection of solid organ transplant?
Immunosuppressives before and after transplant HLA matching
vif
Influences particle infectivity
The receptors of innate immunity are blank and the receptors of adaptive immunity are blank?
Innate=constant Adaptive= variable
Cognate Interaction
Interaction of B and T cells specific for same antigen
Function
Many allergens are proteases
Half life of Ab is on the order of blank?
Months
What other immune cell also mediate graft-versus-leukemia effects
Natural killer cells
How does mucin give immunity?
Net like: Slows transit of pathogens and provides reservoir for Ab and antimicrobial peptides
Type III Immune reactant
Non-specific IgG antibody
Fungal infections
Pneumocystis carinii Cryptococcus neofrormans Candida species Histoplasma capsulatum Coccidiodes immitis
Killed or Inactivated Vaccines
Preparations of disease-causing virus for which the ability to cause disease has been destroyed or weakened (heat or radiation)
What are M cells?
Specialized to transport microorganism to gut-associated lymphoid tissue. They constantly transport microbes and antigens from the gut lumen to gut-associated lymphoid tissue
Immunological synapse more on this??
T cell interaction with B cell Tells B cell to become activated
Isotype Switching in B cells
Takes place primarily in germinal centers
Where is IgM found in the body?
The Heart
What happens to naive T-cells in the T-cell area?
The become clones of effector TFH cells
What are important considerations for vaccine design?
The state and maturity of the immune system
What is the lamina propria?
Tissue layer immediately basal to the enterocytes
Tissue mast cells orchestrate IgE-mediated reactions through the release of what?
Tissue mast cells orchestrate IgE-mediated reactions through the release of inflammatory mediators
haploidentical transplant
Tissue or organ transplant from a donor who shares one HLA haplotype with the patient but differs in the second.
What is an inactivated toxin called?
Toxoid
What is graft-versus-host disease?
Transplanted tissue attacks recipient
Incompatibility of blood group antigens causes what type of hypersensitivity reaction?
Type II
env
Viral spike envelope: gp120 and gp41 glycoproteins, CD4 receptor
Transplant rejection
When a kidney is transplanted, the recipient's T cells attack the transplant
Graft-versus-host disease
When hematopoietic cells are transplanted, the T cells in the transplant attack the recipient's tissues
What is the correlation between thymus involution and rheumatoid arthritis
With age there is an inverse correlation between the decreasing capacity of the thymus to make new T cells and the increasing incidence of rheumatoid arthritis.
Vaccination
a procedure in which the adaptive immune response is manipulated in an antigen-specific manner to stimulate protective immunity against a pathogen without causing the disease itself.
AIDS
acquired immunodeficiency syndrome
Prednisolone
activated form of prednisone. Immunosuppresive drug given before a transplant. Alters lymphocyte homing, so that lymphocytes are barred from entering secondary lymphoid tissues and sites of inflammation. Instead they congregate in bone marrow. In this way, naive lymphocyte cannot be activated by alloantigens, and effector T cells cannot enter and attack the graft.
Somatic hypermutation results in
affinity maturation of the antibody response
What type of cells are intraepithelial lymphocytes?
alpha beta and gamma delta CD8 T cells Present in the absence of infection Already activated=effector
Cyclosporin A
an immunosuppressive drug that specifically prevents T-cell activation and effector function. Also called cyclosporine. Interferes with calcineurin activity. In the presence of cyclosporin, IL-2 is never make, and T-cell activation is shut down at an early stage.
Antivenom
an infusion of antibodies specific for the venom (produced by immunizing large domestic animals with venom)
Hypersensitivity I-II and III
antibody mediated
serotype
antigenically different strain of a bacterium or other pathogen that can be distinguished by immunological means, for example by antibody-based detection tests. Also used to describe different types of human alloantigen such as HLA and blood group antigens.
For blood infections
antigens enter spleen
minor histocompatibility antigens
any antigen derived from a polymorphic cellular protein that can lead to the rejection of a tissue or organ transplant in a genetically non-identical tissue
immunodeficiency diseases
any inherited or acquired disorder in which some part or parts of the immune system are either absent or defective, resulting in failure to mount an effective immune response to pathogens
sympathetic opthalmia
autoimmune disease response that sometimes follows damage to an eye and affects both the damaged eye and healthy eye
Type I hypersensitivities are characterized by
both early and late responses.
Goblet cells
cells that are interspersed between the enterocytes that secrete mucus
Major histocompatibility complex
closely linked family of genes which encode for cell surface histocompatibility molecules that present antigen to T cells
Coating a bacterium with IgE does what?
coating a bacterium by IgE activates mast cells to induce violent reactions that expel parasites from the body.
Rheumatoid arthritis
common inflammatory disease of the joints that is due to an autoimmune disease
lamina propria
connective tissue underlying the epithelium and lymphoid tissues in the gut.
methotrexate
cytotoxic drug used to inhibit graft-versus-host reactions in hematopoietic cell transplant recipients.
Allogeneic
differing genetic constitution between members of the same species (as between different inbred mouse strains or humans that are not identical twins)
secretory IgA or SIgA
dimeric IgA molecule that is produced by plasma cells in mucosal tissues and secreted across the mucosal surface.
Examples of vaccines for toxin producing bacteria
diphtheria & tetanus vaccines
autoimmune disease
disease in which the pathology is caused by an adaptive immune response to normal components of healthy tissue.
primary immunodeficiency diseases
disease in which there is a failure of immunological function as a result of a defect in one or more genes encoding components of the immune system.
secondary immunodeficiency diseases
disease in which there is a failure of immunological function as a result of an infection of the use of immunosuppresive drugs, rather than as a result of defects in genes encoding components of the immune system
Recessive and dominant mutation in the IFN-γ receptor cause
diseases of differing severity
The gastrointestinal tract is invested with
distinctive secondary lymphoid tissues
In order to avoid hyperacute rejection,
donors must be typed for anitbodies against both blood group antigens as well as HLA histocompatibility molecules (MHC)
latency
dormant state of some viruses that does not cause disease.
Antigen-mediated selection of centrocytes
drives affinity maturation of the B-cell response in the germinal center
Negative selection of self-reactive T cells occurs
during development in the thymus
Variolation
early form of immunization which involved the presentation of material collected from smallpox lesions to uninfected individuals with the goal of inducing immunity to future infection with smallpox. (quizlet) -Intranasal or intradermal admin
Chronic skin allergy leads to
eczema
Type IV result
effector T cells/macrophages destroy antigen-coated host cells
Intestinal macrophages
eliminate pathogens without creating state of inflammation
Freund's Complete Adjuvant
emulsion of killed mycobacteria and mineral oil (can't use in humans but great for rabbits making lab antibodies)
Allogeneic differences in MHC class I molecules
enable cytotoxic T cells to eliminate tumor cells
Reverse transcriptase
enzyme that transcribes RNA to DNA
Interact with epithelium to trigger development of secondary lymphoid tissue
establishment of the gut associated lymphoid tissue
Shigella
exploit M cells to infect the colonic mucosa, causing widespread tissue damage.
Central Memory T cells (Tcm)
express L-selectin and CCR7 which allows them to enter secondary lymphoid tissues (to generate more effector T cells)
Effector Memory T cells (Tem)
express other chemokine receptors that gain them access to non-lymphoid tissues
The immune system can be activated by
external stimuli to effectively kill tumor cells and eradicate tumors
B lymphocytes recognize
extracellular pathogens and toxins transported to secondary lymphoid tissues
Immune responses frequently
fail to prevent the growth of tumors
villi
finger-like projection in the wall of the small intestine
Cells make
glucagon insulin somatostatin
What do mast cell granules contain
histamine, heparin, tumor necrosis factor-alpha, chondroitin sulfate, neutral protease, and other degradative enzymes and inflammatory mediators.
Variolation
histological procedure for immunization against smallpox in which a small amount of live smallpox virus was introduced through scarification of the skin
Hypersentivity I
immediate hypersensitivity
toxoid
inactivated proteins of a toxin
Infectious agents
infections trigger an autoimmune response
streptococcus pyogenes
inhabits the pharynx and is a common cause of sore throat. The bacterial adhesin is a cell-surface rotein called protein F that binds to fibronectin, a large glycoprotein component of the extracellular matrix. Secreted IgA antibodies specific for proetin F limit the growth of redient S. pyogenes and prevent them from causing disease.
immunophilins
intracellular protein with peptidyl-prlyl cis-trans isomerase activity that binds the immunosuppresive drugs cyclosproin A, tacrolimus, and sirolimus
B cell co-receptor
is complex of 3 proteins
Transcytosis of dimeric IgA across epithelia
is mediated by the poly-Ig receptor (pIgR)
Dimeric IgA
is the dominant Ig in tears, saliva, milk, and intestinal fluid
What does expression of individual VSG gene depend on?
its location in the "expression site" from which it can be transcribed.
infants with DiGeorge syndrome
lack a thymus and have almost no T cells in their circulation. Have normal number of B cells, but cannot make an effective antibody response against most antigens. Thus, they suffer from opportunistic infections and usually die from infection within the first two years of life unless given a thymus transplant. Some of their B cells are activated to produce low-affinity IgM antibodies. These are predominantly of the minority CD5-expressing B-1 populationof B cells, which do not require T-cell help and do not undergo isotype switching and affinity maturation. This feature argues that the majority population of B cells is non-functional in these patients and this inherently dependent on T-cell help.
iC3b and C3d
ligands for the B-cell co-receptor. Created by the complement receptor CR1 on the surface of B cells. CR1 cleaves C3b, creating iC3b and C3d. C3d then binds CR2 on the surface of B cells.
Prevent pathogens from benefiting from the resources of the human gut
limitation of pathogen species to small numbers that are not harmful
Chronic rejection
months to years post transplant humoral and cell-mediated
Mechanical innate defenses of lungs
movement of mucus by cilia
Fc receptors can activate what?
natural killer cells to destroy antibody-coated human cells (Still Innate Immunity)
Additional signals required depending on
nature of antigen and provided by CD4 helper T cells
Cross-linking of IgE on mast cell surfaces leads to
rapid release of mast-cell granules containing inflammatory mediators
isolated lymphoid follicles
secondary lymphoid tissue in the gut wall that resemble a lymphoid follicle and is composed mainly of B cells. In the large intestine as well as the small intestine.
Exotoxins
secreted toxins.
Virus attenuation by
selecting for growth in nonhuman cells
immunoreceptor tyrosine-based inhibitory motifs (ITIMs)
sequence in cytoplasmic domains of membrane receptors that recruit phosphatases that remove the phosphate groups added by tyrosine kinases.
synergy
simultaneous ligation of the B-cell receptor and co-receptor. This synergy greatly increases B-cell receptor sensitivity to antigen and increases overall signal.
Most allergens are
small, soluble proteins
IgG is transported via
specific Fc receptors
Some inherited immunodeficiences lead to
specific disease susceptibilities
Protective Immunity
specific immunological resistance to a pathogen that is present during the months after a vaccination or recovery from an infection; due to specific antibodies and effector T cells of primary response
Cross-match test
test for pre-existing antibodies to HLA 1. HLA + Luminex bead 2. Recipient serum with anti-HLA antibody mixed together with HLA LUminex bead 3.PE-labeled secondary anitbody (Anti-IgG)
Tumors express Ags
that are recognized as foreign by the host immune system
FcalphaRI
the activating receptor on myeloid cells for IgA antibodies
mycophenolic acid
the active ingredient in which autoantibodies against the acetylcholine receptor on skeletal muscle cells cause a block of signal transmission from nerve to muscle at neuromuscular junctions, leading to progressive muscle weakness and eventually to death.
secondary immune response
the adaptive immune response provoked by a second exposure to an antigen. It differs from the primary response by starting sooner and building more quickly, and is due to the presence of long-lived memory B cells and T cells specific for the antigen.
Peripheral blood mononuclear cells (PBMC)
the cellular fraction of a blood sample that contains mainly lymphocytes and monocytes: that is, cells with a round unlobed nucleus. They are extracted from whole blood by density gradient fractionation in the presence of the hydrophilic polysaccharide Ficoll-Paque.
What is the first solid organ transplanted and the one transplanted most frequently
the cornea of the eye More than 30,000 corneal transplants from cadaveric donors are performed each year in the US Very successful because their are no HLA matching needed or immunosuppressive therapy
Proto-oncogenes
the corresponding normal cellular genes that are responsible for normal cell growth and division
Intestinal epithelial cells contribute to
the defense of mucosal tissue
Vaccination is
the induction of protective immunity against disease by using a form of the causative agent or its antigenic components
antibody-dependent cell-mediated cytotoxicity (ADCC)
the killing of antibody-coated target cells by NK cells having the receptor FcgammaRIII (CD16), which recognizes the Fc region of the bound antibody
neutralization
the mechanism by which antibodies binding to sites on pathogens prevent growth of the pathogen and or its entry into cells. The toxicity of bacterial toxins can similarly be neutralized by bound antibody
self-tolerance
the normal situation whereby a person's immune system does not respond to constituents of his or her body. The circulation lymphocyte population in an individual is thus said to be self-tolerant
Rhesus D antigen (RhD)
the one rhesus antigen that must be matched for successful blood transfusion. RhD mismatch between fetus and mother is the cause of hemolytic anemia of the newborn.
light zone
the part of the germinal center in secondary lymphoid tissue that contains non-dividing centrocytes interacting with follicular dendritic cells.
Graft versus host reaction
the response of mature donor-derived T cells in transplanted bone marrow or other type of hematopoietic cell transplant to the alloantigens of the recipient's tissues.
xenograft
the tissue that is transplanted in which the donor and recipient are of different species
transcytosis
the transport of molecules from one side of an epithelium cell to the other. This involves endocytosis into vesicles within the epithelial cells at one face of the epithelium and release of the vesicles at the other (M cells use this to transport antigens)
anti-CD 20 monoclonal antibody rituximab
theraputic monoclobal antibody that binds to some tumor cells by the Fab arms. FcgammaRIII on NK cells bind to anti-CD 20 monoclonal antibody Fc region. NK cells can then kill the tumor cell.
Autograft
tissue grafted back onto the original donor
Allograft
tissue grafted between allogeneic individuals
Isograft
tissue grafted between syngeneic individuals (e.g., between identical twins or between mice of the same strain)
Xenograft
tissue grafted between xenogeneic individuals (e.g., ape to man)
Principle role of antibodies
to bind to the pathogen using the variable regions and to complement components and receptors on effector cells using their constant region (C regions).
autologous hematopoietic cell transplantation
transplantation of bone marrow or other sources of hematopoietic stem cells in which the donor and recipient are the same person. In such cases, bone marrow is removed from the patient, treated in some way to remove diseased or harmful cells, and then re-infused.
IgE in mucosal immunity
transported across epithelial cells by the FcEIII receptor and is present in small concentrations in saliva, the gut, and the respiratory tract.
Therapeutic anti-Ig E Abs
treatment of allergies successfully
Family studies reveal that HLA type correlated with susceptibility to what?
type 1 diabetes
hematopoietic stem-cell transplantation
type of transplantation in which the role of the graft is to replace the hematopoietic system. Sources of hematopoietic stem cells include bone marrow, peripheral blood, and umbilical cord blood.
Clustering and aggregation of receptors activates
tyrosine kinases
Retroviruses
use reverse transcriptase to copy their RNA genome into DNA
Chronic rejection can sometimes involve
viral infections (immunosuppression) or return of disease
microbial infections
viruses (viral oncogenes)
Islet cell type (express on surface different cell-specific peptides)
α β γ
What parts of the body do mast cells guard?
Mucosal and Epithelial Tissues
What happens when an antigen binds to the Fab regions of an IgE bound to a mast cell?
Multivalent binding causes degranulation of mast cell Inflammatory compounds IMMEDIATE
What allows influenza virus to escape from immunity?
Mutation and recombination
What allows the influenza virus to escape immunity?
Mutation and recombination allow influenza virus to escape from immunity. Influenza evolves new varients through antigenic drift or antigenic shift
Any Vaccine available against HIV infection?
NO
Does the continuing production of memory cells depend on the persistence of antigens?
NO. immunological memory is sustained by populations of long-lives lymphocytes tht were induced on exposure to antigen but then persist in its absence. Although memory population survives, individual memory cells have a limited lifespan. Cells are constantly dying but long-lived plasma cells are secreting new memory cells. This antigen-independent activation and proliferation is driven by signals delivered by cytokines via their receptors on memory cells.
Process of T cells through body
Naive T cells go from thymus to bloodstream Enter lymph nodes from bloodstream by HEV Exit lymph nodes by efferent, go into new by afferent Eventually to thoracic duct, Dumps back into bloodstream
Adjuvant
Natural ligand of toll-like receptors. Component that serves to trigger the innate immune response and establish a state of inflammation at the site of vaccination. This inflammation is necessary for initiating an adaptive immune response against the antigens in the vaccine. Adjuvants are necessary for subunit and conjugate vaccines consisting of one or a few purifies proteins because they do not activate the innate immune system on their own.
How are naïve B cells prevented from creating new antibodies in a secondary response?
Naïve B cell binds pathogen coated with specific antibody (IgG antibody) and sends a negative signal. Memory B cells are instead activated by a specific antibody attached to the pathogen
How are memory T and B cells made?
Naïve T cell is activated by the pathogen, pathogen specific T cells are cloned to make memory T cells. Naïve B cells are activated by TFH t-cells and a clone of pathogen-specific B cells are produced
Contains peptides that bind host MHC class II
Necessary for T-cell priming
What is the net charge of carb chains on mucin?
Negative
Explain fHbp
Neisseria uses fHbp to prevent complement fixation on its surface. fHbp is a surface lipoprotein that binds factor H and uses it to inactivate any C3b deposited on the bacterial surface. Inactivation involves factor I, which cleaves C3b to give iC3b. This prevents formation of the membrane -attack complex and the lysis of Neisseria. However, immunization with the Bexero vaccine, which contains fHbp, counters this evasion. Vaccination generates high-affinity IgG antibodies against fHbp that cover up its interference with complement activation by the alternative pathway. Coating the bacteria with anti-fHbp IgG also activated the classical pathway.
Do all antibodies have a direct inhibitory effect on a pathogen's capacity to live?
No. Only a fraction of antibodies have a direct inhibitory effect on a pathogen's capacity to live and replicate in the human body. The more common outcome is that antibodies bound to the pathogen recruit other molecules and cells of the immune system, which then kill the pathogen or eject it from the body.
Have we made vaccines against pathogens that establish chronic infections?
No. Vaccines have not yet been made against pathogens that establish chronic infections. The diseases for which we have effective vaccines are ones in which the infection is acute and resolves in a matter of weeks, wither elimination of the pathogen or by the death of the host. By contrast, devising vaccines that work against chronic infectious diseases has proved difficult. After infection, pathogens such as the malarial parasite Plasmodium falciparum, and the HIV interfere with the human immune system and make it work in their favor.
Why does trauma sometimes cause autoreactivity?
Not all compartments of the body get exposed to T cells T cells are not tolerant of all tissues Trauma exposes T cells to these tissues See as foreign and develop Ab against
What is the universal blood donor type?
O RhD-
IgA1
O-linked carbohydrate hinge disulfide bonds tailpiece J chain
HIV can never be cured
Once it gains a foothold, it can never be fully eradicated from the body. AIDS virus thwarts even the best drugs by hiding even in the gut.
What is the main effect of complement fixation on leukocytes and why?
Opsonization because nucleated leukocytes are less susceptible to complement-mediated lysis than erythrocytes.
What are the two major functions of Antibodies?
Opsonize: Tag antigen for destruction (Phagocytosis or classical complement) Neutralize: Bind to antigen and interfere with its function (Toxins, proteins needed for growth/infection)
Getting native Ag to lymph node
Opsonized by C3b which is broken down to C3d C3d can be recognized by FDC in primary follicle that hold it there
Peyer's patch
Organized gut-associated lymphoid tissue present in the wall of the small intestine, especially the ileum. Forms a dome-like aggregate of lymphocytes that bulge into the intestinal lumen. The patches vary in size and contain between 5 and 200 B-cell follicles with germinal centers, interspersed with T-cell areas that also include dendritic cells. In the small intestine but not the large intestine.
What is an example of something that causes a Type 2 response?
PNC covalently bound to a self protein
Which one is bigger pandemic or epidemic?
Pandemic=Worldwide Epidemic= Large population
What is an example of a Type 4 response?
Poison-ivy Inflammation from CD8 T cells responding to chemically modified self-peptide on MHC 1
What type of vaccine is given orally and why?
Polio Natural route of infection is ingestion Must induce immunity at the gut
What is the net charge of antimicrobial peptides?
Positive Links with mucin
Function of Follicular Dendritic Cells
Present antigens to naive B cells so they can interact with it
Immunoediting
Process by which a person is protected from cancer growth Elimination Equilibrium Escape
Passive transfer of immunity
Process of transferring preformed immunity from an immune subject to a nonimmune subject via transfer of whole serum, purified antibody, or intact effector or memory lymphocytes (adoptive transfer)
IL-3, IL-5, GM-CSF
Promote eosinophil production and activation
vpu
Promotes CD4 degradation and release of virus from cell
TNF-α (some stored preformed in granules)
Promotes inflammation, stimulates cytokine production by many cell types, activates endothelium.
What enzyme must be present and active in order for translated HIV proteins to become active?
Protease Post-translational cleavage
Protection against smallpox was achieved how?
Protection against smallpox is achieved by immunization with the less dangerous cowpox virus.
IgA (dimeric)
Protection mucous membranes and secretions
IgM
Protection of blood
IgE
Protection of connective tissues. IgE provides a mechanism for the rapid ejection of pathogens from the body
IgA
Protects GI tract of newborn - Transfer by breast milk - Dimeric form (IgA2 subclass)
IgG
Protects fetus and newborn - Maternal circulation to fetal circulation - Transfer across placenta mediated by FcRB - IgG levels similar in mothers and newborns
Molecular type
Proteins, because only they induce T-cell responses
Vaccines for toxins producing bacteria
Purify the toxin and treat it with formalin to destroy its toxic activity to make toxoid
environmental factors
Radiation, carginogens
Function of IgE
Rapid ejection of pathogen from body Sneezing, coughing, vomiting and diarrhea Allergies Fc binds to mast cells, basophils and eosinophils
Passive transfer of immunity
Receiving antibodies not made by self Placenta, breast milk
What is FC-epsilon-R1?
Receptor on mast cells, basophils and activated eosinophils that IgE binds to.
FcEpsilonRI
Receptor present on the surface of mast cells, basophils, and activated eosinophils that binds free IgE with very high affinity. When antigen binds to IgE and cross-links FcEpsilonRI, it causes cellular activation and degranulation.
Isolated virulence gene
Receptor-binding protein Virulence Core proteins
IFN-gamma receptor deficiency, recessive allele
Recessive mutation: Prevent any expression of IFNgammaR1 at the cell surface. The macrophage and monocyte of patients with two recessive alleles carry only IFNgammaR2 at their surfaces and are unresponsive to IFNgamma. For this group disease is usually more severe and appears at an earlier age. Heterozygotes are healthy because the protein made from the defective allele does not interfere with that made from the normal allele, which assembles with IFNgammaR2 and moves to the cell surface as functional IFN-gamma receptor.
Immunological effects of abnormal developing immune system
Reduction in secretory IgA and serum immunoglobulin Reduction in systemic T-cell numbers in their activation Reduced cytotoxicity of CD8 T cells Impaired lymphocyte homing to inflammatory sites Reduced numbers of lymphocytes in mucosal tissues Impaired responses of Th17 CD4 T cells Reduced ability of neutrophils to kill bacteria
What is the problem with over-activation of eosinophils?
Release toxins damaging to host and pathogen Can cause heat failure, neuropathy, and airway damage
What is an anti-TNF alpha drug?
Remicade (infliximab), Humira (adalumimab) and Enbrel (etanercept)
Where are M cells found?
Same layer as enterocytes Apical surfaces faces gut lumen Basal surface faces GALT directly
Streptococcal exotoxin
Scarlet fever; shock
Which response (primary or secondary) has a lower threshold of activation?
Secondary
Peyer's Patches
Secondary lymphoid organs that underlie the gut epithelium; doesn't have afferent lymphatics
Basophils
Secrete compounds causing symptoms similar to those from mast cells Myeloid lineage
Esoinophils
Secrete compounds causing symptoms similar to those from mast cells myeloid lineage Can directly attack parasites by releasing toxic compounds (important cuz parasites and big are cannot be engulfed)
TH1 Effector Functions
Secretes Interferon-gamma and activate macrophages (disrupts parasite infected tissue with inflammatory response); Also activate B cells to produce IgG (not effective against helminthes)
Perpetual sampling of the gut lumen's content leads to adaptive immune responses in the GALT
Secretion of dimeric A
What antibodies protect mucosal surfaces from microbial invasion?
Secretory IgM and IgA
Effects of corticosteroids on the immune system
See chart
Immunological effects of cyclosporin and tacrolimus
See chart
The differences between central and effector memory T cells
See chart
Differences between the primary and secondary immune responses
See chart.
What is the consequence of pathologies that cause massive production and release of numerous cytokines?
Shock
How does the systemic immune system respond to infection in non-mucosal tissue?
Short violent episodes of localized and intense inflammation. Activation of tissue macrophage which secrete inflammatory cytokines that create a state of inflammation in the infected tissue. Neutrophils and other effector cells of the innate immunity are recruited from the blood to the infected tissue, and dendritic cells migrate out of the infected tissue to the draining secondary lymphoid tissue to initiate adaptive immunity. This brings in T cells and pathogen specific antibodies that travel to the infected tissue, where they work in conjugation with the innate immune system to eliminate the pathogen and terminate the infection. In the recovery phase, inflammation and immunity are suppressed, the damaged tissue is repaired, and both pathogens and effector cells of the immune system become excluded from the now healthy tissue.
NFAT
Signals from the T-cell receptor activate AP-1 and increase intracellular Ca2+ concentration. Raised intracellular Ca2+ activates calcineuin, a phosphatase that activate NFAT. Activated NFAT migrates to the nucleus and binds to Ap-1 to form an active transcription factor. Activation of the IL-2 and other genes leads to clonal explansion of the T cell. Cyclosporin and tacrolimus inhibit T cell activation by interfering with the serine/threonine phosphatase calcineurin, therefore blocking the pathway.
Deficiency of complement protein Factor 1
Similar effects to deficiency of C3
What is the only infectious disease of humans that has been eradicated worldwide by vaccination?
Smallpox.
What is a Type 3 response caused by?
Soluble immune complexes formed by Ag and IgG. Bulky: deposited in blood vessels and alveoli Fc regions can fix complement->inflammation
Induces neutralizing antibody
Some pathogens (such as poliovirus) infect cells that cannot be replaced (eg neurons). Neutralizing antibody is essential to prevent infection of such cells
Induces protective T cells
Some pathogens, particularly intracellular, are more effectively dealt with by cell-mediated responses
Staphylococcal enterotoxin
Staph food poisoning
Path of B cell interaction
Starts in T cell area Cognate pairs move to medulla then to B cell area of cortex ->secondary follicle germinal center
What happens if a B cell encounters its antigen in the T cell zone?
Stay there Process and load antigen Present to T cells B and T cells interact Tfh effector secretes cytokines and CD40 ligand Initiates B cell activation and differentiation
Effects of corticosteroids
Steroid hormones diffuse across the plasma membrane to bind specific receptors in the cytoplasm. In the absence of steroid, the receptors associate with another cytoplasmic polypeptide called Hsp90 (heat-shock protein of 90 kDa molecular weight). Binding steroid induces conformational change in the receptor, causing dissociation of Hsp90. This allows the receptor:steroid complex to turn on the transcription of selected genes. Corticosteroids are most effective as immunosuppressive drugs when administered before transplant is performed. The pattern of gene expression in the recipient is then already changed by the time of transplantation and alloantigenic challenge. Many side effects: fluid retention, weight gain, diabetes, loss of bone mineral, and thinning of the skin.
IL-4, IL-13
Stimulate and amplify TH2-cell response
Consequence of Grave's Disease
Stimulate function due to TSH receptor and thyroid
What causes Grave's disease?
Stimulation by anti-TSH receptor antibody
What happens when you get infected with a helminth?
Strong TH2 response IgE isotype switching Mast cell activation and recruitment of mass and esosinophils
What are the two types of macrophages found in the lymph node?
Subcapsular Sinus Macrophages and Medullary Sinus Macrophages
What is an adjuvant?
Substance that induces inflammation by antigen-independent mechanisms Helps body generate an adaptive immune response
What type of vaccine is used for Hepatitis B?
Subunit vaccine
Tacrolimus (FK506)
Supresses T-cell activation by the similar mechanism of celcineurin inhibition.
Naive B cell contains/does what compared to plasma cell?
Surface Ig, surface MHC class 2, growth, somatic hypermutation, isotype switching Does not have high rate of Ig secretion
Deficiency of complement C5-C9
Susceptibility to Neisseria
Deficiency of complement C3
Susceptibility to encapsulated bacteria (pyogenic infection)
Deficiency of complement protein Factor D, properdin (Factor P)
Susceptibility to encapsulated bacteria and Neisseria but no immune-complex disease
leukocyte adhesion deficiency
Syndrome due to the mutation of CD18 gene. Affects phagocytosis. Phagocytes are unable to engulf bacteria opsonized with complement. Children with this disease have persistent infection with pyogenic bacteria, respond poorly to antibiotics, and usually succumb during the first two years of life.
Purposes of commensal microorganisms
Synthesize metabolites Break down plant fibers Inactivate toxic substances Prevent pathogen benefit from human gut Trigger development of secondary lymphoid tissue
Where can T cells be activated by dendritic cells presenting Ag that were taken from the gut?
T cell area of GALT (Peyer's patches and isolated follicles) Draining lymph nodes
Type IV immune reactant
T-cell/macrophages
What type of T cell response takes place in the gut?
TH2 Non-inflammatory
What do M cells do?
Take up Ag in gut lumen by endocytosis Transport it through cytoplasm to release at basal surface=transcytosis Dendritic cells take up Ag on the basal side
Mechanical innate defenses of eyes/nose
Tears Nasal cilia
Is Graves caused by CD4 TH1 or CD4 TH2 response? Is the a lot of inflammation of the thyroid tissue?
The CD4 TH2 response that mediates Graves' disease produces little inflammation or lymphocytic infiltration of the thyroid tissue, which retains its normal morphology.
The amount and affinity of antibody ________ after successive immunizations with the same antigen
The amount and affinity of antibody increases after successive immunizations with the same antigen
Antibodies made in a primary immune response persist for how long and do what?
The antibodies made in a primary response (secreted by plasma cells residing in the bone marrow or in the tissue beneath a mucosal surface) are sustained for several months after the infection has been cleared. These antibodies provide protective immunity, ensuring that another invasion by the same pathogen does not cause the infection.
What the problem with encapsulated bacteria?
The capsule prevents the fixation of complement by the alternative pathway. ONly when antibodies have bound to the capsule does complement fixation lead to bacterial clearance. Consequently, the aim of vaccination aginst such bacteria is to produce complement-fixing antibodies that bind to the capsule. These bacteria include pneumococcus, salmonellae, meningococcus, E. coli, and others. The capsule determines both the pathogenicity and the antigenicity.
NFkappabeta
The central transcription factor of the inflammatory response. A key immunosuppressive effect of hydrocortisone and prednisolone is to prevent the action of NFKappaBeta (NFKB). Corticosteroids increase the production of Ikappabetaalpha, the inhibitory regulator that prevents NFkappabeta from gaining access to the nucleus and turning on the cytokine and other genes that create a state of inflammation.
What happens in the lymph node once cognate pairs are formed?
The cognate pair moves to the medullary cords from the cortex where both cells divide to form a primary focus
How do effector B cells enter the gut-associated lymphoid tissue from the blood?
The combined interactions of integrin alpha4:beta7 on the B cells with MAdCAM-1 on the intestinal vascular endothelium, and B-cell CCR9 binding to chemokine CCL25 emanating from the intestinal epithelial cells.
vaccination
The deliberate induction of protective immunity to a pathogen by the administration of killed or non-pathogenic forms of the pathogen, or its antigens, to induce an immune response.
How does the concept of cross-linking naïve B cells relate to hemolytic disease of newborns?
The primary response makes low affinity IgG against RH is made, so the baby is healthy. The secondary immune response has higher affinity IgG is made and destruction of fetal erythrocytes occurs.
How do primary and secondary response differ?
The secondary immune response is greater than primary and is stronger. Isotype switching clones of B cells are used to bind better.
Celiac disease is cause by what?
The selective destruction of intestinal epithelial cells. In celiac disease, inflammation of the small intestine is caused by a CD4 T cell response. The T cells are specific for gluten-derived peptides that have been deaminated by tissue transaminase and presented by HLA-DQ8 or HLA-DQ2 molecules.
What does the body do to limit the size of the commensal organisms in the gut lumen and prevent them form infecting the tissues?
The specific IgA antibodies are made against the commensal species that are constantly secreted into the gut lumen.
What happens to centrocytes that have the highest affinity for the antigen?
They survive and go to produce plasma cells or antibodies
Staph Toxic Shock Syndrome (TSST-1)
Toxic shock syndrome
T/F There is a higher incidence of autoimmune disorders in females
True
T/F: Common themes of allergens are that they can be proteases and can be proteins that induce a T cell response?
True
T/F: HIV virus can switch from being macrophage-tropic to lymphocyte-tropic.
True
T/F: Half of all heart and kidney transplants fail within 10 yrs due to chronic rejection
True
T/F: Red blood cells do not contain MHC I or MHC II
True
How do Trypanosomes evade immune system mechanisms?
Use gene conversion to change their surface antigens
What type of vaccine for BCG?
Whole bacteria vaccine
Autoimmune diseases require
a breakdown in T cell tolerance
Centroblasts
actively dividing B cells
People lacking IgA
are able to survive, reproduce, and generally remain healthy
Subversion of IgA action by
bacterial IgA-binding proteins
trauma
can cause disruption of cell or tissue barrier allowing a formerly sequestered antigen to become recognized
High mutation rate
challenges the development of effective vaccines
Staphlyococcal superantigen-like proteins (SSLPs)
family of structurally related superantigens that subvert and compromise human immunity in a variety of ways. The purpose of SSLP7 is to prevent monomeric IgA from delivering the bacterium to phagocytes. In the absence of SSLP7, IgA binds to a bacterium with its Fab arms to FcalphaRI on neutrophils and macrophages with its Fc region. This activates the phagocyte to engulf and destroy the bacterium bound to the Fc receptor. SSLP7 has binding sites for the Fc region of IgA and for the C5 complement protein. These interactions create a large constrained complex in which IgA binding to FcalphaRI and complement mediated killing of the bacterium are both prevented.
T helper cells that form the conjugate pair forms are known as
follicular T helper cells (Tfh)
Antigen provided by
follicular dendritic cells
Do not confuse conventional dendritic cells that serve as professional APCs with
follicular dendritic cells in germinal centers. They are totally different cell types. DC does not equal FDC.
Secondary mediators
formed when membrane phospholipids are enzymatically cleaved
X-linked hyper-IgM syndrome
genetic immunodeficiency disease in which B cels cannot switch their immunoglobulin heavy-chain isotype, and so make unusually high amounts of IgM and no other isotypes. It leads to abnormal susceptibility to infections with pyogenic bacteria, particularly in the sinuses, ears, and lungs. It can be due to several different underlying mutations. Also called hyper IgM immunodeficiency. Like XLA patients, regular infusions of intravenous immunoglobulin help to prevent infections, and antibiotics are used to treat their infections.
Intrinsic factors
genetic mutations on Oncogenes and tumor suppressor genes
Examples of Killed/Inactivated Vaccines
influenza, rabies, Salk polio vaccine
Immediate phase
minutes; wheal and flare. Mast cell degranulation
variola
name given to both the smallpox virus and the disease it causes: smallpox
Each lymphocyte produces
only a single receptor out of the billions possible
Immunodeficiency of patients lacking B-cell co-receptors bc of defective CD19 or CD81 genes
patients have low levels of antibody, almost no isotype switching, and generally poor B-cel responses to infections and vaccines.
PEFR
peak expiratory flow rate; Breathing capacity
Chronic inflammatory disease of the gut mucosa
people who lack functional receptor for Il-10 suffer from chronic inflammatory disease of the gut mucosa that resembles the more prevalent Crohn's disease and is mediated by inflammatory TH1 and TH17 subsets of CD4 T cells. Cells that lack IL-10 cytokine receptor will have an effect on TH1 and TH17 that will consequently cause inflammation
tingible body macrophages
phagocytic cell that is seen in histological sections engulfing apoptotic B cells in germinal centers. (The B cells that didn't "win")
Chediak-Higashi Syndrom
phagocytosed materials are not delivered to lysosomes because of a defect in the vesicle fusion mechanism. The mutations causing this disease are in the CHS1 gene on chromosome 1, which encodes the lysosomal trafficking protein that is critical for lysosome function. Leads to persistent and re-occurring infection.
Proliferation and differentation
plasma cells and memory B cells
Dimeric IgA made by
plasma cells in mucosal-associated lymphoid tissues (GALT and BALT)
Thymus-Independent Antigens
polysaccharides, lipopolysaccharides, and peptidoglycans on the bacterial cell wall that activate B-cells without CD4 helper T cells (very few antigens)
IgG in mucosal
predominates in secretions of the nose, lower respiratory tract, and both female and male urogenital tract. Monomeric
Intravenous immunoglobulin (IVIG)
preparation of serum gamma globulin containing many different antibodies that is used as a treatment to replace antibodies and increase platelets in immunodeficiency and autoimmune disease
Seroconversion
presence of detectable levels of antibodies against HIV
High-affinity neutralizing antibodies
prevent viruses and bacteria from infecting cells
Effect of Therapeutic Anti-IgE
prevents mast cell from acquiring cell-surface IgE. Mast cell cannot be activated through FcεRI and downregulates its cell-surface expression.
Immunological memory is induced by the blank adaptive immune response?
primary Utilized during the secondary adaptive immune response
Recognition stimulates
proliferation and differentiation
Chronic asthma
restricts breathing
The goal of tissue typing
to avoid acute and chronic rejection
autoinflammatory diseases
type of disease characterized by chronic and recurrent bouts of systemic inflammation mediated by cells of innate immunity, and which does not involve antibodies or effector T cells. Some autoinflammatory diseases have a genetic component, such as familial Mediterranean fever and the hereditary periodic fevers. Examples: Hyper-IgD syndrome Blau Syndrome Majeed Syndrome Early-onset enerocolitis
Ischemia
when an organ is deprived of blood
histocompatible
when the donor and host have compatible tissue types that can coexist without provoking too strong an immune response.
DTP
widely admistered vaccine that provides protection against three bacterial diseases: diptheria, tetanus, and the whooping cough. The components of the vaccine are: 1. diptheria toxoid 2. tetanus toxoid 3. inactivate pertussis bacteria Example of a combination vaccine
Hypersensitivity II-III
within hours of exposure
Effector lymphocytes in mucosal tissue
γδ T cells CD4 cell Macrophage mast cell plasma cell IgA CD8 Dendritic cell CD8 cell
Cytoplasmic granules contain
"inflammatory mediators" = histamine
Cell deleted
(Central Tolerance) Apoptosis induced by inhibiting BCL-2 survival pathway or by activating death receptors
Eosinophil collagenase
(enzyme produced by eosinophil) Remodels connective tissue matrix
Latency
(immune evasion) hiding in a tissue until the immune environment favors re-emergence
Systemic anaphylaxis
(in circulation) Type I. - Often initiated by an injected or gut-absorbed allergen
Platelet activating factor
(lipid mediator of eosinophil) Attracts leukocytes. Amplifies production of lipid mediators. Activates neutrophils, eosinophils, and platelets.
Antibody preventing viruses mechanisms
1. Adult with anti-influenza virus IgA antibodies 2. Virus cannot infect cells 3. Student remains healthy
What needs to happen to have T-cell activate a B cell?
1. Ag needs to get to lymph node Native (B cell rec) and processed (T cell rec) 2. T cell at lymph node 3. B cell at lymph node 4. B and T cell need to interact
GVHD mechanism
1. Allogeneic hematopoietic cell transplant contains mature and memory T cells 2. T cells circulate in blood to secondary lymphoid tissues. Alloreactive cells interact with dendritic cells and proliferate 3. Effector CD4 and CD8 T cells enter tissues inflamed by the conditioning regimen and cause further damage
Linked recognition mechanism
1. Antigen binding to B-cell receptor delivers the first signal to the B cell 2. T helper cell delivers the second signal via CD40 ligand and cytokines
Antibody prevention without antibodies mechanism against bacteria
1. Brother without antibodies against S. pyogenes 2. Bacteria stay in the pharynx and multiply 3. Bacterial population expands out of control and damages its environment: brother suffesr a sore throat
Examples of pathogens that sabotage or subvert immune defense mechanisms
1. Myobacteria tuberculosis: commandeers the macrophages's pathway of phagocytosis for its own purposes. On being phagocytosed, M. tuberculosis prevents the fusion of phagosome and lysosome. It then survives and flourishes within the cell's vesicular system. 2. Toxoplasma gondii: parasite that creates its own specialized environment within the cells that it infects. This protozoan encloses itself in an impermeable membrane-enclosed vesicle that does not fuse with other vesicles or membranes of the cell. Prevents presentation by MHC molecules and T cell activation. 3. Treponema palladium: cause of syphilis. evades specific antibody by coating itself with human proteins. This is also a strategy pursued by the schistosome, a parasitic helminth worm.
Activation of B and T cells mechanism
1. Native T cells and B cells enter peyers patches 2. Naive lymphocytes are activated and become effector T cells 3. Effector cell leave PP 4. And reach the blood 5. Come back to mucosal tissues
Three components of immunological memory
1. long-lived plasma cells 2. Memory T cells 3. Memory B cells
What is the mixed lymphocyte reaction?
A cellular test of HLA difference between transplant donor and recipient and its potential for graft rejection
Allergy
A type I hypersensitivity reaction
What is an example of something that causes a Type 3 response?
Ab's generated against proteins from a nonhuman species
Autoimmunity
Ability of the immune system to differentiate between self and non-self antigens. Immune response against self antigens
Describe a bone transplant
Ablate pt's own bone marrow: chemo/rad Pt given bone marrow infusion Successful if original bone marrow is replaced with donor's
What is IgM major effector function?
Activation of complement pathways, only requires one molecule
Type II hypersensitivity-related autoimmune diseases
Antibody responses against red blood cells
What are leukotrienes and prostaglandins made from?
Arachdonic acid
Difference between DTP and DTaP?
Both have toxoid of diptheria and tetanus DTP: Killed pertussis DTaP: Pertussis toxoid and antigens (no whole bacteria)
Which type of vaccine protects against poliovirus?
Both inactivated and live-attenuated protect against poliovirus. Poliovirus infects mucosal surface, indicating that an oral vaccine would be superior to a vaccine injected intradermally. However, one of the challenges in delivering an oral vaccine is to prevent its degradation in the gut before it can infect the intestinal epithelium.
HIV Co-receptors
CCR5 CXCR4
Formation of Granulomas leads to
Chronic Granulomatous Disease
Chronic Response
Chronic response mediated by cytokines and eosinophil products
What are CTLs directed against?
Class I MHC differences
IgE
Class of immunoglobulin having epsilon heavy chains. IgE is involved in reactions against internal parasites, particularly helminth worms, and in allergic reactions. Only a small quantity is and and it is very transient in circulation. Binds to antigens as a cell-surface receptor for antigen. Binds to FcepsilonRI, which is carried by mast cells, basophils and activated eosinophils.
What usually happens at the later stages of HIV infection (years after initial infection)?
Clinical Latency HIV survives in CD4 T cells Slow decline CD4 T cells Leads to AIDs and death
Combinations of what distinguish memory T cells from naive and effector T cells?
Combinations of cell-surface markers distinguish memory T cells from naive and effector T cells. The combination of CD45RA, CD45RO, L-selectin (CD62L), and CCR7 is commonly used to distinguish memory T cells from naive and effector T cells. The IL-7, which is essential for the renewal and survival of memory cells, also distinguished memory cells from effector cells.
_________ is absent from mucosal secretions.
Complement
Antibodies bound to a pathogen can initiate what pathway?
Complement Pathways
Complement activation by IgG requires what? the participation of two or more IgG molecules.
Complement activation by IgG requires the participation of two or more IgG molecules. IgG molecules bind to antigens on the bacterial surface. C1q then binds to two or more IgG molecules and initiates complement activation.
Mesenteric Lymph Nodes
Defends the gut
How do we fight helminth infections?
Drive the worm into the gut lumen so they are expelled in the feces; Must use a TH2 CD4 T cells response because it fails to eliminate the worm but causes deadly inflammation
T/F. AIDS is when you are HIV positive
False Have to be HIV positive and have <200 per microliter T cell count OR: Could have another AIDs associated condition
GVL
Graft vs leukemia effect = experimenting with adding back T cells to destroy any cancer cells
Which HLA allotypes are the most important to match for transplantation?
HLA-A, -B, -C, and -DR
Deficiency of complement protein C1INH
Hereditary angioedema (HAE)
Viral infection
Herpes simplex Cytomegaloviru Varicella-zoster
Examples of pathogens that "hide" from immune system
Herpes simplex virus, Varicella-zoster herpes virus, Epstein Barr virus
What HLA haplotypes make heterozygotes more susceptible to diabetes than homozygous individuals?
Heterozygous individuals who have both the DQ2 and DQ8 haplotypes are more susceptible to a novel HLA-DQ heterodimer, assembled only in hereozygous individuals consisting of the DQ8 alpha chain DQA1*03 and the DQ2 Beta chain DQB1*02:01.
What is used to neutralize toxins and animal venoms?
High-affinity IgG and IgA
RNA Viruses facilitate progression to cancer
Human T-cell leukemia virus type 1 HIV-1 HHV8 (human herpesvirus 8)
Cytokines produced in reponse against helminth worms
IL-3 IL-4 IL-5 IL-9 IL-10 IL-13
What is the dominant immunoglobulins in tears, saliva, milk, and intestinal fluid
IgA
What three antibody isotypes are important to protect blood borne pathogen-- septicemia-- and the spread of micro-organisms by neutralizing those that enter the blood
IgM, IgG, monomeric IgA
Two parts compartments
Inductive and Effector
At what stage of immune complex formation is a Type 3 reaction likely to occur?
Intermediate: comparable amounts of antigen and antibody
Intermolecular spreading occurs in what type of autoimmune disease
Intermolecular spreading occurs in systemic autoimmune disease
What is a therapy for autimmune diseases
Intravenous immunolgobulin is a therapy for autoimmune disease
Immunological Tolerance
Lack of reactivity to self-antigens or foreign tissue antigens in an organ graft achieved without the need for long-term immunosuppression while retaining competence and reactivity to all foreign antigens.
Morphology of B cells
Large nucleus and small cytoplasm
Effective B cell-mediated immunity depends on help from T cells
Lesson from patients suffering from DIgeorge Syndrome
Components of Influenza virus
Lipid bilayer Matrix protein Nucleocapsid Hemagglutinin Neuraminidase
What type of vaccine is used for measles/mumps?
Live-attenuated vaccine
What is AIDS?
Massive reduction in CD4 T cells Caused by HIV
What causes the immediate reaction of Type I?
Mast cell degranulation=within 30 mins
Why do autoimmune diseases occur?
Mechanisms of self tolerance that fail 1. Negative selection in bone marrow and thymus 2. Expression of tissue-specific proteins in the thymus 3. No lymphocyte access to some tissue 4. Suppression by Treg 5. Induction of anergy in autoreactive B and T cells
Mechanisms of human immunity are revealed by what?
Mechanisms of the human immunity are revealed by the study of inherited immunodeficiency syndrome
Type IV hypersensitivity
Mediated by CD4 T cells Autoimmune diseases Organ transplant (Delayed H)
Icosomes
(Immune complex coated bodies) are shed from FDC's and taken up by centrocytes. Centrocytes must obtain, internalize and present antigen for differentation into plasma cells
Platelet-activating factor
(Lipid mediator) Attracts leukocytes. Amplifies production of lipid mediators. Activates neutrophils, eosinophils, and platelets.
Leukotrienes C4, D4, E4
(Lipid mediator) Cause smooth muscle contraction. Increase vascular permeability. Cause mucus secretion.
RAG-1/2 deficiency
(Recombinase activating gene) Required for TCR and Ig gene rearrangement
Receptor edited
(Somatic hypermutation) Receptor edited by VDJ recombination or BCR hypermutation to reduce binding to self antigen
Systemic lupus erythematosus (SLE)
(Type 3 hypersensitivity related autoimmune disease) Circulating IgG antibodies against common cellular constituents like cell surface components and constituents of cytoplasm and nucleus , splicesosomes, and a small cytopasmic ribonucleoprotein complex. - Deposition of immune complexes in the skin
Autoimmune hemolytic anemia
(Type II hypersensitivity related autoimmune disease) antibodies are raised against cell surface antigens on red blood cells, resulting in destruction of red cells and anemia
Type I diabetes mellitus
(insulin dependent diabetes mellitus, IDDM) Destruction of the insulin-producing B cells of the pancreas by CD8 T cells (cytotoxic T cells) that recognize peptides from a β cell specific protein and kill the β cell
Leukotrienes C4, D4, and E4
(lipid mediator of eosinophil) Cause smooth muscle contraction. Increase vascular permeability. Cause mucus secretion.
Elicitation
(minutes) - Second allergen exposure - Allergen binds IgE "fixed" to mast cell - Cross-linking and degranulation - Release of pharmacologically active factors
TIL cells
(tumor infiltrating cells) include CTLs that recognize cancer antigens/peptides. But these CTLs were anergic: could not kill targets or produce y-IFN. Many patients make anti-tumor antibodies, but are mostly IgM-will not efficiently induce effector responses and may indicate a lack of T cell priming
Importance of CCR5
- CCR5 is the receptor for the chemokines CCL3, CCL4, and CCL5, all macrophages and T chemoattractants
Hyper IgM Syndrome
- Deficiency in IgG, IgA, and IgE - Increased IgM in serum - B cells express IgD and IgM on membrane - X-linked (deficiency of CD40 ligand) - Recurrent infections
What are factors that influence the KINETICS of Graft Rejection?
- Degree of genetic difference between graft donor and recipient ( i.e., HLA) - Quantity/quality of tissue engrafted - Type of tissue engrafted - Immune status of recipient - Previous exposure to graft
Inactivated (killed) vaccines
- Whole-agent vaccines - Subunit vaccines (Both safer than live vaccines) - Microbes don't provide many antigenic molecules to stimulate the immune response - Often contain adjuvant
IgM and protection against blood borne pathogens
- blood-borne Ab - first made but pentameric so large size decreases extent to which it can passively leave the blood and penetrate infected tissues - Not able to signal other leukocytes - Fc region can bind to complement - Prevents septicemia
palatine tonsils
aggregates of secondary lymphoid tissue at the sides of the throat
Somatic mutations can alter
antibody specificity and increase diversity
Commensal Microorganisms
- symbiotic relationship - most bacterial infections of the gut tissue are caused by commensals
anti-idiotypic antibodies
antibody that binds to an epitope in the antigen-binding site of another immunoglobulin.
Effects of IgE-mediated mast cell degranulation in Airways
-Decreased diameter, increased mucus secretion. -Expulsion of airway contents through coughing, sneezing, and expulsion of phlegm
Two distinct functions of the Fc Region of Antibodies
-Deliver antibody to anatomical sites that would otherwise be inaccessible -Link bound antigen to molecules or cells that will effect its destruction
Effects of IgE-mediated mast cell degranulation in Blood vessels
-Increased blood flow, increased permeability. -Edema and inflammation, increased flow of antigens in lymph to lymph nodes
Effects of IgE-mediated mast cell degranulation in Gastrointestinal tract
-Increased fluid secretion, increased peristalsis -Expulsion of gastrointestinal contents by diarrhea and/or vomitting
MS - IL-4
-TH2 cells - IL4, STAT6, GATA3
MS - TGFB
-Treg cell - TGFB, FOXP3
How does the body prevent inflammation in mucosal surface?
-Use Treg cells to turn off inflammatory T cells - Macrophages are good at phagocytosis and do not initiate or maintain inflammation - No inflammatory cytokines - Express MHC II but lack B7 co-stimulator
What two strategies does the mucosal immune system use the prevent massive infection?
1. It is proactive and is constantly making adaptive immune responses against the microorganisms populating the gut. The result is that the healthy gut tissue is populated with effector T cells and B cells that stand guard and are poised to respond to any invader from the gut lumen. The advantage of a proactive strategy is that infections can be stopped earlier and with greater force than is possible in non-mucosal tissues. 2. Be sparing in the activation of inflammation, because the molecular and cellular weapons of the inflammatory response inevitably cause damage to the tissues where they work, which for mucosal tissues, particularly the gut, is more likely to exacerbate the infection than clear it up.
Attenuation utilizing recombinant DNA techniques
1. Mutate virulence gene OR Delete virulence gene 2. Resulting virus is viable, immunogenic but avirulent. It can be used as a vaccine. (ex: rabies)
What are mechanisms that contribute to immunological self-tolerance
1. Negative selection of B cells in the bone marrow 2. Expression of tissue-specific proteins in the thymus so that they participate in negative selection of T cells 3. Negative selection of T cells in the thymus 4. Exclusion of lymphocytes from certain peripheral tissues: brain, eye, testis 5. Induction of anergy in autoreactive B and T cells that reach the peripheral circulation 6. Suppression of autoimmune responses by regulatory T cells
Influenza immune evasion mechanism
1. Neutralizing antibody binding to hemagglutinin prevents virus V from infecting cells of person P 2. While infecting person Q, virus V mutates to give virus V* with altered hemagglutinin 3. Virus V* infects person P because antibody made against V does not neutralize V*
What is an example of a type 2 reaction?
1. PNC allergy: Binds to RBC so body recognizes as foreign PNC specific IgE mast cells are made that cause anaphylaxis 2. ABO blood type
Name 2 reasons why the body's immune system fails?
1. Pathogens can escape or subvert immune system 2. Inherited deficiency of immune system
Anti-HLA antibodies can arise from what?
1. Pregnancy 2. blood transfusion 3. previous transplant
Herpes virus mechanism
1. Primary infection 2. Trigeminal ganglion 3. Latent phase 4. Reactivation of infection 5. Back to primary infection
Antiviral drug mechanism
1. Productive infection of CD4 T cells accounts for more than 99% of virus in plasma. 2. Infected cells are short-lived, so HIV must continually infect new cells 3. If virus production is blocked by a drug, the virus is rapidly cleared from the blood. 4. CD4 T- cell numbers rapidly increase, replacing those lost by infection
What are some immunosuppressive Treatments to Prevent Graft Rejection?
1. Radiation 2. Immunosuppressive therapies, cytotoxic drugs, T cell inhibitors 3. Immune Tolerance - activate Treg cells
How does the gut/ mucosal immunity prevent inflammation?
1. Regulatory T cell (CD4treg)- turn off inflammatory T cells. IL-10 is a cytokine secreted by Treg that suppresses inflammation by turning off the synthesis of inflammatory cytokines.
What are the two effective rotavirus vaccines?
1. Rotarix: attenuated human rotavirus that has common P8 and G1 variants of the VPa and VP7 glycoproteins. 2. RotaTeq: based on a cattle rotavirus that is nonpathogenic in humans. Consists of 5 viral strains, four expressing different human VP7 variants and cattle VP4, and one expressing cattle VP7 and the human P8 variant of VP4.
Swelling mechanism
1. Subcutaneous antigen, low dose 2. Mast cell activation 3. Increased vascular permeability leads to localized swelling (release of fluid, cells, proteins) ** process is involved in hives (urticaria)
What are the goals of the primary immune response?
1. Subdue the ongoing infection by a harmful pathogen that is outrunning innate immunity. This is accomplished by clonal expansion of pathogen-specific naive T cells and B cells to produce large populations of shot-lived effector B and T cells that work together to eradication the invading microorganisms. 2. Ensure that future invasions by the pathogen will be met by an immune response of overwhelming force. Mediating such secondary immune responses are long-lived pathogen-specific memory T cells and Memory B-cells.
Symbiotic relationship of commensals
1. Synthesize essential metabolites 2. Break down plant fibers in food 3. Inactivate toxic substances in food or made by pathogens 4. Prevent pathogens from benefitting from the resources of the human gut 5. Interact with epithelium to trigger development of secondary lymphoid tissue
What are five ways in which commensal gut microbiota benefit their human host?
1. Synthesize essential metabolites 2. Breakdown plant fibers in food 3. Inactivate toxic substances in food or made by pathogens 4. Prevent pathogens from benefiting from the resources of the human gut 5. Interact with epithelium to trigger development of secondary lymphoid tissue
Virus attenuation mechanism
1. The pathogenic virus is isolated from a patient and grown in human cultured cells 2. Cultured virus is used to infect monkey cells 3. The virus acquires a variety of mutations that allow it to grow well in monkey cells 4. The virus no longer grows well in human cells (it is attenuated) and can be used as a vaccine
The Germinal Center Response Mechanism
1. The primary focus for expansion of antigen-activated B cells is in the medullary cords 2. The secondary focus for expansion of antigen-activated B cells is in the primary follicle 3. Expansion of antigen-activated B cells in the primary follicle creates the germinal center
Chronic autoimmune diseases caused by autoreactive T cells that arise in the course of combating infection
1. The same MHC molecule presents both a pathogen peptide and a self peptide that mimics it 2. Naive T cell is activated by the pathogen peptide presented by the particular MHC molecule 3. Effector Th1 cell responds to the self-peptide mimic and activates the macrophage, causing inflammation
Trypanosomes mechanism of changing surface antigens
1. There are many inactive trypanosome VSG genes but only one site for expression 2. Inactive genes are copied into the expression site by gene conversion 3. Many rounds of gene conversion can occur, allowing the trypanosome to vary the VSG gene expressed
HIV infection mechanism
1. Virion binds to CD4 and co-receptor on T cell 2. Viral envelope fuses with cell membrane, and viral genome enters cell 3. Reverse transcriptase copies viral RNA genome into double-stranded cDNA 4. Viral cDNA enters nucleus and integrates into host DNA 5. T-cell activation induces some transcription of provirus 6. RNA transcripts are spliced to allow synthesis of the early proteins Tat and Rev 7. Tat amplifies transcription of viral RNA. Rev increases transport of RNA to cytoplasm 8. Gag, Pol, and Env are made and assembled with viral RNA into virions which bud from the cell
What happens to short-lived plasma cells?
1. complexes of antigen and antibody bind to FcgammaRIIBI and induce the cell to die by apoptosis. 2. Loss of contact with stromal cells and of the survival signals they give.
What are the two kinds of mast cells?
1. mucosal mast cell: produces the protease tryptase. Depends on the effector T cells that populate the mucosal tissues. Result is tissue specific differentiation. 2. connective tissue mast cell: produces chymotryptase.
What biological properties of smallpox contributed to the success of the vaccination
1. smallpox evolves slowly and its antigenic epitopes are conserved, so that immunity acquired as an infant is effective against smallpox if it infects later on in life 2. the vaccine is a live virus that establishes an infection at the injection site in the skin, a tissue affected by natural smallpox infection. Thus the stimulation of the innate and adaptive immune responses by the vaccine mimics that caused by smallpox infection and produces memory cells that will provide effective defense against smallpox. 3. It only affects humans, meaning that there are no reservoirs of the virus in other animals. Once the chain of transmission between humans has been broken, the virus cannot survive.
In what two ways do memory T cells differ from naive T cells that increase the speed of the secondary response?
1. some memory T cells recirculate to peripheral tissues rather than through the secondary lymphoid organs, and so memory CD8 T cells and CD4 TH1, TH2, and TH17 cells can be activated directly at a site of infection by dendritic cells and macrophages presenting their specific antigens. 2. Their activation requirements are less demanding than those of naive T cells because they, like the effector T cells, do not require c0-stimulation through CD28.
Successful primary immune responses lead to
1. the production of effector T and B cells 2. Immunological memory
What are leukotrienes?
100x more potent than histamine
Colon
10^12/mL
Bacterial counts in stomach
10^3/mL
Small Intestine
10^5-8/mL
Immunosurveillance
1957-Burnet & Thomas proposed that lymphocytes act as sentinels in recognizing and eliminating nascent transformed cells
How many CDR loops on an Ig molecule?
6 3 CDR loops on each Fab variable region (arms) and there are two Fabs (arms)
Late phase
6 hours. Swelling due to leukotrienes, chemokines, and cytokines.
What causes the late-phase reaction of Type I?
6-8 hrs later Leukotrienes, chemokines and cytokines Delayed cuz must be synthesized
Mixed lymphocyte reaction
A cellular test that has been used to assess the extent to which a patient's T cells could respond to a transplanted organ from a live donor. Blood lymphocytes, monocytes, and dendritic cells are isolated from a patient seeking a kidney graft and from a possible kidney donor. The donor's cells are irradiated so that they act only as stimulators and not as responders. The patient's cells and the donor's cells are cultured together for five days. During this time alloreactive T cells of the patient are activated by the allogenic HLA class I and class II molecules of the donor. After 3 or 4 days of culture the proliferation of the differentiating T cells is measures. After 5 days of culture the capacity of effector CD8 T cells to kill donor cells is assessed. Proliferation measures the magnitude of the alloreactive response, killing of donor cells measures its capacity for graft rejection.
Prodrug
A drug that is given to patients in an inactive form, and only in the human body does it become converted to the active form. Prednisone is an example.
MHC Class II deficiency
A genetically determined immunodeficiency in which MHC class II molecules are not produced and which results in a lack of CD4 T-cell function
FcEpsilonRII
A low affinity receptor for IgE Fc regions that regulates the production of IgE by B cells Very different structure than FCEpsilonRI
Panel Reactive Antibody (PRA)
A measure of the likelihood that a patient seeking a transplant is sensitized to potential donors. The patient's serum is tested against tissue from a representative panel of individuals for antibodies that would cause that immediate hyperactive rejection of a graft. The PRA is the percentage of individuals in the panel whose cells react with the patient's antibodies.
Omalizumab
A monoclonal antibody used in clinical practice to reduce the symptoms of IgE-mediated allergic diseases such as asthma. On binding to IgG (the monoclonal antibody), omalizumab covers up the site of IgE that binds to FcEpsilonRI on mast cells, basophils, and eosinophils. The antibody thus prevents IgE from arming these effector cells and enabling them to respond to antigens and allergens that have stimulated the production of specific IgE. When first proposed, the sue of anti-IgE as a therapy for allergic disease was met with concern and skepticism. These negative reactions were founded on the kowledge that anti-IgE antibodies were routinely used in laboratory expirements to activate mast cell degranulation by cross-linking IgE molecules bound to mast cell FcEpsilonRI. The experimental anti-IgE antibodies that activate mast cells bind to epitopes on IgE that are away from the binding site for FcEpsilonRI, whereas the therapeutic antibody covers up the binding site for FcEpsilonRI.
What is the most common human immunodeficiency?
A partial lack of C4 Lack of C4A = systemic lupus erythematous (SLE) Lack of C4B = lowered resistance to infection
Vaccination
A procedure that presents the immune system with a harmless variant of a pathogen, thereby stimulating the immune system to mount a long-term defense against the pathogen (quizlet)
Hepatitis B virus
A subunit vaccine is used. The hepatocytes of patients infected with HBV secrete the surface protein into the blood as minute particles. The first version of the anti-hepatitis B vaccine contained surface protein that was purified from the plasma of HBV-infected people. HBV subunit vaccine was one of the first vaccines to be made using recombinant DNA technology and it did not involve viral particles. The gene encoding the HBV surface antigen was inserted into the genome of baker's yeast. The recombinant yeast was then grown in mass cultures, from which the surface protein was purified in large quantity.
Wiskott-Aldrich syndrom (WAS)
A syndrome involving the platelets as well as the lymphocytes. It shows up in childhood as a history of recurrent infections but is less immunologically severe than SCID. Patients have normal levels of T and B cells but cannot make good antibody responses and are therefore kept on a course of intravenous immunoglobulin. The relevant gene on the X-chromosome encodes the Wiskott-Aldrich syndrome protein (WASP). This protein is involved in the cytoskeletal reorganization that is needed before T cells can deliver cytokines and signals to the B cells, macrophages, and other target cells with which they can form cognate interactions during development and participation in the immune response.
Serum sickness
A type III hypersensitivity reaction. Usually occurs 7-10 days after administration of the theraputic antibody and is characterized by chills, fevers, rash, arthritis, vasculitis, and sometimes glomerulonephritis.
What guards healthy mucosal tissue in the absence of infection?
A variety of effector lymphocytes guard healthy mucosal tissue in the absence of infection. Outside the lymphoid tissues, the gut epithelium contains CD8 T cells, and the lamina propria is well populated with CD4 T cells, CD8 T cells, plasma calls, mast cells, dendritic cells (DC), and macrophages. These cells are always in an activated state because by the gut's diverse and changing contents. The CD8 T cells include both alpha:beta and gamma:delta cells.
Smallpox
A viral disease characterized by a rash of spots that develop into virus-loaded pustules that leave permanent scars on survivors. The rash frequently involved the face, and the disease was mainly spread by face to face contact.
Adenosine deaminase (ADA) deficiency or purine nucleoside phosphorylase (PNP) deficiency
ADA and PNP are enzymes involved in purine degradation. Deficiencies in these enzymes account for 15% of SCID patients. Autosomoally inherited.
What are one of the primary destructive forces in the rejection process?
Activated cytotoxic CD8+ T lymphocytes (CTLs)
What molecule attacks parasites coated with IgE?
Activated eosinophils attack parasites coated with IgE. Large parasites, such as worms or the schistosome larva (SL) shown here, cannot be ingested by phagocytes. However, they can be attacked by activated eosinophils that are coated with anti-parasite IgE antibodies bound to FcERI. When the eosinophils encounter the parasite, the parasite's antigens will cross-link the IgE bound to FcERI and activate the eosinophils to secrete the toxic and crippling contents of its granules directly on to the surface of the parasite.
Humoral/Antibody Immune Response
Activation of naive B cells by most antigens requires help from CD4 T cells
Result of Type II
Activation of the complement cascade directed at host cells
Acute rejection is what type of hypersensitivity reaction caused by what?
Acute rejection is a type IV hypersensitivity reaction caused by effector T cells responding to HLA differences between donor and recipient
Combination vaccines
Administration of antigens from several pathogens
Active immunization
Administration of antigens so patient actively mounts a protective immune response
Explain the progression of the primary response, secondary, tertiary, quaternary, etc.
Affinity maturation in the secondary immune response produces a second generation of memory B cells that are superior to those that emerged from the primary response. A third infection will be met by a tertiary antibody response that is even better than that made in the secondary response, and so on. Successive infections with the same pathogen sharpen the defenses of the adaptive immunity and immunological memory.
When is herpes simplex infectious to others?
After initial immune response subsides and the virus emerges from latency in neurons to infect epithelial cells
How long do vaccina-specific antibodies and T cells last after vaccination?
After vaccination, the amount of vaccina-specific antibody in the blood rapidly increases to a maximum level and then, over the next 12 months, decreases to about 1% of the maximum. Specific anti-vaccinia antibodies continue to be made for as long as 75 years after the last exposure to vaccinia virus, the smallpox surrogate that is used for vaccination. Many vaccinated individuals retain populations of vaccinia-specific CD4 T cells and CD8 T cells.
What is a Type 1 response caused by?
Ag binding to IgE attached to the Fc receptor on mast cell Mast cell degranulates=inflammatory
What is a Type 4 response caused by?
Ag-specific T cells
What are some functions of the commensal microorganisms in the human GI tract?
Aids in digestion. In the mouth, food is physically broken down by chewing in an environment populated by more than 750 species of bacteria. In the stomach, acid and enzymes are used to chemically degrade the masticated food in an environment that is relatively unfriendly to microbes. Here, the main function of the mucus is to protect and buffer the epithelium from the corrosive effects of hydrochloric acid secreted in the stomach. As food travels along the GI tract and becomes increasingly degraded, it passes through environments with increasing numbers of resident bacteria.
Low molecular mass
Allergen diffuses out of particle into mucus
High solubility
Allergen is readily eluted from particle
High stability
Allergen survives in dessicated particles
Type 1 hypersensitivity
Allergic rhinitis Asthma Systemic anaphylaxis (Immediate H)
Allergy is prevalent in what type of countries
Allergy is prevalent in countries where parasite infections have been eliminted. Without the presence of helminth works and other parasites in the human body, IgE-mediated immunity has lost its natural substrat and focus of attention. As a consequence to this ecological disruption, the Th2 arm of immunity is more prone to develop in an unguided fashion, in which its powerful forces are no longer ranged against parasitic infection but are increasingly aimed at harmless environmental agents.
Allogeneic hematopoietic cell transplantation is the preferred treatment for many what?
Allogeneic hematopoietic cell transplantation is the preferred treatment for many cancers, particularly malignancies of immune system cells.
Alloreactive T-cell co-stimulation can be blocked with a soluble form of what?
Alloreactive T-cell co-stimulation can be blocked with a soluble form CTLA4. CTLA4 is the inhibitory receptor that recognized B7 and is used as a negative regulator of T-cell activation. To facilitate this function, CTLA4 binds B7 with 20 times the strength of CD28, so that when CTLA4 is expressed it outcompetes CD28 binding B7. Drugs that use this strategy: 1. Belatacept
Rapamycin (sirolimus)
Alternativ and earlier name for the immunosuppressive drug sirolimus, which is used to prevent the rejection of organ transplants. Blocks T-cell activation at a later stage by preventing signal transduction from the IL-2 receptor. More toxic than either cyclosporin A or tacrolimus but is a useful component of combination therapy.
Review of Complement Pathways
Alternative- Responds to environmental signals Lectin- Mannose-binding lectin binds to pathogen Classical- C3 reactive protein binds to pathogen
IL-3, IL-5, GM-CSF released by eosinophils
Amplify eosinophil production by bone marrow. Cause eosinophil activation.
FcRn (FcRB)
An Fc receptor that transports IgG across epithelial and has a structure resembling an MHC class I molecule. Fluid-phase endocytosis of IgG from the blood by endothelial cells of the blood vessel incorporate FcRn on the surface into the vesicle. The acidic pH of the endocytotic vesicle causes the association of IgG with FcRn, protecting it from proteolysis. The FcRn receptor binds to the Fc part of immunolgobulins. On reaching the basolateral face of the endothelial cell, the basic pH of the extracellular fluid dissociates IgG from FcRN.
anaphylaxis
Anaphylaxis is a severe, potentially life-threatening allergic reaction. It can occur within seconds or minutes of exposure to something you're allergic to, such as a peanut or the venom from a bee sting.
Prostaglandins
Another thing mast cells produce. Promotes the dilation and increased permeability of blood vessels and also acts as a chemoattractant for neutrophils.
How does Enbrel work?
Anti-TNF alpha fusion protein Has human Ig Fc regions and Fab regions with TNF receptor Binds TNF alpha which can then be cleared from system
How does the mucosal surfaces prevent pathogen invasion?
Antibodies coat the microbial surface and impede bacterial invasion and proliferation. They are also neutralized by binding antibodies
Molecular mimicry
Antibodies or T cells generated in response to an infectious agent cross-react with self antigens
How do antibodies allow macrophages to engulf bacteria?
Antibody coated bacteria binds to Fc receptors, macrophage membrane surrounds the bacterium, forms a vesicle, lysosomes degrading the pathogen
What drive affinity maturation?
Antigen-mediated selection of centrocytes
Type II Immune reactant
Antigen-specific IgG antibody
Thymus-Dependent Antigens
Antigens that need the help of CD4 helper T cells to activate B cells
What type of vaccine for Salmonella typi?
Attenuated bacteria vaccine
CCL3
Attracts monocytes, macrophages, and neutrophils
Grave's disease
Autoantibody acting as agonist causing hyperactivity and severe metabolic disorders
Autoantibodies have specificity for...
Autoantigen: self antigens
Autoimmune disease can be an adverse side effect of an immune response to what?
Autoimmune disease can be an adverse side effect of an immune response to infection
Graves' disease
Autoimmune disease in which antibodies against thyroid-stimulating hormone receptor cause the overproduction of thyroid hormone and the symptoms of hyperthyroidism. Caused by agonist autoantibodies specific for the TSH receptor. By mimicking the natural ligands, the antibodies bound to the TSH receptor cause chronic overproduction of thyroid hormones that is independent of regulation by TSH and insensitive to the metabolic needs of the body. causes heat intolerance, nerousness, irritability, warm moist skin, weight loss, and enlargement of the thyroid. Also causes outwardly bulging eyes. Associated with HLA-DR3.
Deficiency of complement protein DAF and CD59
Autoimmune-like conditions including paroxysmal nocturnal hemoglobinuria
What is a centrocyte?
B cell interacting with CD4 T cell Can become memory B cell or plasma cell
cytotoxic drug
Because cytotoxic drugs do not act until after alloreactive T cells have recognized graft alloantigens, they are usually administered only after transplantation.
Is influenza an RNA or DNA virus?
Because influenza is an RNA virus, the replication of its genome is more prone to error than the replication of DNA viruses such as smallpox and measles. The errors generate a mutant virus, enabling influenza to evade human immunity. New strains of influenza spead through the human population every year due to the high rates of mutation. The main target of neutralizing antibodies are the hemagglutinin (H) and neuraminidase (N) surface glycoproteins that allow the virus to bind to cells of the respiratory epithelium and infect them. Good neutralizing antibodies block the virus infection, prevent viral replication, and target viral particles for phagocytosis
Activation of B lymphocytes
Begins with antigen binding by receptors resulting in crosslinking of receptors
Mast cells
Bind to IgE Fc region before IgE binds to anything IgE activates mast cell: release granules containing histamine
What is the most widespread kind of transplantation?
Blood transfusion
What is the most common transplanted tissue?
Blood. It is given to 1 in 4 people at least once in their life.
What is tissue typing mainly used for?
Bone Marrow transplants ** this is to prevent GVHD
What is a therapy for genetic and malignant diseases of hematopoietic cells?
Bone marrow transplant. Example A patient's diseased hematopoietic system is destroyed by chemotherapy and irradiation. An infusion of hematopoietic stem cells obtained from healthy HLA-mathced donor is then given. Over a period of months the hematopoietic stem cells in the graft reconstitute the patient with a healthy hematopoietic system.
SSLP7 mechanism
By binding to C5 and IgA, SSLP7 protects bacteria from being killed (not delivered to phagocyte)
How does HIV escape the immune response and develop resistance to antiviral drugs?
By rapid mutation
What is the difference between C4A and C4B
C4A thioester bond is more susceptible to attack by the amino groups of macromolecules, whereas the C4B thioester bond is more susceptible to attack by the hydroxyl groups. Humans differ in the number and type of genes for complement component C4
What do macrophage-tropic HIV variants target?
CCR5 Co-receptor found on macrophages, dendritic cells and CD4 T cells Spread of HIV in population
What cell surface protein is unique to B cells?
CD20
How does autologous BM transplant work?
CD34+ Cells are isolated from cancer patients to remove malignant cells. Experimenting with adding back T cells to destroy any cancer cells
What type of cells are found in the lamina propria?
CD4 T cells, CD8 T cells, Plasma cells Dendritic, macrophages, eosinophils and mast cells
How do CD4 T cells aid in B cell activation?
CD4 TFH cells recognize MHC class 2 receptors with peptide and activate B cells by delivering cytokines to the cell (which cause it to divide and proliferate)
T cells response against helminth worms
CD4 Th2 Cells
Induction requires
CD40L to CD40
CD45RA vs. CD45RO
CD45 is a tyrosine phosphate involved in antigen-activated signaling from the T-cell and B-cell receptors. Naive and memory T cells make different isoforms of the CD45 protein by alternate splicing of CD45 mRNA> Naive T cells express predominately the CD45RA isoform, which functions poorly with the T-cell receptor complex and transduces weak signals when the T-cell receptor recognizes specific antigen. Memory T cells express CD45RO, which has a smaller extracellular domain than CD45RA, owing to three exons being spliced out of CD45RO mRNA. CD45RO interacts well with the T-cell receptor complex and transduces strong signals when the T-cell receptor recognizes antigen.
Chance factor MS
CD8+ T cells expressing two distinct antigen receptors fail to be tolerized and can induce autoimmunity
What do lymphocyte-tropic HIV variants target?
CXCR4 on activated CD4 T cells Causes disease
Poliovirus
Can cause disease as well as variable paralysis called poliomyelitus or infantile paralysis that can kill or cripple the affected individuals, who are mostly children. Transmitted by the fecal-oral route. Infects mucosal surfaces, indicating that an oral vaccine would be superior to a vaccine injected intradermally. Like smallpox, poliovirus infects only humans, so that if it is completely eliminated from human species, the virus will then be extinct in the 'wild' and restricted only to research laboratories.
Explain the possible mechanisms of viral immune evasion?
Can interfere with processing/loading of peptide onto MHC I Can subvert NK efficacy: can prevent from sensing fewer MHC
Allergens being stable in what form contributes to what?
Can survive in dried form Kicked up in air-inhaled Induce TH2 Active IgE production Type I hypersensivity
What type of vaccine for N. meningitidis?
Capsular polysaccharide conjugate vaccine Causes meningitis
What type of vaccine for H. influenzae?
Capsular polysaccharide conjugate vaccine Causes pneumonia and meningitis
What type of vaccine for S. pneumo?
Capsular polysaccharide conjugate vaccine Causes pneumonia and meningitis
Why do we use polysaccharide capsule vaccines?
Capsules prevent complement via alternative complement Vaccine makes capsule binding Ab-> classical complement
Early Rotavirus vaccine Problems
Caused bowel obstruction which could be fatal in 1 out of 7,000 children; vaccination was stopped in the U.S. because only 1 in 100,000 got the Rotavirus
Rotavirus
Caused by a viral infection of the epithelial lining of the small intestine. The infection cause acute diarrhea.
What is the secondary lymphoid tissue directly associated with the gut called?
GALT Can generate adaptive immune response at the site of infection
Mast cells
Cells resident in mucosal and epithelial tissues lining the body surfaces. Present in all vascularized tissues except the central nervous system and the retina, mast cells serve to maintain the integrity of the tissue where they reside, alert the immune system to local trauma and infection, and facilitate that repair of damage caused by infection or wounds. They contain 50-200 large granules that contaian inflammatory mediators. They express FcEpsilonRI, toll-like receptors, and Fc receptors for IgA and IgG. Mast cells thus contribute to both the innate and adaptive immune system.
2 components of innate immunity
Cellular=macrophages and neutrophils Humoral= Complement
Bcl-XL
Centrocytes with receptors having superior affinity for antigen are induced to express Bcl-XL, an intracellular protein that prevents apoptosis and ensures the cell's survival.
How do corticosteroids act as immunosuppressives?
Change pattern of gene expression via nuclear signaling to give an anti-inflammatory effect
Adjuvant
Chemicals added to increase effective antigenicity
Explain the mechanism of evasion for varicella-zoster herpes virus
Chickenpox initially Virus goes dormant in dorsal root ganglia After initial immune response subsides, reappears to cause painful rash on sections of body inneverated by the the infected part of spinal cord=shingles
Subunit Vaccines
Composed of only isolated, antigenic components of a pathogen and not the pathogen itself (either live or dead)
Waldeyer's Ring
Composed tonsils and adenoid; guard the entrance of the GI and respiratory tracts
How do TFH work to activate B cells?
Conjugates form between TFH and B cell that share the same antigen specifity; the t-cell expresses CD40 receptors and adhesion molecules holds the conjugate together; A synapse forms and the t-cell sends cytokines across
Getting T cells to lymph node
Continuous circulation Looking for specific peptide: MHC complex that is loaded onto dendritic cells Stops when finds it
What does GALT do to aid in pathogen prevention?
Continuously sample the contents of the gut lumen
rev
Controls export of transcripts from the nucleus
gag
Core proteins and matrix proteins
Small Pox and Cow Pox Vaccination
Coxpox and smallpox viruses share some surface antigens, immunization with cowpox induces antibodies against cowpox antigens. Cowpox antibodies then bind an neutralize the smallpox virus.
Cross-linking of IgE on mast-cell surfaces leads to what?
Cross-linking of IgE on mast-cell surfaces leads to the rapid release of mast-cell granules containing inflammatory mediators. Mast cells have numerous granules containing inflammatory mediators such as histamine and serotonin. The cells have high-affinity Fc receptors (FcepsilonRI) on their surface that are occupied by IgE molecules in the absence of antigen. When antigen cross-links the complexes of IgE and FcERI, the mast cell is activated, leading to the degranulation and the release of inflammatory mediators into the surrounding tissue, as shown in the right panels.
What is required for B-cell activation?
Cross-linking of surface IgM with antigen; Ig-alpha and Ig-Beta sends out the activation signal which changes gene expression
How do you prevent a hyperacute rejection from occurring during solid organ transplants?
Cross-match test Take lymphocytes from donor and blood from recipient and ensure that the recipient does not attack the donor
Blocking what signaling can prevent alloreactive T-cell activation
Cytokine. Blocking cytokine signaling can prevent alloreactive T-cell activation Drug examples that use this strategy: 1. Anti-CD25 Antibodies 2. Rapamycin (sirolimus)
What influences isotype switching?
Cytokines secreted by T cells
receptor antagonist
Do not activate signaling on binding to the receptor but they block the natural ligand from binding to the receptor and activating its signaling function.
Where is the appendix?
Dead end at intersection of small and large intestines
How long can memory B and T cells provide protection for?
Decades or even for life
Inactivate toxic substances in food or made by pathogens
Degradation of toxins into harmless components that can be used by human cells
How do dendritic cells in the epithelium capture pathogens in the gut lumen
Dendritic cells can extend processes across the epithelial layer to capture antigen from the lumen of the gut without disturbing the barrier function of the epithelium.
Describe how bone marrow transplants can be used in cancer
Destroy bone marrow of someone with chemo. Donor bone marrow attacks residual host WBC that are cancerous that were not eliminated by ablation.
Conjugate vaccines
Different epitopes recognized by B and T cells are synthetically linked together
Explain evasion due to genetic variation
Different strains of pathogen have different epitopes that will not be recognized by the antibodies already made for that pathogen as well/at all Serotypes with different capsular polysachs
Which isotype does the baby receive from their mother's milk during pregnancy
Dimeric IgA (this is an example of passive transfer of immunity)
Which two Ig types can do transcytosis across gut epithelium?
Dimeric IgA and IgM
Transcytosis of dimeric IgA
Dimeric IgA is made by plasma cells lying just beneath the epithelial basement membranes of the mucosal tissues, such as the gut. The IgA dimer bound to the J chain diffused across the basement membrane and is bound by the poly-Ig receptor on the basolateral surface of an epithelial cell. Receptor binding is mediated by the Ch3 constant domains of the IgA. The bound complex crosses the cell in a membrane vesicle and is delivered to the apical surface. There the receptor undergoes cleavage, which releases a complex of dimeric IgA bound to a fragment of the secretory component. The carbohydrate of the secretory piece tethers the IgA to the mucus that coats the apical surface, thus preventing the antibody from being washed away into the gut lumen and beyond. The residual membrane-bound fragment of the poly-Ig receptor is nonfunctional and is degraded.
Function of IgA
Dimeric form goes through epithelial cell to lumen =Mucosal immunity Monomeric protects internal tissues and protects bloodstream
What is the result of defective genes encoding the membrane associated CD40 ligand?
Diminished production of antibodies because CD40 ligand is a component on T cells that needs to bind to CD40 on B cells in order to activate them. CD40 ligand is encoded on the X chromosome, so most patients with a hereditary deficiency in CD40 ligand are male.
What is DTP and DTaP?
Diptheria, tetanus and pertussis
What causes acute rejection?
Direct pathway of allorecognition
What is an autoimmune disease?
Disease caused by adaptive immunity that becomes misdirected at health cells and tissues of the body.
IFN-gamma receptor deficiency, dominant allele
Dominant mutation: In the dominant mutation, IFNgammaR1 is truncated such that much of the cytoplasmic tail, which binds Jak1 and initiates signaling is missing. The truncated IFNgammaR1 associated with IFKgammaR2 protein and is taken to the surface as a receptor that binds IFK-gamma but cannot transduce a signal. At the cell surface, these defective receptors compete for IFN-gamma with the normal receptors that incorporate IFNgammaR1 made from the normal allele. This competition is further weighted against the functional receptors because the absence of the cytoplasmic domain from IFNgammaR1 prevent the mutant receptor from being recycled by endocytosis. It therefore accumulates at the cell surface, at levels fivefold higher than the normal receptor. Becayse of the interference of mutant receptors, the response of patients' macrophages and monocytes to IFN-gamma is much reduced compared to healthy people, but it is much greater than in patients carrying two recessive alleles. Dominant mutants cause a less sever immunodeficiency, which tends to be detected at a later age.
Graft-versus-host disease in bone marrow transplants
Donated bone marrow see's patient's body as foreign and attacks it
What is GVHD caused by?
Donor T cells in graft attacking recipient's tissues
Direct pathway of allorecognition
Donor dendritic cells in the graft carry complexes of donor HLA molecules and donor peptides on their surfaces. The dendritic cells travel to the spleen, where they move to the T cell areas. Here, they activate the recipient's alloreactive T lymphocytes. After activation, the effector T cells travel in the blood to the grafted organ, where they attack cells expressing the complexes of peptide and either HLA class I or HLA class II recognized by their T-cell receptors.
Primary function of IgM
Early proection against blood-borne pathogens
What is an acute rejection of solid organ transplant?
Effector T cells respond to HLA differences between donor and recipient: Recipient T cells destroy organ Takes days to develop
Central Tolerance
Eliminate many potentially autoreactive cells through NEGATIVE SELECTION ** Takes place in central lymphoid tissues (Bone marrow and Thymus)
Explain the defense against toxins.
Endocytosis of receptor;toxin complex, dissociation of the complex poisons the cell but neutralizing antibodies prevent the toxins from binding to the receptors
What does histamine cause?
Endothelial leakiness Smooth muscle contraction Increased mucus secretion (Congestion, runny nose, sneezing, coughing, vomiting, diarrhea...)
Primary Immunodeficiency diseases
Enhanced susceptibility to infection or autoimmunity
Anatomical changes of abnormal developing immune system
Enlarged cecum Longer small intestine Underdeveloped mesenteric lymph nodes Underdeveloped Peyer's patches Fewer isolated lymphoid follicles
Molecules released by mast cells
Enzyme Toxic mediator Cytokine Chemokine Lipid mediator
Chemical innate defense of eyes/nose
Enzymes in tears (lysozyme)
pol
Enzymes: reverse transcriptase, protease, and integrase
Recruitment of Eosinophils
Eosinophils express FcεR only upon activation. Produce very toxic molecules that can kill parasites.
What is the immediate treatment for systemic anaphylaxis?
Epinephrine
How to treat Type I hypersensitivity?
Epinephrine injection (Reverse endothelial leakiness and relaxes smooth muscle) Antihistamines, corticosteroids, cromolyn sodium
Mechanical innate defenses of skin, gut, lungs, eyes/nose
Epithelial cells joined by tight junctions
Mechanism of destruction of RBC's
Erthrocytes bind anti-erythrocyte autoantibodies leads to: 1. FcR-expressing cells in spleen, that leads to phagocytosis and erthrocyte destruction 2. Complement fixation and CR1-expressing cells in spleen, which leads to phagocytosis and erythrocyte destruction 3. Complement activation and intravasular hemolysis, which leads to erythrocyte and lysis destruction
What is the purpose of erythrocyte CR1
Erythrocyte CR1 helps to clear immune complexes from the circulation. Small soluble immune complexes bind to CR1 on erythrocytes, which transport them to the liver and spleen. Here they are transferred to the CR1 of macrophages and taken up for degradation.
What is the most numerous cell that expressed the complement receptor CR1?
Erythrocyte. So, the vast majority of immune complexes become bound to the surface of red blood cells.
What three mechanisms destroy erythrocytes in autoimmune hemolytic anemia
Erythrocytes bind anti-erythrocyte autoantibodies and then 1. FcR-expressing cells in the spleen cause phagocytosis and erythrocyte destruction 2. Complement fixation and CR1-expressing cells in spleen cause phagocytosis and erythrocyte destruction 3. Complement activation and intravascular hemolysis cause erythrocyte and lysis destruction
Direct inhibition of antibody response
Evasion by interference of antibody function
Herpes simplex virus
Example of latency. Enters SENSORY neurons (long-lived and express low levels of molecules of the MHC)
Effector cells against helminth worms
Expanded populations of eosinophils, basophils, and mast cells
T/F: Fewer people have AIDS these days than in the past.
FALSE: More people are living with AIDS than in the past Due to therapies
CD23
FCEpsilonRII is a homotrimer of the CD23 polypeptide, which has a C-type lectin domain and a long extended stalk. The trimer resembles a small bouquet of flowers in which each binding site domain is a separate flower, the three stalks oligomerize, and the cytoplasmic domains engage signaling molecules. Each of the three CD23 polypeptides binds with low affinity to a different IgE molecule.
nef
Facilitates viral replication. Downregulates CD4, MHC class I, and MHC class II
T/F: IgE only forms complexes with mast cells, basophils and eosinophils in the presence of infection.
False IgE: FC-epsilon-R1 complexes form in the absence of antigens
T/F A mast cell will contain IgE of one specificity
False Single mast cell will have receptors with multiple different Ag specificities
T/F: Humans can make antibodies to A, B and O antigens
False: Humans do not make anti-O, only make anti-A and anti-B.
T/F The mucosal surfaces of the body are stagnant
False: Mucosae is dynamic Replaced every few days Prevents pathogen attachment
T/F Once activated, lymphocytes remain at the site of activation to perform their effector function
False: Once activated, lymphocytes leave the GALT and drain to mesenteric lymph nodes, reenter circulation and REDISTRIBUTES throughout GALT
T/F: The production of antibodies during the secondary immune response is delayed.
False: Rise in Ab levels upon reinfection after primary immune response is immediate
T/F: Type O can receive any blood type
False: Can only receive Type O because it has anti-A and anti-B antibodies already
T/F T cell receptors undergo the same diversity as B cell
False: T cells undergo somatic recombo only B cells do somatic recombo and somatic hypermutation
Low dose
Favors activation of IL-4 producing CD4 T cells
What part of the Ig molecule is responsible for the effector function of the antibody?
Fc
FcgammaRI
Fc receptor specific for IgG and is constitutively expressed by monocytes, macrophages, and dendritic cells. Binds with high affinity, stimulating the internalization and destruction of antigen:antibody complexes. It binds most strongly to IgG3. Can bind IgG3 in the absence of antigen but still is not activated until antigen binds.
Mast cells
Fc-epsilon-RI receptors and cytoplasmic granules are constitutive
Functions of IgM
First Ab High avidity Classical complement pathway activation: early on Cannot move easily through blood and tissues though: bulky
IgM
First antibody produced in any antibody response. Pentameric. 10 antigen-binding sites. Quickly activates the complement cascade by the classical pathway. It's bulk limits the extent to which this antibody isotype can passively leave the blood and penetrate infected tissue.
Explain the mechanism of evasion for EBV
First exposure causes acute infection of B lymphocytes (mono) Infection cleared by CD8 T cells that kill infected B cells Not all infected B cells killed=latency Malignant transformation of these cells causes B-cell lymphoma
What can IgG do?
Fix complement; only two have to bind to activate complement pathways
What organizes B-cells into Primary Follicles?
Follicular Dendritic Cells
Histamine
Formed by decarboxylation of histidine amino acid. Accounts for 10% of granule weight. Binds to one of the four possible histamine receptors (H1-H4)
IgG
From IgM by isotype switching. Dominant blood borne antibody. Actively transported from the blood into the extracellular spaces within the tissue.
Blood Monocyte functions
Functions: Phagocytosis Killing Chemotaxis Respiratory burst Antigen presentation Cytokine production Co-stimulation
What are four examples of mucosal surfaces?
GI tract Respiratory tract Urogenital tract Certain exocrine glands
what disease can help engraftment and prevent relapse of malignant disease?
GVHD
Belatacept
Generic name given to an immunosuppressive drug that was approved for use in transplantation in 2011. It targets the co-stimulation of T cells and is a synthetic fusion protein that consists of the extracellular B7-domains of the CTLA4 with the Fc fragment of IgG1. Alloreactive T-cell receptor binds foreign MHC and generates signal 1. Belatacept binds B7 and prevents engagement of CD28 and generation of signal 2. The interaction prevents the CD28 receptors of alloreactive T cells from binding to B7 and generating the co-stimulatory signal necessary for their activation. Belatacept as measured by graft survival, is the best of the older, established drugs and is better than the others in preserving kidney function. Belatacept is associated with increases incidence of episodes of acute rejection.
Antigenic Variation
Genetic variation prevents effective long-term immunity
Genetic variation within some species of pathogens prevents what?
Genetic variation within some species of pathogens prevents long-term immunity. Antibodies directed against macromolecules on the surface of pathogens are the most important source of long-term protective immunity to many infectious diseases. Some species of pathogen evade such protection by existing as numerous different strains, which differ in the antigenic macromolecules on the outer surface. S. pneumonaie have over 90 serotypes
what opened up new avenue for making vaccines?
Genome sequencing of human pathogens
What is mucin?
Glycoprotein Protein core with covalently linked carbs coming off Disulfide bonds between mucin molecules
What is mucus made of?
Glycoproteins, proteoglycans, peptides, enzymes, ions and lots of water
Failure to reconstitute immunity for bone marrow transplants may occur if...
Graft does not share at least one MHC I and one MHC II alleles with host Will not be able to respond to infections of self cells
Name the diseases mediated by antibodies against cell-surface receptors
Graves' disease Myasthenia gravis Insulin-resistant diabetes Hypoglycemia
What viruses on the "wish list?"
HIV Hep C Common cold Rotavirus was but now have a vax for it
What is the purpose of integrase?
HIV enzyme used to incorporate cDNA into host genome Then host machinery produces viral proteins
What is the most important genetic component of autoimmune diseases?
HLA (Human leukocyte antigen)
What is the dominant genetic factor affecting susceptibility to autoimmune disease
HLA HLA genes account for 50% of the genetic predisposition to autoimmune conditions.
Which HLA class are more likely to be associated with autoimmune diseases
HLA Class II So CD4 T cells are inherently more likely to lose tolerance to a self antigen than are CD8 T cells.
Liver transplants
HLA matching does not seem to effect transplantation. ABO type is the only genetic factor affecting donor selection. They do use cyclosporin and tacrolimus.
What is the most important matching for hematopoietic cell transplantation
HLA matching of donor and recipient is the most important matching for hematopoietic cell transplantation. To some extent, almost all patients receiving a hematopoietic cell transplant suffer from GVHD. The severity of GVHD correlates strongly with the extent of HLA mismatch
HLA-DR5
HLA-DR5 patients make antibodies against the spliceosome, a nuclear ribonucleoprotein complex.
What happens when CD4 T cell count drops to <200 per microliter?
Have AIDS
Where is IgG found in the body?
Heart and extracellular fluid
What do basophils do?
Help start the TH2 response Drive isotype switching to IgE
hematogglutinin
Hemagglutination can be used to identify RBC surface antigens (with known antibodies) or to screen for antibodies (with RBCs with known surface antigens).
A primary immune response against influenza virus produces antibodies that bind to _____________.
Hemaglutinin and neuraminidase
Hematopoietic cell transplantation can induce tolerance of what?
Hematopoietic cell transplantation can induce tolerance of solid organ transplant
Which virus can be cleared by 30% of the population effectively but causes a chronic infection in 70%?
Hep C!
Example of Subunit Vaccine
Hepatitis B vaccine is a surface antigen with which most anti-Hepatitis B antibodies react (protects 85% of people)
Explain the mechanism of evasion for herpes simplex virus
Hides Latent: does not replicate enough to produce peptide that trigger immunity Hide in neurons: neurons don't have a lot of MHC I
What two isotypes are used to neutralize microbial toxins and animal venoms?
High-affinity IgG and IgA. High-affinity IgG is the main source of neutralizing antibodies for the tissures of the human body, whereas high-affinity IgA dimers serve a similar purpose at mucosal surfaces.
neutralizing antibodies
High-affinity antibodies that bind to the microbial ligand and prevent the microbe's attachment to human epithelium and stop the infection before it starts. Because many infections start at mucosal surfaces, neutralizing antibodies are often dimeric IgA.
How antibodies against desmolgein cause skin blistering
IN the early phase, antibodies are made against epitopes of the EC5 domain. These epitopes are not accessible to antibody in functional membrane-associated desmoglein, but the antibodies can bind to soluble degradation products of desmoglein. Soluble immune complexes of antibody desmoglein are bound and processed by B cells specific for epitopes of the EC1 and EC2 domains. This causes epitope spreading in the later phase of the autoimmune response and the synthesis of high-affinity IgG4 antibodies specific for the EC1 and EC2 epitopes. These epitopes of membrane-associated desmoglein are accessible to antibody, which interfered with the physiological adhesive interactions of desmoglein that are necessary for maintaining skin integrity. Consequently, the antibodies cause the outer layers of the skin to separate, giving blisters.
Homing of effector T cells to the gut is controlled by what?
Homing of effector T cells to the gut is controlled by adhesion molecules and chemokines. Antigen-activated T cells in mucosal lymphoid tissue become effector cells that leave in the lymph and them populate mucosal tissue from the blood. This homin is mediated by integrin alpha4:beta7 on the effector T-cell binding to blood vessel MAdCAM-1 (left panel). In the lamina propria T cells are guided by chemokine CCL25, which is made by the CCR9 receptor on the T cells. Interaction with the gut epithelium is enhanced by T-cell integrin alphaE:beta7 binding to epithelial cell E-cadherin.
HIV-AIDS
Host-pathogen interaction that combines immune evasion and immunodeficiency
What do the cytokines made by helper T cells (TFH cells) determine?
How B cells switch their immunoglobin isotype. They switch their heavy chain isotype to produce IgG, IgA, or IgE. The type of infection determines what cytokine is released by the TFH cell.
Most tissue specific antigens are not presented by APC's and are not , therefore, on cells that express B7 co-stimulatory molecules (induces anergy).
However, perhaps dead or infected cells are taken up by APC's, which present self-antigens and activate effector T cells
How are viruses attenuated?
Human virus is used to infect monkey cells Acquires mutations that help it grow in monkey cells Now it can't grow well in human cells anymore
hyperacute rejection
Hyperacute rejection is a type II hypersensitivity reaction caused by preexisting antibodies binding to the graft. Because HLA class I molecules are expressed constitutively on vascular endothelium, preexisting antibodies against HLA class I variants can also cause hyperacute rejection.
Allogenic transplantation can trigger what?
Hypersensitivty reaction
IFN-gamma
IFN-gamma is the major cytokine that activates macrophages, and is made by NK cells during the innate immune response and by TH1 CD4 T cells and CD8 cytotoxic T cells during the adaptive immune response. When IFN-gamma binds to IFN-gamma receptors on a macrophage surface, the cell is induced to make changes in gene expression and become better at engulfing and killing bacteria.
Primary pathologies caused by massive production and release of numerous cytokines:
IL-1 IL-2 TNF-α
DCs acquire antigens from M cells leading to
IL-10 production
What antibody is constantly made against commensal pathogens?
IgA (they must not breach the epithelial barrier)
IgE-mediated immune responses defend the body against what?
IgE-mediated immune responses defend the body against multicellular parasites. (helminth worms)
Which isotype is transported across the placenta and delivered directly into the fetal blood stream during pregnancy?
IgG
How does IgG pass from mother to child? IgA?
IgG - Fetal Circulation IgA - Breast Milk
What two isotypes can activate complementation
IgG and IgM
Autoimmune hemolytic anemia
IgG and IgM antibodies bind to components of the erythrocyte surface, where they activate complement by the classical pathway. This leads to assembly of the membrane-attack complex and hemolysis--the lysis of red blood cells. Alternatively, erythrocytes coated with antibody and C3b are cleared from the circulation, principally by the Fc and complement receptors of phagocytes in the spleen. These mechanisms induce a deficiency in red blood cells.
Il-4 induces
IgG1 IgE
TGF-β induces
IgG2b IgA
IFN-γ induces
IgG3 IgG2a
IFN-γ inhibits
IgM IgG1 IgE
TGF-β inhibits
IgM IgG3
IL-4 inhibits
IgM IgG3 IgG2a
B cells activate which type of immunoglobulins in mucosal tissue?
IgM and IgA; IgM is first and undergoes affinity maturation and Isotype switching
What are the most effective antibodies at activating complement?
IgM and IgG3
Rheumatoid factor
IgM antibody with specificity for human IgG that is produced in some people with Rheumatoid arthritis.
Which Ig type can compensate for deficiency is which other Ig type?
IgM can compensate for IgA deficiency Pretty common to be IgA deficient
What is the first antibody to be produced during an antibody response?
IgM is the first antibody produced. It is secreted as a pentamer by plasma cells in the bone marrow, the spleen, and the medullary cords of lymph nodes.
Getting processed Ag to lymph node
Immature dendritic cells grab and process Ag found at site of infection Process and load onto peptide: MHC complex Carry to draining lymph node
What causes Type III reactions?
Immune Complex
Deficiency of complement C1, C2, C4
Immune-complex disease
alemtuzumad or anti-CD52
Immunosuppresive drug used before transplantation. humanized rat monoclonal IgG that is specific for CD52. CD52 is expressed on almost all lymphocytes, monocytes, and macrophages, and anti-CD52 antibodies induce a profound, long-lasting lymphopenia. THe cell-surface complex of CD52 and anti-CD52 is unusually efficient in fixing complement.
Prednisone
Immunosuppresive drug used before transplantation. immunosuppressive drug most extensively used in organ transplantation, is a synthetic derivative of hydrocortisone, the principal steroid made by the adrenal cortex. This is a pro-drug. Prednisone has no immunosuppresive activity until it is enzymatically converted in vivo to prednisolone.
rabbit antithymocyte globulin (rATG)
Immunosuppresive drug used before transplantation. polyclonal mixture of high-affinity antibodies that binds to T cells, B cells, NK cells, and dendritic cells, as well as to endothelial cells. The bound rabbit IgG fixes human complement well and delivers the leukocytes to be killed by phagocytes.
Treatment for Myasthenia gravis
Immunosuppressive drug combined with plasmaphoresis
How to prevent acute rejection of solid organ transplant?
Immunosuppressives before and after surgery HLA matching
Best scenario for Cancer Therapy
Kill all the tumor cells without destroy others in the body
Result of hygiene hypothesis
In childhood the development of the immune system is held back. It becomes poorly educated, exercised, and inexperienced in fighting real world infections. It turns to fighting imaginary infections and in the process causes a range of debilitating allergic diseases.
graft-versus-host leukemia (GVL) effect or graft-versus-tumor (GVT) effect
In hematopoietic cell transplantation as therapy for leukemia, some degree of genetic incompatibility between donor and recipient is thought to help T cells or NK cells from the transplant to eliminate residual leukemia cells in the recipient.
After undergoing somatic hypermutation, centrocytes with high-affinity receptors for antigen are rescued for apoptosis. Explain
In the germinal center, TFH cells induce dividing centroblasts to undergo somatic hypermutation. The centrocytes expressing mutant IgM then test their B-cell receptors against the intact antigens displayed by the FDCs. Centrocytes whose B-cell receptors have acquired mutations that reduce the affinity are induced to die by apoptosis. Centrocytes with receptors having superior affinity for antigen are induced to express Bcl-XL, an intracellular protein that prevents apoptosis and ensures the cell's survival. These centrocytes go on to become plasma cells.
IN the latter stages of allergic reactions, what are principally responsible for inflammation, smooth muscle contraction, the constriction of airways and the secretion of mucus from mucosal epithelium.
In the latter stages of allergic reactions, leukotrienes are principally responsible for inflammation, smooth muscle contraction, the constriction of airways and the secretion of mucus from mucosal epithelium.
Mechanism of Blood monocytes arriving to intestine
In the presence of TGF-b, blood monocytes that arrive to the intestine differentiate into intestinal macrophages by losing their inflammatory potential
In primary immune response, IgM usually switches to what?
In the primary response to an antigen, IgM is first switched to IgG or IgE. the majority of responding B cells switch to IgGq and the minority switch to IgE. The IgE switched B cells quickly leave the germinal center to become plasma cells, and so the IgE they make at this early stage in the immune response has few or no somatic mutations and low or undetectable affinity for antigen.
In the secondary immune response, which B cells are activated and which are inhibited?
In the secondary immune response, memory B cells are activated and naive B cells are inhibited. To ensure that low-affinity IgM are not made in the secondary response, the activation of naive pathogen specific B cells is suppressed.
What are the side effects of auto-immune drugs?
Increased risk of developing opportunistic infections or re-emergence of contained infections
What is causes Chronic Rejection?
Indirect pathway of allorecognition - usually involves alloantibodies
Passive immunization
Individual acquires immunity through the transfer of antibodies formed by immune individual or animal
HLA polymorphisms influence the progression to AIDS
Individuals with HLA-B*27 and HLA-B*57 show slow progression to AIDS. These allotypes stimulate stronger CD8 T-cell responses to HIV-infected cells
T cell cytokines
Induction or inhibition of isotypes
What type of vaccine is used for influenza?
Killed/inactivated virus vaccine
What is the major threat to patients lacking antibodies?
Infection by pyogenic (pus forming) bacteria. These encapsulated bacteria, which include H. influenzae, S. pneumoniae, S. pyogenes, and S. aureus, are not recognized by the phagocytic receptors of macrophages and neutrophils, so they frequently escape immediate elimination by the innate immune response. Such infections are usually cleared when the bacteria are opsonized by specific antibody and complement and then taken up and killed by phagocytes. For patients lacking antibodies, infections with pyogenic bacteria tend to persist unless treated with antibiotics.
What immune mechanism is definitely not an aspect of mucosal immunity?
Inflammation (No complement)
Multiple Sclerosis
Inflammatory chronic demyelinating disease of the CNS
What does TNF-alpha do?
Inflammatory cytokine released by mast cell activation Endothelium becomes sticky and leaky
Mechanism of elimination
Inflammatory mediators promote physical removal. Constriction of smooth muscle. Increased blood vessel permeability
What does a doctor do if someone is bitten by a poisonous snake?
Infuse them with antibodies specific for the venom. These antibodies were produced by immunizing large domestic animals with the venom. This is a form of passive immunity.
Consequence of Myasthenia gravis
Inhibit function due to AChR receptor degradation on muscle
Graft rejection
Instead of fighting off a pathogen the immune system is trying to rid the body of foreign antigens (mainly MHC molecules)
How do intestinal epithelial cells contribute to the innate immune responses in the gut?
Intestinal epithelial cells have Toll-like receptors on their apical and basolateral surfaces which recognize flagellin, the protein from which bacterial flagella are constructed. Toll-like receptors on the apical surface allow the cells to sense bacteria that overcome the defenses of the mucus and reach the epithelium; those on the basolateral surface sense invading bacteria that penetrate the epithelium. The cytoplasm of the epithelium contain NOD1 and NOD2 receptors, which detect the components of bacterial cell walls. Signals generated from NOD and toll like receptors lead to activation of NFkB and formation of the inflammasome by NOD-like receptor P3. These events lead to the production and secretion of antimicrobial peptides, chemokines, and cytokines such as Il-1 and IL-6 by the epithelial cells. The defensins kill the bactera and chemokine attract neutrophils, monocytes, and eosinophils, T cells, and immature dendritic cells from the blood.
What type of vaccine is used for rabies?
Killed/inactivated virus vaccine
Characteristics of Central memory cells (Tcm)
L-selectin positive CCR-7 positive Circulate in lymphoid organs Stem-cell-like; can be activated by antigen and cytokines
Characteristics of Effector memory cells (Tem)
L-selectin-negative CCR-7 negative Circulate in non-lymphoid tissues Already differentiated; have high levels of effector molecules
What is cross linking (clustering)
Many copies of the same transmembrane receptor on the surface of B cell. They diffuse laterally across membrane and congregate to one spot on membrane to bind to antigen multiple times.
Intestinal macrophages eliminate pathogens without creating a state of what?
Intestinal macrophages eliminate pathogens without creating a state of inflammation. Intestinal macrophages do not respond to infection by secreting inflammatory cytokines. They lack B7 co-stimulators and also the capacity to make cytokines needed to activate and expand naive T cells: IL-1, IL-10, IL-12, IL-21, IL-22, and IL-23. In short, the intestinal macrophage is not a professional antigen presenting cell and cannot initiate adaptive immune responses. Neither are intestinal macrophages the instigators of inflammation like their counterparts in non-mucosal tissues, but they can fully perform their role of (1) recognizing microorganisms and (2) killing them in an environment free of inflammation. Because of these qualities, some immunologists describe the intestinal macrophage as "inflammation-anergic" macrophages. They also prevent expression of a subset of cell-surface receptors and adhesion molecules that are used by macrophages in systemic immunity to generate inflammation, including Fc receptors for IgA, and IgG, the bacterial LPS receptor, complement receptors, IL-2 and IL-3 receptors, and LFA-1. Another method is modification of the signals sent by the cell-surface receptors of intestinal macrophages, for example TLR1 and TLR3-TLR9. This is achieved in various ways that all fail to activate NFkB. Under the influence of TGF-beta and other cytokines made by intestinal epithelium, stromal cells, and mast cell; the monocytes will differentiate into intestinal macrophages by losing their inflammatory potential
Crossing linking causes what type of signaling?
Intracellular signal cascades Phosphorylation of cytoplasmic tails of Ig-alpha and Ig-beta->intracellular signal cascade that alters gene expression in nucleus
Problem with polysaccharide capsule vaccines?
Invokes feeble T-cell independent B-cell response Need to conjugate to an immunogenic protein to illicit a T-cell response
What occurs to B cells in the germinal center?
Isotype switching and affinity maturation (somatic hypermutation)
Comparison of the diversity of parasite-specific or allergen-specific antigen receptors on a B cell and a mast cell
Isotype-switched B cells are programmed to make one type of IgE molecule that is specific for a single antigen or allergen. In contrast, a mast cell passively acquire IgE molecules with different specificities and made by different B cells, which bind to the cell-surface Fc receptor for IgE, FcEpsilon RI. A mast cell displays around half a million FcEpsilonRI molecules on its surface and so can be armed with a variety of different IgEs at high density. By comparison, a B cell has only 50,000-100,000 B-cell receptors.
In the absence of microbiota, what happens to the immune system?
It develops abnormally. Enlarged cecum Longer small intestine Underdeveloped mesenteric lymph nodes Underdeveloped Peyer's patches Fewer isolated lymphoid follicles Smaller spleen Reduction in secretory IgA and serum immunoglobulin Reduction in systemic T-cell numbers and in their activation Reduces cytotoxicity of CD8 T cells Impaired lymphocyte homing to inflammatory sites Reduced numbers of lymphocytes in mucosal tissues Impaired responses of Th17 CD4 T cells Reduced ability of neutrophils to kill bacteria
What happens in the Peyer's Patch?
It produces effector cells that travel in the lymph and blood to gain access to the lamina propria of mucosal tissue
Opportunistic Malignancies
Kaposi's sarcoma Non-Hodgkins lymphoma EBV-positive Burkitt's lymphoma Primary lymphoma of the brain
How do super-antigens lead to immune evasion?
Leads to overstimulated immune response Generalized, non-specific that does little to nothing to clear pathogen Also exhausts the T cells to lead to apoptosis
Peripheral Tolerance
Limit the activation of mature self-reactive T cells/B cells that exited the central organs. Lymphocytes may be tolerized by clonal deletion, anergy or immunological ignorance
Which type of virus vaccines illicit the strongest response?
Live-attenuated Can get into epithelial cells and replicate, then can infect other cells: better widespread immunity
What type of vaccine is used for yellow fever?
Live-attenuated vaccine
How are low-levels of pathogen-specific Ab maintained over long periods of time?
Long-lived plasma cells that continuously synthesize Ab for years. Maintains a constant level of Ab (see graph)
Practical considerations
Low cost per dose Biological stability Ease of administration Few side-effects
How are low levels of pathogen-specific antibodies maintained?
Low levels of pathogen-specific antibodies are maintained by long-lived plasma cells. Survival of these plasma cells is sustained by interactions with bone-marrow stromal cells and with IL-6 secreted by the stromal cells.
Chemical innate defenses of Gut
Low pH Enzymes Antibacterial peptides
Besides T cells, which other cells can HIV bind to?
Macrophages and dendritic cells because they also have CD4
Functions of IgG
Major protein component of blood Can have affinity that exceeds avidity of IgM Taken from blood to endothelial side: receptors recognize Fc portion Can do classical complement pathway but need more than 1
Transcytosis
M cells capture bacteria from the gut lumen and deliver them and their antigens to dendritic cells and lymphocytes in the Peyer's patch. Leads to production of bacteria-specific effector T cells, and plasma cells making bacteria-specific secretory antibodies.
When tissues become inflamed, cells are induced to increase the expression of what?
MHC class I and II molecules. These changes, which increase the number of different peptide antigens presented by a cell and their density on the cell surface, can lead to interactions with clones of T cells that were not sensitive to the lower levels of antigen presentation. The greatest changes occur when the inflammatory cytokine IFN-gamma induces MHC class II expression in cells that normally do not express these MHC molecules. Such cells, which include thyroid cells, pancreatic Beta cells, astrocytes, and microglia, are conspicuously present in the tissues targeted by autoimmunity.
How are mast cells activated?
Mast cell activation occurs in the presence of any antigen that can cross-link the IgE molecule bound to a FcERI at the cell surface. This can occur by antigens with repetitive epitoped that cross-link IgE molecules of the same specificity, or by antigens possessing two or more different epitopes that cross-link IgE molecules of different specificities. Once a mast cell's receptors have been cross-linked, degranulation occurs within a few seconds, releasing the stored mediators into the immediate extracellular environment.
Where is IgE found in the body?
Mast cells (connective tissue beneath epithelium, particularly in the skin)
Where are mast cells found vs where are eosinophils found?
Mast cells are tissue residents Eosinophils are summoned to the site of infection by mast cells: residents of connective tissue under epithelia
What type of antibodies protects children after birth?
Maternal dimeric IgA (from breast milk)
Where are IgM first made?
Medulla
Where are initial IgM secreting B cells expanded? (Primary focus)
Medullary cords Plasma cells for IgM
IgG biases the activation of what type of B cell?
Memory B cell Good for pathogens that have constant Ag: i.e measles (not influenza)
Why are naive B cells given a negative signal by IgG molecules during the secondary response?
Memory B cells are already antigen-specific. Quicker response to pathogen: differentiate into plasma cells faster than naive B cells could More efficient interaction with T cells Smaller pool of pathogen required to induce B cell response
How are naive and memory B cells distinguished?
Memory B cells have immunoglobin genes and cell-surface immunoglobin that have been altered by isotype switching and somatic hypermutation. They have surface immunolglobin and do not secrete antibody. They express CD27, which distinguished them from naive and effector B cells.
What is considered the largest connection of lymph nodes in the body?
Mesenteric (GI draining lymph nodes)
Microbiome
Microorganisms that have co-evolved with the human
What happens if a B cell does not encounter its antigen in the T cell zone?
Migrate outward to B cell zone of cortex
What is the name of the condition in which IgG molecules complex?
Mixed essential cryoglobulinemia Auto Ab's have specificity for the Fc region of IgG Rheumatoid factor
Features of inhaled allergens that promote priming of the Th2 cells that drive the IgE response
Molecular type Function Low dose Low molecular mass High solubility High stability Contains peptides that bind host MHC class II
What is used to treat Rheumatoid arthritis?
Monoclonal antibodies that target TNF-alpha and B cells are used to treat rheumatoid arthritis
Where is IgA found in the body?
Monomeric: Heart and extracellular fluid Dimeric: Secretions of mucosal epithelium (GI tract and lungs)
Why does antigenic shift occur?
Recombination with the genome of a different species Drastic changes to epitopes: existing Ab are not effective at all anymore
Explain how pregnancy is a natural situation that leads to the production of anti-HLA antibodies
Mother and father usually differ in HLA class I and class II type. During gestation, cells of the fetus and fetal circulation are not exposed to cells of the maternal adaptive immune system. The trauma of birth exposes the maternal circulation to fetal cells and stimulates the production of antibodies against paternal HLA. The presence of anti-HLA antibodies in the maternal circulation has no detrimental effect on subsequent pregnancies, but will complicate any future search for a compatible organ transplant should one be needed.
Examples of pathogens that subvert the immune system
Mycobacterium TB Treponema pallidum (syphilis) Viruses Staphylococcal enterotoxin and TSS toxin-1
Bacterial infections
Mycobacterium tuberculosis Mycobacterium avium intracellulare Salmonella species
Examples of Conjugate Vaccines
N. meningitides vaccines
Getting B cells to lymph node
Naive B cells enter via lymph or blood stream (HEV's) Attracted by chemokine gradients to T cell zone
Naive lymphocytes activated in a Peyer's patch give rise to effector cells that do what?
Naive lymphocytes activated in a Peyer's patch give rise to effector cells that travel in the lymph and blood to gain access to the lamina propria of the mucosal tissue. Pathogens from the intestinal lumen enter a Peyer's patch through an M cell and are taken up and processed by dendritic cells. Naïve T cells (green) and B cells (yellow) enter the Peyer's patch from the blood at a high enothelial venule (HEV). The naïve lymphocyte are activated by antigen, whereupon they divide and differentiate into effector cells (blue). The effector cells leave the Peyer's patch in the lymph, and after passing through mesenteric lymph nodes they reach the blood, by which they travel back to the mucosal tissue where they were first activated. The effector cells leave the blood and enter the lamina propria and the epithelium, where they perform their functions: killing and cytokine secretion for effector T cells, and secreting IgA for plasma cells.
What sometimes forms at sites inflamed by autoimmune disease
Organized lymphoid tissue sometimes forms at sites inflamed by autoimmune disease.
DNA Viruses facilitate progression to cancer
Papillomavirus Hepatitis B virus Epstein-Barr virus
Helminth
Parasitic worms that live and reproduce in the intestines
centroblasts
Part of a primary follicle in the lymph node formed wherelarge dividing B cell present in germinal centers. somatic hypermutation occurs in these cells, and antibody secreting and memory B cells derive from them. B cells and T cells will divide and bind via CD40 CD40 ligand
germinal Center
Part of the secondary follicle formed by the expanding population of antigen-specific cells (B lymphoblast with the TFH cell), and this is where the B cells undergo affinity maturation and isotype switching of their antibodies
Superantigens
Pathogen derived antigens that sabotage the immune response
Why do we use bacterial toxin vaccines?
Pathogenicity of bac due to toxins Block toxin=block disease Neutralizing Ab bind to toxin and prevent it from binding to cellular target
patients needing a transplant outnumber the available organs
Patients who are eligible for a transplant have to wait 2-3 years on average in the US States before they receive the transplant.
What autoimmune disease targets epidermal cadherin?
Pemphigus Vulgaris Type II Blistering of the skin
B cells activated in mucosal tissue give rise to plasma cells secreting what at mucosal surfaces?
Pentameric IgM and dimeric IgA. Some effector B cells settle in the lamina propria, where they complete their differentiation into plasma cells that make pentameric IgM molecule and secrete it into the subepithelial space. By transcytosis, the poly-Ig receptor carries the antibody from the basal side to the luminal side of the cell, where IgM is released and bound by the musuc. This transport mechanism for secretory IgM is the same as that used for secretory IgA. The others remain in the B cell area of the gut-associated lymphoid tissue, where they undergo affinity maturation and isotype switching. The switch is usually to IgA isotype, the dominant class of immunoglobulins in mucosal secretions.
What does it mean if someone has a positive blood type?
Person has the RhD transmembrane protein present on their RBC
Examples of adjuvants?
Pertussis of DTP Alum TLR agonists
What are the secondary lymphoid organs of the intestine?
Peyers Patches and ILFs
Fc region on IgG also interacts with...
Phagocytic cells: opsonizes pathogens (like C3b) NK cells
Intestinal Macrophage functions
Phagocytosis Killing ** No activation of T cells; lack ability to regulate co-stimulation
3 barriers to infection
Physical Chemical Microbiological
rheumatoid factor (RF)
Plasma cells make (antibodies) IgM, IgG, and IgA that binds to the Fc region of patient's own IgG
Effect of toxic mediators
Poison parasites. Increase vascular permeability. Cause smooth muscle contraction.
What is an example of something that causes a Type 1 response?
Pollen
What is a hyperacute rejection of solid organ transplants?
Pre-existing recipient antibodies bind to transplant and cause complement deposition->inflammation Blood vessels in donor organ come from donor and have donor MHC I: destroys blood vessels in organ Immediate: before surgery is even finished
Extrinsically regulated
Regulation by: - Limited survival factors (BAFF, IL-7) - Limiting costimuli (CD40L, TLR ligands, B7 molecules) - Active suppression - LImiting innate inflammatory mechanisms
C1 inhibitor (C1INH)
Regulatory protein in plasma that inhibits the enzyme activity of activated complement component C1. C1INH deficiency causes the disease hereditary angiodema, in which spontaneous complement activation causes episodes of epiglottal swelling and other symptoms.
What is transplant rejection?
Recipient's immune system attacks transplanted tissue
Chronic rejection
Rejection of organ grafts that occurs years after transplantation and is characterized by degeneration and occlusion of the blood vessels in the graft. Reactions in the vasculature of the graft that cause thickening of the cessel walls and a narrowing of their lumens. Caused by complexes of HLA molecules and anti-HLA antibodies that deposit in the blood vessels of the organ transplant. Chronic rejection is a type III hypersensitivity reaction caused by IgG antibodies made against the allogenic HLA class I molecules of the graft, forming immune complexes that deposit in the blood vessels of the transplanted kidneys. The antibody rituximab is used to treat chronic rejection.
Acute rejection
Rejection of trasnplanted cells, tissues, or organs from a genetically dissimilar donor that is due to a T-cell response stimulated by the 'foreign' HLA antigens on the transplant. Type IV Hypersensitivity. Takes several days to develop To prevent acute rejection, all transplant patients are conditioned with immunosuppresive drugs before transplantation and maintained on them after transplantation.
What causes swelling ?
Release of histamine by mast cells in skin
Which autoimmune drugs are monoclonal Ab?
Remicade=chimeric Humira=fully human Rituxan=chimeric
Effect of mast cell enzymes
Remodel connective tissue matrix
Why does antigenic drift occur?
Replication of genome is error-prone Small changes in epitopes make existing Ab no longer as effective
What does HIV look like?
Retrovirus Center is RNA and protein Surrounded by lipid envelope from host that also has viral proteins
Why does HIV have a high mutation rate?
Reverse transcriptase is an error-prone enzyme
How does Rituxan work?
Rituximab: Anti-CD20 agent Binds CD20 found on all B cells->leads to removal of B cells from circulation
Rotavirus Vaccination Story
Rotarix- an attenuated human rotavirus having common VP4 and VP7 variants RotaTeq vaccine- mixture of 5 cattle rotaviruses that are nonpathogenic for humans but each has been engineered to express a different human VP4 or VP7 glycoprotein
What virus took at least 30 years of research and development to make a vaccine?
Rotavirus.
Type III hypersenstivity
Rxn against therapeutic mAbs
How does systemic immune response occur?
Short violent episodes of localized and intense inflammation to stop sporadic infections of non-mucosal tissues
What is SLE?
System lupus erythematosus Type III Complexes with cellular components that contain nucleic acids Causes butterfly rash: vasculitis (glomerulitis and arthritis too)
Why does asphyxiation occur during type I reactions?
Systemic anaphylaxis Airway constriction and tissue edema of epiglottis
Where do T cells congregate
T cell zone Deep cortex of lymph node where the HEV's are located
TFH cells
T follicular helper cells-- effector CD4 T cell present in lymphoid follicles that cooperates with B cells to help antibody production
Adenosine deaminase (ADA) deficiency
T, B and NK deficiency due to toxicity of accumlated metabolites. First successful gene therapy done in patient
T-cell activation can be targeted by what?
T-cell activation can be targeted by immunosuppressive drugs. (The immunosuppresive drugs inhibit T-cell activation) x Drugs that use this strategy: 1. Cyclosporin 2. Tacrolimus
What is significant about IgM and IgA that allows it to bind to mucin polypeptide?
The heavy chains have cysteine residues on the C terminal region and can form disulfide bonds with mucin polypeptides
Tfh Cells help antigen activated B cells through cell-surface interactions between what?
TFH Cells help antigen activated B cells through cell-surface interactions between CD40 ligand of the TFH cell and the CD40 protein of the B cell. They form a conjugate pain. Cytokines are secreted into the narrow space between the TFH cell and the B cell. This cognate pairs activates NFkappaBeta which activates transcription of ICAM-1, which engages integrin LFA-1 on the T cell. LFA-1 and ICAM-1 bind. This strengthens the cognate interation and this 'synapse' forms where the cytokines from the T cell are released.
What factors enhance switching to the IgA isotype?
TGF-beta 1. iNOS: produced by dendritic cells and induces 2. expression of the B cells TGF-beta receptor 3. vitamin A derivative retinoic acid 4. IL-4, IL-10 5. B-cell activating factor (BAFF) 6. a proliferation-inducing ligand (APRIL) Mneumonics: APRIL is BAFFled when she doesn't get an (Ig)A
What allows for expression of FC-epsilon-R1 on eosinophils?
TH2 response: cytokines and chemokines Resting eosinophils do not express FC-epsilon-R1
Intestinal epithelial cells express
TLRs NOD 1-2 receptors NFkB activation Activation of the inflammasome Cytokine secretion, IL-6, IL-1
How are naive B cells suppressed during secondary immune responses
TO ensure that low-affinity IgM are not made in the secondary response, the activation of naive pathogen specific B cells is suppressed. This suppression is mediated by immune complexes composed of the pathogen of its antigens bound to antibodies made by the B cells activated in the primary response. These complexes bind to the B-cell receptor of pathogen-specific naive B cells and also to the inhibitory Fc receptor, FcgammaRIIBI, which is expressed by naive B cells but not by memory B cells. This cross linking of the B cell receptor and the Fc receptor delivers a negative signal that inhibits the activation of the pathogen-specific naive B cell and induces its death by apoptosis.
Which hypersensitivity reaction is the tuberculin test an example of?
Type 4 Memory T cells go to site of intradermal injection if been exposed to pathogen
What is "delayed type hypersensitivity?"
Type 4 Reaction happens 1-3 days after exposure T cell response
What happens if a pregnant woman has Graves' disease?
Temporary symptoms of antibody-mediated autoimmune diseases can be passed from the affected mothers to their newborn babies. The mother has Graves' disease and Graves' opthalmopathy, which causes her eyes to bulge. IgG autoantibodies against the thyroid-stimulating hormone receptor (TSHR) pass from the mother to the fetus in utero and passively give the baby a temporary Graves' disease that disappears with the degradation of maternal IgG in the infant's circulation.
What effector T cell does a naive T cell become when it finds its peptide: MHC?
Tfh CD4 T cell
Immune response against HIV
Th1, Th2, and neutralizing antibodies and CD8 T cells that kill virus-infected cells
Where does the second signal for activation come from?
The B-cells receptor associating with B-cell co-receptor; CR2 on the B-cell co-receptors binds to complement deposited on a pathogen
Explain the RotaTeq and the Rotavirus
The RotaTeq vaccine contains a mixture of 5 cattle rotaviruses that are nonpathogenic for humans, each of which has been engineered to express a different human VP4 or VP7 glycoprotein. Viral coat proteins VP4 and VP7 are the major targets for neutralizing antibodies. Like oral poliovirus vaccine, they can be made without sophisticated biotechnology by simple growth in tissue culture, and they are readily transferable to the poorer countries, where most mortality from rotavirus infection occurs. Rotavirus is a major cause of severe childhood diarrhea.
What determines what type of isotype switching occurs?
The cytokines produced by the TFH cells which in turn is determined by the nature of the infection and the dendritic cell that nurtured the TFH cell
In viral infections, numerous effector CD8 T cells give rise to relatively few memory T cells. How are the memory T cells "chosen"
The effector CD8 T cells express IL-7 receptor. In number that exceed the naive CD8 T cells that contributed to the primary response by 100-1000 fold, ensuring that any future infection with the virus will be met with overwhelming force
How do dendritic cells sample the contents of the intestine?
The extend a process that goes between enterocytes without disturbing any barrier function
What makes the eye particularly good for transplants?
The eye has evolved an immunological environment that suppresses inflammation while maintaining sufficient protection against pathogens. The cornea is transparent and lacks vasculature, while the aqueous humor of the anteror chamber contains immunomodulatory factors that inhibit the activation of T cells, macrophages, neutrophils, and complement. IN particular, the TGF-Beta causes the resident cells to downregulate T-cell co-stimulatory factors such as CD40 and precents the secretion of IL-12.
Bruton's tyrosine kinase (BTK)
The gene that has a defect in the XLA disease. BTK contributes to the intracellular signaling from the B-cell receptor and is necessary for the development and differentiation of pre-B cells.
indirect pathway of allorecognition and chronic rejection
The indirect pathway of allorecognition is responsible for stimulating the production of the anti-HLA antibodies that cause chronic graft rejection. The processing and presentation of allogenic HLA class I by a dendritic cell (DC) of the recipient activates helper CD4 T cells, which in turn activate B cells that have bound and internalized allogenic donor HLA molecules. Cognate interactions lead to the production of an anti-HLA class I antibody. Anti-HLA class II antibodies can be produced similarly. Because activated endothelium expresses both HLA class I and II molecules, antibodies against both classes of HLA molecule can contribute to chronic rejection.
Plasma cells have a distinctive appearance that distinguishes them from all other forms of B cells. Explain it.
The nucleus of a plasma cell has a characteristic 'clock-face' pattern, resembling the hands and face of a clock. Further distinguishing plasma cells from other cells is the extensive RER, a typical feature of cells that synthesize and secrete large quantities of proteins.
Anatomy of the germinal center
The place where activated B cells undergo affinity maturation and isotype switching
SSLP7
The purpose of SSLP7 is to prevent monomeric IgA from delivering the bacterium to phagocytes. In the absence of SSLP7, IgA binds to a bacterium with its Fab arms to FcalphaRI on neutrophils and macrophages with its Fc region. This activates the phagocyte to engulf and destroy the bacterium bound to the Fc receptor. SSLP7 has binding sites for the Fc region of IgA and for the C5 complement protein. These interactions create a large constrained complex in which IgA binding to FcalphaRI and complement mediated killing of the bacterium are both prevented.
What does the survival and proliferation of CD4 and CD8 T cells depend on?
The survival and proliferation of CD4 and CD8 T cells depends on signals from the IL-7 and IL-15 receptors.
What type of response is the inflammation from an insect bite?
Type 4 TH1 CD4 T cells cause inflammation: responds to protein from bite
Another consequence of superantigens
They can deplete the immune system of antigen-reactive T cells, thereby causing an immunosuppressed state
How can highly mutable viruses escape immune response?
They escape immunological memory because the epitopes are slowly changing so they are not recognized until every epitope has changed.
Where do TFH cells go once activated? What do they do?
They move to the boundary region where they look for antigen peptides being presented on MHC II molecules by B cells in the boundary region
What must be true about thymus-independent antigens?
They must be located closely on the bacteria because B-cell receptors must be clustered so that signalling is strong enough
What is the consequence of recombinant viruses arising in pigs?
They were simultaneously infected with avian and human viruses, now these recombinant viruses if jump back to humans can cause severe epidemics/pandemics
Herd Immunity
Those people in a population who have no protective immunity against a pathogen are largely protected from infection when the majority of the population is resistant to the pathogen
Memory B Cells
Those that survive affinity maturation and go on to be longer lived and high affinity receptors
What is the purpose of centroblasts?
To produce large number of Isotype switched and differentiated B-cells
What type of blood is considered to be a universal recipient?
Type AB Does not have any anti-blood group antibodies Tolerant to all antigens (A, B and O): Can accept any blood type
Examples of GALT?
Tonsils in oral cavity Peyer's patches in small intestine Isolated lymphoid follicles Appendix
Toxins and Mucosal Surfaces
Toxins is bound to the gut lumen, secretory IgA can remove the products from the lamina propria, the toxin is then carried into the lumen and removed
Parasitic infections
Toxoplasma species Cryptosporidium species Leismania species Microsporidium species
What other allergy-linked genes are implicated?
Transcription factors and proteins regulating epigenetic modifications
tat
Transcriptional regulator
How do dendritic cells grab Ag from gut?
Transcytosis from M cells "Snorkel" mechanism: extends process up between epithelial cells to grab Ag in the lumen
DImeric IgA transfer to epithelial surface
Transcytosis. Receptor mediated transport of macromolecules across epithelial cells
Transfer of which antibody from mother to child is important allergic disease
Transfer of IgE and antigen from mother to child. During pregnancy, IgE and IgE bound to antigen can be transferred from the mother's circulation to that of the fetus. Antigens can also bind to this maternal IgE in the fetus. Complexes of antigen and IgE are bound by the FCepsilonRII on fetal antigen-specific T cells. This gives rise to TH2 cells that help antigen-specific B cells that have taken antigen to become plasma cells secreting antigen-specific IgE. By this mechanism, the mother could provide fetus with protective immunity against helminths before the baby is born and first exposed to these parasites. Conversely an allergic mother can pass on the allergy to her child.
Allograft
Transplant between genetically different individuals (Daughter to mother kidney transplant)
Isograft
Transplant between two genetically identical individuals (Identical twins give kidney)
Autograft
Transplant from one part of person to different part of the same person (Skin graft for burns)
In what way does organ transplantation involve procedures that inflame the donated organ and the transplanted organ
Transplant recipient organ: -dialysis before transplantation Donated organ: -from a cadaver-- usually died in violent or traumatic way -removal of the organ -transport of the organ -ischemia
Transplant rejection and graft-versus-host disease are what type of sensitivity?
Transplant rejection and graft-versus-host disease are type IV hypersensitivity reactions.
Poly-Ig receptor
Transports both IgM and IgA
What T cell prevents inflammation?
Treg
T/F Effector lymphocytes populate healthy mucosal tissue even when there isn't an infection
True Goal of immune cells in the gut is to contain commensal organisms and pathogens NOT to obliterate them like in the rest of the body's surface
T/F Macrophages do not release cytokines in the gut
True: No inflammatory response Macrophages do secrete cytokines in the rest of the body
Trypanosomes use what to change their surface antigens?
Trypanosomes use gene conversion to change their surface antigens. Trypanosome genome contains more than 1000 genes encoding these variable surface glycoproteins (VSG). At any time, an individual trypanosome produces only one form of VSG. Rearrangement occurs by a process of gene conversion in which the gene in the expression sire is excised and replaced by a copy of a different but homologous gene.
Example of pathogen that continuously alters its surface epitopes?
Trypanosomes: protazoan parasite Gene rearrangement changes cell-surface glycoproteins
Mast cell enzyme products
Tryptase, chymase, cathepsin G, carboxypeptidase
Bacterial diseases caused entirely by the effects of toxic proteins secreted by the bacteria.
Two most important: 1. Diptheria- cause by the diptheria toxin 2. Tetanus- caused by the tetanus toxin To acoid contracitng these diseases, infected individuals need to have supplies of high-affinity neutralizing antibodies that bind irreversibly to the toxin and inhibit its toxic activity. Then, the toxins are neutralized immediately upon secretion, befoer they can influence the behavior of human cells and cause disease. Such vaccines are made by purifying the toxin and treating it with formalin to destroy its toxic activity. The inactivated proteins, called toxoids, retain sufficient antigenic activity to provide protection against disease. Diptheria and tetanus vaccines are thus comparable to the viral subunit vaccines.
Name a T cell mediated autoimmune disease?
Type 1 diabetes T cells destroy pancreatic beta cells Type IV RA and MS too
What type of hypersensitivity reaction could occur during a blood transfusion?
Type 2
What type of hypersensitivity is chronic viral hepatitis associated with?
Type 3 Continuous production of Ag: Ab complexes because virus is not cleared (Same with subacute bacterial endocarditis)
What is serum sickness?
Type 3 reaction Give antibodies from another species to try and cure a disease but causes hypersensitivity reaction if introduced again later
What is myasthenia gravis?
Type II Attack of acetylcholine receptor by Ab: causes degradation of receptors Impaired muscle contraction
What is Goodpasture syndrome?
Type II Autoimmune attack of non-collagenous domain of basement membrane collage type IV Causes glomerulonephritis and pulmonary hemorrhage
What is autoimmune hemolytic anemia?
Type II Destruction of RBC by Ab-mediated complement and phaogcytosis
What type of reaction is a streptoccocal infection considered?
Type II Molecular mimicry Acute rheumatic fever
What type of reaction is Grave's Disease and what is the target?
Type II TSH receptor Overstimulates receptor by Ab
Every autoimmune disease resembles what type of hypersensitivity reaction
Type II, III, or IV hypersensitivity reaction
What type hypersensitivity is chronic asthma classified as?
Type IV
What type of disease is rheumatoid arthritis?
Type IV T cells against joint antigen
What causes MS?
Type IV T cells against myelin protein Causes neurodegeneration and paralysis
Type IV hypersensitivity exhibits what bias?
Type IV hypersensitivity reactions exhibit the bias that the majority are mediated by CD4 TH1 cells and a minority by CD8 T cells
What type of blood is considered to be a universal donor?
Type O Can be given to A, B, AB and O because humans do not make anti-O antibodies
Effector Compartment
Underlying connective tissue called the lamina propria; where the effector cells are
How can you limit ischemia and inflammation with organ transplant
Use an organ from a live person (usually a family member that donates the organ) rather than a cadaver.
Why DTaP?
Uses acellula pertussis component which used a pertussis toxoid
Conjugate Vaccines
Vaccine made from capsular polysaccharides bound to an immunogenic protein such as tetanus toxoid
Subunit vaccine
Vaccines against viruses causing hepatitis A and B have been made using just antigenic viral components
How does TB avoid destruction?
Vesicular infection Wants to be phagocytosed: then prevents lysosome fusion with phagosome
Immunosuppression of host
Virally encoded cytokine homolog of IL-10
Live-attenuated virus vaccines?
Virus can still replicate but is worse at replicating than normal virus (Punch drunk)
Killed/inactivated virus vaccines?
Virus is no longer able to replicate
Which of the four groups of pathogens have evolved the greatest variety of mechanisms for subverting or escaping immune defenses?
Viruses have evolved the greatest variety of mechanisms for subverting or escaping immune defenses. This is because their replication and life cycle depend completely on the metabolic and biosynthetic processes of human cells. Viral self-defense strategies include the capture of cellular genes encoding cytokines, which then expressed by the virus can divert the immune response. The synthesis of proteins that inhibit complement fixation, and the synthesis of proteins that inhibit antigen processing and presentation by MHC class I molecules.
Why are mucosal surfaces a common place for entry of infections?
Vulnerable due to permeability necessary for communications
Oral tolerance
We typically don't make antibodies against degradation products of food. DCs take up antigens, and in presence of IL-10 Tregs develop.
What is the main cause of alloreactions in hematopoietic cell transplantation?
What is the main cause of alloreactions in hematopoietic cell transplantation is mature donor-derived CD4 and CD8 T cells in the transplant that respond to the recipient's HLA allotypes in a graft-versus-host reaction (GVHR). This GVHR is the major cause of morbidity and mortality after hematopoietic cell transplantation. Causes graft0versus-host disease (GVHD), which can attack almost every tissue fo the body.
What is systemic anaphylaxis?
When allergen enters blood stream Widespread mast cell activation Increased vascular perm, smooth muscle contraction
Explain the initiation of the classical pathway of complement by IgM
When soluble pentameric IgM in the 'planar' conformation has established multipoint binding to antigens on a pathogen surface, it adopts the 'staple' conformation and exposes it's binding sites for the C1q component of C1. Activated C1 then cleaves C2 and C4, and the C2a and C4b fragments form the classical C3 covertase on the pathogen surface. Conversion of C3 to C3b leads to the attachment of C3b to the pathogen surface and the recruitment of effector function.
Type of bacterial vaccines?
Whole bacteria, bacterial toxins, capsular polysaccharides
Types of viral vaccines
Whole viruses (Killed/inactivated and live/attenuated) and viral components (subunit vaccines)
Genetic diseases for which bone marrow transplantation is a therapy
Wiskott-Aldrich Fanconi anemia Kostmann syndrome Osteoporesis Ataxia telangiectasia diamond-blackfan syndrome mucocutaneous candidiasis cartilage-hair hypoplasia mucopolysaccharidosis Gaucher's syndrome Thalassemia major sickle-cell anemia
appendix
a distinctive secondary lymphoid organ of the large intestine. It consists of a blind-ended tube about 10cm in length and 0.5cm in diameter that is attached to the cecum. It is packed with lymphoid follicles, and appendicitis results when it is overrun by infection.
minor histocompatibility loci
a gene encoding a protein that can act as a minor histocompatibility agent.
Bacterial superantigens stimulate
a massive but ineffective CD4 T-cell response
commensal
a microorganism that habitually lives on or in the human body; one that normally causes no disease or harm and can be beneficial
Relative Risk
a numerical indicator of "risk", not certainty
hemolytic anemia (disease) of the newborn
a potentially fatal disease caused by maternal IgG antibodies directed toward paternal antigens expressed on fetal red blood cells. The usual target of this response is the Rh blood group antigen. Maternal anti-Rh IgG antibodies cross the placenta to attack the fetal red blood cells. Also called erythroblastosis fetalis.
common gamma chain
a protein chain that is the signaling component component of several cytokine receptors, including those for IL-2, IL-4, IL-7, IL-9, and IL-15. When one of these cytokines bind to its receptor, common gamma chain interacts with the protein kinase Jak3 to produce intracellular signals. In the absenc of gamma chain, none of the 5 cytokines can induce signaling, so SCID results.
poly-Ig receptor (PlgR)
a receptor present on the basolateral membrane of mucosal epithelial cells that binds polymeric immunoglobulins, especially dimeric IgA but also pentameric IgM, that have been produced in mucosal tissues and transports them across the epithelium by transcytosis
What is HIV?
a retrovirus that causes a slow progressive chronic disease (lentivirus)
Waldeyer's Ring
a ring of lymphoid organs that guards the entrance to the GI and respiratory tracts-- includes the palatine tonsils, adenoids, and lingual tonsils.
Tonsilitis
a secondary lymphoid organ- the tonsil- becomes overwhelmed by a bacterial pathogen. Such abundance of antigen results in the less stringent selection for better antibodies, and those that are made cannot terminate the infection, which now follows a chronic course. Tonsillitis can usually be overcome by a course of antibiotics, but mat beed to be combined with surgical removal of the infected lymphoid tissue.
Severe Combined Immunodeficiency disease (SCID)
a sever immune deficiency disease in which neither antibody not T-cell responses are made. It is usually the result of genetic defects that lead to T-cell deficiencies, and is fatal in childhood if not teated with hematopoietic cell transplantation
Pemphigus vulgaris
a severe autoimmune disease resulting in blistering of the skin. It is caused by IgG antibodies make against desmogleins, adhesion molecules of the cell junctions called desmosomes that bind skin keratinocytes tightly to each other.
pamphigus foliaceus
a skin blistering disease caused by autoantibodies specific for desmoglein. An adhesion molecule in the cell junctions that hold keratinocytes together, desmoglein is a cell-surface protein with five extracellular domains (EC1-EC5). The autoimmune response starts by making harmless antibodies against the Ec5 domain; over time, the response can spread to make antibodies against the EC1 and EC2 domains. These antibodies cause disease and are IgG4 isotype.
If the B cell presents appropriate peptide on its surface MHC-II molecule
a stable B cell-T helper cell conjugate pair forms, leading to proliferation of B cells and differentiation into plasma cells
Epstein-Barr virus (EBV)
a third type of herpesvirus that causes persistent infection. EBV infects B cells by binding to the CR2 component of the B-cell coreceptor complex. Even after the immune system clears the virus, the virus persists in the body because a minority of B cells become latently infected. This involves shutting of synthesis of most viral proteins except EBNA-1, which maintains the viral genome in these cells. Latently infected cells do not present a target for attack by CD8 cytotoxic cells because the proteasome is unable to degrade EBNA-1 into peptides that are bound and presented by MHC class I molecules. After recovery from initial exposure to EBV, it is unlikely for reactivation to cause disease.
S. aureus enterotoxin B (SEB)
a toxin secreted by strains of staphylococcus that acts on the gut to cause the symptoms of food poisoning. It is also a superantigen. Activates Vbeta1.1, 3.2, 6.4 and 15.2 CD4 T cells.
toxoids
a toxin that has been deliberately inactivated by heat or chemical treatment so that it is no loner toxic but can still provoke a protective immune response as a vaccine.
What is a hypersensitivity reaction?
allergic reaction over-reaction of immune system to environmental antigens that are not harmful
The Sabin vaccine (TVOP)
a trivalent (contains three different poliviruses) oral live-attenuated virus vaccine that came out in 1963. Because the trivalent oral polio vaccine (TVOP) gave better protection and was easier to administer, it started to replace the killed virus vaccine. Strain 3 of this TVOP can become pathogenic again with a back-mutation at just one of these positions. Regardless, the inclusion of strain 3 in the vaccine prevents more cases of disease than it causes. Because of the reversion rate, TVOP is no longer recommended for routine use in the United States, and IPV is not the vaccine of choice.
live-attenuated virus vaccines
a vaccine composed of live viruses having an accumulation of mutation that impeded their growth in human cells and their ability to cause disease. ex) measles, mumps, and yellow fever
Subunit vaccine
a vaccine composed only of isolated antigenic components of a pathogen and not the pathogen itself, either alive or dead. Ex) Hepatitis B virus subunit vaccine
combination vaccine
a vaccine that provides protection against more than one pathogenic organism and disease. DTP is an example
Inactivated Vaccines (killed vaccines)
a vaccine which contains viral particles that have been deliberately killed by heat, chemicals, or radiation.
cyclophosphamide
alkylating agent used as an immunosuppresive drug. It acts by killing rapidly dividing cells, including lymphocytes proliferating in response to antigen.
gut-associated lymphoid tissue (GALT)
all lymphoid tissue closely associated with the GI tact, including the palatine tonsils, Peyer's patches in the intestine, and layers of intrepithelial lymphocytes. Have two functionally distinct compartments: the inductive compartment and the effector compartment.
immune complex disease
accumulation of the immune complexes in the blood. Immune complexes: protein complex formed by the binding of antibodies to soluble antigens. The size of immune complexes depends on the relative concentrations of antigen and antibody. Large immune complexes are cleared by phagocytes bearing Fc and complement receptors. Small soluble immune complexes tend to be deposited on the walls of small blood vessels, where they can activate complement and cause damage.
Direct allorecgonition leads to
acute rejection
autoimmune response
adaptive immune response directed at an antigenic component of the responder's own body.
What forms Waldeyer's ring around the entrance of the gut and airway?
adenoids and tonsils
Contrasting other tissues
admit effector cells only when infected
lingual tonsils
aggregates of secondary lymphoid tissue at the back of the tongue
FcgammaRIII
an activating receptor for IgG, with relatively low affinity. It is the only Fc receptor expressed by NK cells, in which it is responsible for antibody-dependent cell-mediated cytotoxicity (ADCC). Also expressed on macrophages, neutrophils, and eosinophils. Also called CD16.
Histamine
an amine derivative of the amino acid histidine. One of the inflammatory mediators released by mast cells. Histamine exerts a variety of physiolofical effects through three kinds of histamine receptor- H1, H2, H3- which have been defined on different cell types. Acute allergic reaction involve the binding of histamine to the H1 receptor on nearby smooth muscle cells and on endothelial cells of blood vessels.
alloantigens
an antigen that differs between members of the same vertebrate species, such as HLA molecules and blood group antigens. Alloantigens are determined by the different alleles of polymorphic genes.
multiple sclerosis
an autoimmune disease in which autoimmune effector cells attack the myelin sheath of nerve cells to produce sclerotic plaques of demyelinated tissue in the white matter of the central nervous system. Disease symptoms include motor weakness, impaired vision, lack of coordination, and spasticity (excessive contraction of muscles). The effects of activated TH1 CD4 cells and the interferon-gamma they secrete are the cause of multiple sclerosis, which resembles a T cell-mediated type IV hypersensitivity reaction.
Type 1 diabetes
an autoimmune disease in which insulin-secreting Beta cells of the pancreatic islet cells of Langerhans are gradually destroys. Also called insulin-dependent diabetes mellitus (IDDM) or juvenile-onset diabetes (because it usually appears early in life, in childhood or adolescence).
Sheddases
an enzyme that cleaves a cell-surface protein to produce a free soluble form of protein ADAM10 is an example. ADAM10 can cleave the CD23 polypeptide at different sites to produce either monomeric or trimeric forms of soluble CD23.
immune dysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX)
an immunodeficiency disease caused by a lack of FoxP3, a transcription factor necessary for the development of regulatory T cells.
reverse vaccinology
an innovative approach to vaccine development that discovers new knowledge of the physiology of the pathogen and how it exploits the human immune system
Potentially self-reactive lymphocytes can pass the central tolerance point
and become part of the peripheral T-cell/B-cell repertoire
chronic granulomatous disease (CGD)
antibacterial activity of phagocytes is compromised by their inability to produce the superoxide radical O2-. Mutations affecting any of the four proteins with NADPH oxidase system can produce the phenotype. Patients suffer from chronic bacterial infections, often leading to granuloma formation.
Chemical Innate defenses of lungs
antibacterial peptides
Plasma cells produce
antibodies
xenoantibodies
antibodies made against xenograft (tissue from a different species)
alternative testing
assess and quanitfy total or allergen-specific IgE serum levels using ELISA or Western blot methods (unusual)
Commensal microorganisms
assist the gut in digesting food and maintaining health
Somatic mutations occur
at a very high rate and are focused on the Ig V regions only
receptor agonists
autoantibodies that mimic the natural ligand of the receptor and cause the receptor to transduce activating signals in the absence of its ligand.
Autoimmune polyendocrinopathy-candidias-ectodermal dystrophy (APECED)
autoimmune disease caused by a lack of a protein autoimmune regulator (AIRE), which results in the production of T cells reactive to a number of tissues in the body. Also known as autoimmune polyglandular disease (APD).
Goodpasture's syndrome
autoimmune disease in which autoantibodies against type IV collagen of the basement membrane of blood vessels endothelium cause extensive vasculitis.
Myasthenia gravis
autoimmune disease in which signaling from nerve to muscle across the neuromuscular junction is impaired. Antagonistic autoantibodies bind to the acetylcholine receptors on muscle cells, inducing their endocytosis and intracellular degradation in lysosomes. The loss of cell-surface acetylcholine receptors makes the muscle less sensitive to neuronal stimulation. Consequently, patients with myathenia gravis suffer progressive muscle weakening as levels of autoantibody rise. Symptoms: droopy eyes and double vision. Treatment: drug pyridostigmine, an inhibitor of the enzyme cholinesterase, which degrades acetylcholine. Also associated with HLA-DR3 (like Graves' disease)
rheumatic fever
autoimmune disease involving inflammation of the heart, joints, and kidneys, which can follow 2-3 weeks after a throat infection with certain strains of Streptococcus pyogenes. It is caused by antibodies made against bacterial antigens that cross-react with components of heart tissue. The antibodies form immune complexes that become deposited in the affected tissues.
organ-specific or tissue-specific immune disease
autoimmune disease targeted at a particular organ, such as the thyroid gland in Grave's disease
systemic autoimmune diseases
autoimmune disease that involves reaction to common components of the body and whose effects are not confined to one particular organ
Signal 1
crosslinking of Ig receptors and signal transduction through Igα and Igβ **other molecules as well
How are autoimmune diseases classified?
based on the types of immune responses with which you are already familiar (I.e. hypersensitivity reactions, types II, III, and IV)
Some rare individuals are resistant to HIV
because they lack CCR5
For many chronic infections a minority of people who are exposed to the pathogen
become resistant to long-term infection
Receptors generated by somatic gene modification and somatic hypermutation
bind to one or more self components in the body
Evasion of IgA mediated defense
by staphylococcal superantigen-like protein 7
Mutations acquired by somatic cells during oncogenesis
can give rise to tumor-specific antigens
Conversion of a proto-oncogene to an oncogene
can lead to abnormal stimulation of cell cycle
Oncogenes
cancer-causing genes
Immunological Memory
capacity of the immune system to make a quicker and stronger adaptive immune response to successive encounters with the antigen; due to long-live antigen specific effector cells (in bone marrow and low)
The serotypes of Streptococcus pneumoniae differ in their
capsular polysaccharides
Dendritic Cells
carry antigens from sites of infection to secondary lymphoid tissues
Inflammation of mucosal tissues is associated with
causation NOT cure of disease
T. brucei
cause of African sleeping sickness
How does herpes simplex virus operate
cause of cold sore. First infects epithelial cells and then spreads to sensory neurons serving the area of infection. The immune response clears virus from the epithelium, but the virus persists in a latent state in the sensory neurons. Various types of stress can reactivate the virus. After reactivation, the virus travels down the axons of the sensory neurons and reinfects the epithelial tissue. Viral replication in epithelial cells and the production of viral peptides restimulates CDD8 T cells, which kill the infected cells, creating a new sore. This cycle can be repeated many times throughout life. Neurons are a favored site for latent viruses to lurk because they express very small numbers of MHC class I molecules, further reducing the potential for presentation of viral peptides to CD8 T cells.
chromic thyroiditis or Hashimoto's disease
caused by a CD4 TH1 response, which produces both antibodies and effector CD4 T cells that are specific for thyroid antigens. Lymphocytes infiltrate the thyroid, causing a progressive destruction of the normal thyroid tissue and a corresponding loss of the capacity to make thyroid hormones. Treatment: Replacement therapy with synthetic hormones taken orally on a daily basis.
Shingles
caused by the herpesvirus varicella-zoster. It remains latent in one or a few ganglia, chiefly dorsal root ganglia, after the acute infection of epithelium-- chickenpox-- is over. Stress of immunosuppresion can reactivate the virus, which then moves down the nerve and infects the skin. The disease caused by the reactivation of varicella-zoster is commonly known as shingles. Reactivation of varicella-zoster usually occurs once in a lifetime, unlike herpes simplex virus.
microfold cells (M cells)
cell in the gut mucosa that facilitates the transport of pathogens and antigens from the gut lumen of secondary lymphoid tissues underlying the gut epithelium. The luminal (apical) surface of the M cells, with its characteristic folds, has adhesive properties that facilitate the endocytosis of microorganisms and particles. The surface also carries a variety of cell-surface receptors and adhesion molecules that recognize microbial antigens.
Paneath cells
cells that are interspersed between the enterocytes that secrete defensins, lysozyme, and other antimicrobial factors
Somatic hypermutation in a clone of expanding B cells produces what?
centrocytes with a diversity of B-cell receptors with a range of affinities for the antigen to which the founder B cell was specific
B-cell receptor and co-receptor cooperation in B cell activation by a pathogen/soluble antigen leads to
changes in gene expression in nucleus
oral tolerance
characteristic tolerance of the immune system for 'foreign' antigens such as food, ingested into the gastrointestinal tract. In Peyer's patches, the dendritic cells that acquire antigens from M cels are present in the region of the subepithelial dome. These dendritic cells express CCr6, the receptor for chemokine CCl20 produced by follicle-associated epithelial cells. These dendritic cells secrete IL-10, which prevents any production of inflammatory cytokine by the T cells that the dendritic cells activate.
bronchiectasis
chronic inflammation of the bronchioles of the lung. Can be cause in XLA patients. To avoid this, XLA patients are given monthly injections of intravenous immunoglobulin. Intravenous immunoglobulin contains antibodies against common pathogens and provides passive immunity.
Indirect allorecognition leads to
chronic rejection - Donor's DCs die
serpins
class of protease inhibitor proteins that inhibit serine and cysteine proteases. The C1 inhibitor is an example of a serpin.
FcgammaRII
class of receptor present on various myeloid cells that binds the Fc regions of IgG antibodies with relatively low affinity. The class comprises an activating receptor, FcgammaRIIA, which promotes the internalization of bound antigen:antibody complexes, and two inhibitory receptors (FcgammaRIIB1 and FCgammaRIIB2), for which binding of IgG inhibits the activation of the receptor bearing cell.
Coating a bacterium with IgG does what?
coating a bacterium with IgG promotes it uptake and destruction by a phagocyte
Most bacterial infections of gut tissue are caused by what?
commensals. Many potential pathogens belong to the facultatively anaerobic, Gram-negative phylum Proteobacteria, which includes Salmonella, Shigella, and others. Pathogenic variants of these normally harmless bacteria arise as new genetic variants acquire properties called virulence factors that enable them to leave the gut lumen, breach the gut epithelium, and invade the underlying lamina propria.
Activation of B cells and T cells in one mucosal tissue
commits them to defending all mucosal tissues
Newly formed centrocytes move from the dark zone into the light zone of the germinal center and do what?
compete for access to the limited amount of antigen displayed on the dendrites of the FDCs. In this competition the centrocytes having the antigen receptors of highest affinity are more likely to be activated by the limiting amount of antigen.
Binding of IgM to antigen on a pathogen's surface activates
complement by classical pathway
leukocytosis
condition in which there are increased number of leukocytes in the blood. It is commonly seen in acute infection.
DQ6 allotype
confers strong resistance to type 1 diabetes
Killed/inactivated vaccines
consist of virus particles treated with formalin or physically treated with heat or irradiation
crypts
contain Paneth cells- secrete defensins, lysozyme, and other microbial factors
B cell activation requires what?
cross-linking of surface immunoglobin to antigen. This initiates a cascade of intracellular signals
B-cell receptors are activated by
cross-linking with antigens
What determines whether antigen-activated B cells turn into plasma cells or memory cells?
cytokines made by helper T cells IL-10: centrocytes differentiate into plasma cells IL-4: centrocytes turn into memory B ells
Mucosal Immune System
defends against pathogens breaching mucosal surfaces
Systemic Immune System
defends against pathogens that entire via the skin
Complex disease Myasthenia Gravis
defined by age of onset, thymic pathology, MHC associations and the presence of the absence of Ab specific for non-AChR antigens
IgE binding to Mast cells, eosinophils, basophils induces
degranulation (protection against parasites)
ANtigen binding initiates
degranulation of mast cells
Result of Type III
deposition of antibody-antigen complexes in sensitive tissues and activation of the complement cascade
hyperthyroid
describes an abnormally high production of thyroid hormones by the thyroid gland
NODS
detect components of bacterial cells walls. Activate NFkappabeta, and NFkappabeta regulates transcription. This transcribes chemokines, cytokines, and other mediators that recruit and activate neutrophils and monocytes.
Cytokines made by helper T cells
determine B cells differentiate into plasma or memory cells
Cytokines made by Helper T cells
determine how B cells switch their immunoglobulin isotype
Mucosal surfaces
developed a large and complex immune apparatus that is anatomically and functionally distinct from that found elsewhere in the body
intraepithelial lymphocyte
distinctive types of alpha: beta CD8 T cell and gamma:delta T cell that are integrated into the epithelial layer of the small intestine. They express T cell receptors with a limited range of antigen specificities, and they have a distinctive combination of chemokine receptors and adhesion molecules that enables them to occupy their unique position within the intestinal epithelium. They express chemokine receptor CCr9 but instead of alpha4:beta7 integrin, they express alphaE: beta7 integrin, which attaches the T cell to E-cadherin on the surface of epithelial cells.
IgA2
disulfide bonds tailpiece N-linked carbohydrate J chain secretory component
IgM and IgA procent mucosal surface
do NOT use complement system... page 284
Dendritic cells bearing antigen
enter the draining lymph node, where they settle in the T-cell areas
Poliovirus
enters the human body by oral route, binds to CD155 molecule on M cells and is delivered to Peyer's patches, where it establishes local infections before spreading systemically. IgA has not been made against it (if you aren't vaccinated) so it can infect epithelial.
How does cancer arise?
from a single cell that accumulated MULTIPLE mutations
herd immunity
general immunity to a pathogen in a population based on the acquired immunity to it by a high proportion of members over time. A few unvaccinated people in a community are still relatively safe from a disease if most others are vaccinated because the disease does not have enough hosts to sustain the chain of infection. Herd immunity is lost if too many people stop getting vaccinated.
memory cells
general term for a lymphocyte that is responsible for the phenomenon of immunological memory
Hereditary Angioedema (HAE)
genetic disease that results from deficiency of the C1 inhibitor of the complement system (C1INH). In the absence of C1 inhibitor, spontaneous activation of the complement system causes diffuse fluid leakage from blood vessels, the most serious consequences of which is epiglottal swelling leading to suffocation. Treated with infusions of recombinant C1INH protein, some of which is purified from the milk and transgenic rabbits expressing the human C1INH gene.
X-linked agamaglobulinemia (XLA)
genetic disorder in which B-cell development is arrested at the pre-B-cell stage and neither mature B cells nor antibodies are formed. The disease is due to a defect in the gene encoding the protein tyrosine kinase BTK, which is located on the X chromosome.
Environmental contributions to loss of self-tolerance
genetically predisposed individuals at highest risk develop disease at a maximum frequency of about 20%
Mucins
gigantic glycoproteins that endow the mucus with the properties to protect epithelial surfaces impeding movement of microorganisms and particles
influenza hemagglutinin
glycoprotein in the coat of the influenza virus that binds to certain carbohydrates on human cells, the first step in infection of cells with the virus. Changes in the hemagglutinin are the major source of the antigenic shift that heralds a major new pandemic. The protein is called a hemigglutinin because it can agglutinate red blood cells
Mucus contains
glycoproteins, proteoglycans, peptides, and enzymes that protect epithelial cells from damage and help to limit infections
synergic transplant/ isograft
graft of a tissue or organ from one genetically identical individual to another
autograft
graft of tissue taken from one anatomical site and transplanted to another in the same individual
what is the purpose of waldeyer's ring?
guard entrance to the gut and airways
Inactive mast cell
has preformed granules containing histamine and other inflammatory mediators
Mast cells, basophils, and activated eosinophils
have IgE receptor. - Fc-epsilon-RI = high affnitiy for Fc region of IgE
Two subclasses of IgA
have complementary properties for controlling microbial populations
Effective B cell-mediated immunity depends on
help from CD4 T cells
B lymphocytes generally require
help from activated T lymphocytes for differentiation into plasma cells
Tumor-suppressor genes
help prevent uncontrolled cell growth
BLIMP-1
helps lymphoblasts become plasma cells by stopping transcription of genes necessary for proliferation. Cells will then increase expression of immunoglobulin chains and factors involved in their synthesis and secretion
CMV**
herpesvirus human cytomegalovirus. has 10 proteins that interfere in diverse ways to diminish the capacity of MHC class I molecules to stimulate NK-cell and CD8 T cell responses against CMV-infected cells, such as interfering with the TAP or tapasin proteins, by interfering with the proteasome, by causing their degradation, or by retaining the MHC class I molecules in the endoplasmic reticulum. A second group of saboteurs interfere with inhibitory NK-cell receptors CD94LNKG2D and LILRB1, which sense missing self-MHC class I, and with activating NKG2D receptor, which recognized the ligands MIC and ULBP.
neutralizing antibody
high affinity IgA and IgG antibodies that bind to pathogens and prevent their growth or entry into cells
Effective N. meningitides Vaccine
high-affinity, neutralizing IgG to the bacterial polysaccharide and the development of immunological memory
What type of viruses can escape immunological memory?
highly mutable ones
Mast cell Toxic mediator products
histamine, heparin
Hygiene hypothesis
hypothesis advances to explain the increasing incidence over the past 50 years of hypersensitivity and autoimmune diseases in developed countries. It is proposed that the increase has occurred because widespread hygiene, vaccination, and antibiotic therapy have prevented children's immune systems from becoming used to dealing appropriately with either natural infections or innocuous environmental antigens
Syngeneic
identical genetic constitution (as between individuals of an inbred mouse strain or identical twins)
transplant rejection
immune reaction that is directed toward transplanted tissue from a genetically non-identical donor and leads to death of the graft
Type III hypersensitivity related autoimmune disease
immune-complex mediated autoimmune disease
What are some common side effects of immunosuppressive treatments?
increased susceptibility to infection, and general or selective tissue toxicities
HIV infection leads to
immunodeficiency and death from opportunistic infections
Hyper-IgM Syndrome
immunodeficiency suffered by people who lack CD40 ligand. Becaus their B cells cannot switch immunoglobin isotype, these patients have abnormally high amoutns of IgM in their circulation, but almost no IgG and IgA. In general these patients make poor antibody responses to most antigens, and their secondary lymphoid tissues contain no germinal centers. CD40 is on the X chromosome, so mostly male.
azathioprine
immunosuppresive drug that kills dividing cells. It is used in transplantation to help suppress rejection reactions. Cytotoxic. No selectivity and has serious side effects: damage to bone marrow, intestinal epithelium, and hair follicles.
transfusion effect
improved outcome of transplantation if the recipient has previously been given blood transfusions from people who share an HLA-DR allotype with the organ with which the patient is subsequently transplanted.
Where does isotype switching occur?
in activated B cells mainly within the germinal center.
effector compartment
in the mucosal immune system, a tissue such as the gut lamina propria in which the majority of effector cells arise-- plasma cells, effector T cells, macrophages, mast cells, and eosinophils
inductive compartment
in the mucosal immune system, the lymphoid tissue directly beneath the mucosal epithelium, where interactions between antigen, dendritic cells, and lymphocytes induce adaptive immune responses
Hygiene hypothesis
incidence of autoimmune disease is increasing in developed countries. lack of exposure of children to pathogens alters the way in which the immune system develops so they are less skilled in attacking pathogens while maintaining T cell tolerance
Defective alleles of AIRE lead to
incomplete negative selection and inherited autoimmune polyglandular disease
H2 binding
increase vasopermeability and vasodilation, stimulates exocrine glands, and increases stomach acid; also suppresses degranulation of mast cells/basophils in a negative feedback loop
H1 binding
induces contraction of intestinal and bronchial smooth muscles, increased permeability of venules, and mucous secretion.
Insulitis
infiltration of the pancreatic islets of Langerhans with lymphocytes and other leukocytes. This is a symptom of early type 1 diabetes, but is also seen in the non-autoimmune type 2 diabetes.
Celiac disease
inflammatory condition caused by an immune response in the gut lymphoid tissue that damages the intestinal epithelium and reduces the capacity of those affected to absorb nutrients from their food. This condition can arrest growth and development of children, and in adults causes unpleasant symptoms such as diarrhea and stomach pains and general ill health. Caused by an adaptive immune response to the proteins of gluten, a major component of grains such as wheat, barley, and rye, which are dietary staples for some human populations.
Celiac disease
inflammatory hypersensitivity disease of the gut mucosa caused by an immune response to the gluten proteins present in some cereals such as wheat and barley but not rice.
Follicular Dendritic Cells (FDC)
interaction between B cells and FDCS in the primary follicles of the secondary lymphoid tissues are critical for maturation and survival of B cells. Lack phagocytic activity. FDCs in the B-cell area store and display intact antigens to B cells (they can preserve the antigen for long periods)
intraepithelial pocket
invagination of the basolateral plasma membrane of the M cell in the gut epithelium, which enables the transported antigens and microorganisms to encounter dendritic cells, T cells, and B cells in the underlying lymphoid tissue.
mycophenolate mofetil
is a more recently developed drug with similar effects to those of azathiorine. It is metabolized in the liver to mycophenolic acid, which prevents cell division by inhibiting inosine monophosphate dehydrogenase, an enzyme necessary for guanine synthesis.
Examples of Live-attenuated Virus Vaccines
measles, mumps, polio (Sabine vaccine), yellow fever
type II hypersensitivity
mediated by antibody against cell-surface or matrix antigens. Frequently targets blood cells.
Type IV hypersensitivity
mediated by effector T cells
Selective IgA deficiency due to
lack of isotype switching from IgM to IgA. But other types are more abundant.
Plasma cells
large nucleus and large cytoplasm packed with ER
Drawback of killed/inactivated vaccines
large quantities of pathogenic virus required for production
Acute response in allergic asthma
leads to Th2-mediated chronic inflammation of the airways
IgM response
leads to a version of hemolytic anemia termed COLD HEMAGGLUTININ DISEASE (CHAD). The antibodies agglutinate cells with increasing strength as the temperature drops. Extensive hemolysis when body temperature drops 37 degrees in cold weather
Mutant allele of CCR5 (CCR5-∆32)
leads to premature termination of protein synthesis; nonfunctional CCR5. Only CCR5-∆32 homozygous resist HIV infection
Crosslinking of IgE on mast cell surfaces
leads to rapid release of mast cell granules containing inflammatory mediators
How much damage can be tolerated before health is compromised?
limited amounts of damage
The B cell is an antigen presenting cell allowing for
linked recognition
type III hypersensitivity
mediated by immune-complex disease (immune complexes deposited in tissues)
Memory B cells
long lived antigen-specific B cell that is produced from activated B cells during the primary immune response to an antigen. On subsequent exposure to their specific antigen, memory B cells are reactivated to differentiate into plasma cells as part of the secondary and subsequent immune responses to that antigen
Memory T cells
long lived antigen-specific T cell that is produced from activated T cells during the primary immune response to an antigen. On subsequent exposure to their specific antigen, memory t cells are activated to differentiate into effector T cells as part of the secondary and subsequent immune responses to that antigen.
Mechanical innate defenses of skin and gut
longitudinal flow of air or fluid
Inductive Compartment
lymphoid tissues directly beneath the mucosal epithelium; where interactions between antigen, dendritic cells and lymphocytes induce adaptive immune responses
Successful tumors evade and manipulate the immune response
macrophage inhibitory cytokine is overexpressed by many common cancers
Monomeric IgA and protection against blood borne pathogens
made by plasma cells derived from B cells that Isotype switched in lymph nodes or spleen
Xenogeneic
major genetic differences between different species
Healthy individuals
make IgE only in response to parasitic infections
Downside to Killed/Inactivated Vaccines
make large amounts of pathogenic virus are produced during manufacturing of vaccine
Immunotherapy
manipulate an immune response against tumor cells but not normal cells
How many categories of type I hypersensitivity reactions?
many
What enzymes break down extracellular matrix proteins
mast-cell chymotrypase, trypase, and other neutral proteases that activate metalloproteases in the extracellular matrix.
Not having CCR5
minor immunodeficiency as other chemokine receptors can do the same as CCR5
superantigens
molecule that, by binding nonspecifically to MHC class II molecules and T-cell receptors, stimulates the polyclonal activation of T cells. Small bacterial protein toxins that activate many different T cell clones. Bacterial superantigens activate CD4 T cells by cross linking MHC class II molecules with alpha:beta T -cell receptors and CD28 co-stimulatory molecules in the absence of antigenic peptides
anti-CD25 antibodies
monoclonal antibody against the gamma chain (CD25) of the IL-2 receptor, which blocks activation of the receptor and thus blocks the action of IL-2 in stimulating the proliferation and differentiation of antigen-activated lymphocytes. It is used as an immunosuppressant pretreatment in transplant patients to prevent rejection responses.
adenoids
mucosa-associated secondary lymphoid tissues located in the nasal cavity
MAd-CAM-1
mucosal cell adhesion molecule-1, a mucosal addressin that is recognized by the lymphocyte surface proteins L-selectin and VLA-4. This interaction mediates the specific homing of lymphocytes to mucosal tissues.
Most antigens and pathogens gain access to the body via
mucosal surfaces
mucosae
mucosal surfaces; mucus secreting epithelium such as that lining the respiratory, intestinal, and urogenital tracts. The mammary glans and the conjectiva of the eye are also considered in this category. Mucosal epithelium communicates with the external environment and is the route of entry of most pathogens.
Comparison of naive B cells and plasma cells
naive B cells: -surface Ig -surface MHC class II -growth -somatic hypermutation -isotype switch Plasma cell: -no surface Ig -No surface MHC class II -High-rate Ig secretion -No growth -no somatic hypermutation -no isotype switch
indirect pathway of allorecognition
one means by which alloreactive T cells in the recipient of a transplant can be stimulated to react against the transplant. The alloreactive T cells do not directly recognize the transplanted cells but recognize subcellular material from these cells that has been processed and presented by the recipient's own dendritic cells.
mesenteric lymph nodes
one of a chain of lymph nodes in the mesentery, the membrane that holds the gut in place. These lymph nodes connect by lymphatics to the lymphoid tissues of the gut, and pathogen-bearing dendritic cells are transported there to initiate additional adaptive immune responses against gut pathogens
Central memory T cells (Tcm)
one of the two subsets of memory T cells that are distinguished by different activation requirements. Central memory T cells have a preference for the T-cell zones of secondary lymphoid tissues and take longer than effector memory T cells to mature into functioning effector T cells after encounter with their specific antigen.
Effector memory T cells
one of the two subsets of memory T cells that are distinguished by different activation requirements. Effector memory T cells have a preference for inflamed tissues and are activated more quickly than central memory T cells to mature into their functioning effector T cells after encounter with their specific antigen
The Challenge to eliminate invaders
our immune system must recognize foreign antigens, without accidently recognizing our own antigens and killing our own cells. BUT MISTAKES HAPPEN
pandemic
outbreak of an infectious disease that spreads worldwide. For example, "Spanish flu" following world war 1. New pandemic strains of viruses can often arise recombination of avian and human RNA combine and have a new form of hemagglutinin
epidemics
outbreak of infectious disease that affects many individuals within a population
FcgammaRIIB1 and FcgammaRIIB2
part of FcgammaRII receptor two inhibitory receptors (FcgammaRIIB1 and FCgammaRIIB2), for which binding of IgG inhibits the activation of the receptor bearing cells. FcgammaB1: mast cells and B cells FcgammaB2: macrophage, neutrophils, and eosinophils
dark zone
part of the germinal center in secondary lymphoid tissue that contains dividing centroblasts
Vaccines directed toward
particular viral components. Production of neutralizing antibodies can be directed against surface components of the pathogen
Graft versus host disease
pathological condition caused by the graft-versus-host reaction (GVHR), which is the response of mature donor-derived T cells in transplanted bone marrow or other type of hematopoietic cell transplant to the alloantigens of the recipient's tissues.
Antiviral drugs
rapidly clear the virus from the blood and increase the number of circulating CD4 T cells
immune thrombocytopenia
rare bleeding disorder in which autoantibodies and immune complexes cause platelet destruction and perturb the platelet production
antigenic shift
process by which influenza viruses reassort their segmented genomes and change their surface antigens radically. New viruses arising by antigenic shift are the usual cause of influenza pandemics.
antigenic drift
process by which point mutation in influenza virus genes cause alterations in the structure of viral surface antigens. This causes year-to-year antigenic differences in strains of influenza virus.
intermolecular epitope spreading
process by which the immune response initially reacts against an epitope of one antigenic molecule and then progresses to epitopes on different proteins.
intramolecular epitope spreading
process by which the immune response initially reacts against epitopes in one part of an antigenic molecule and then progresses to respond to other, non-cross-reactive, epitopes in the same molecule
Gene conversion
process whereby one copy of a gene, or part of a gene, is replaced by a different version of that gene, or part of that gene. A dominant form of VSG exists in the pathogen. A small minority has changed the expressed VGS gene and not expresses other forms. The host makes an antibody response to the dominant form of VSG, but not to the minority forms. Antibody-mediated clearance of trypanosomes expressing the dominant VSG facilitates growth of those expressing the minority forms, one of which will come to dominate the trypanosome population In time, the number of trypanosomes expressing the new dominant form is sufficient to stimulate the production of antibodies, which clear the new dominant form. This allows a further form to dominate, and so the cycle continues. Salmonella typhimurium and neisseria gonorrhoeae also use gene conversion.
Atopic individuals
produce IgE against common environmental antigens - most are proteins or glycoproteins - most possess many antigenic sites (epitopes) per molecule
The primary focus of clonal expansion in the medullary cords
produces plasma cells secreting IgM
Hygiene hypothesis
proposes that exposure to some pathogens early in life provides a better T-cell balance. Avoids dominance of Th2 subset, which promotes IgE production by B cells (stimulating allergic responses) - improved hygiene are experiencing increases in asthma and allergy rates
IgM, IgG, and IgA
protect the internal tissue of the body. Prevent blood borne infections and can protect tissues reached by the blood. Neutralize microorganisms in the blood.
General Effector Functions of IgM, IgG, and monomeric IgA
protect the internal tissues of the bodies
IgG and IgA (monomeric)
protection of blood and extracellular fluids
Dimeric IgA
protects the surfaces of the mucosal epithelia that communicate with the external environment and are particularly vulnerable to infection. Made in patches of mucosal-associated lymphoid tissue present in the lamina propria, the connective tissue underlying the mucosal epithelium.
Vaccines
provide long term adaptive immunity (immunological memory)
IgE
provides a mechanism for the rapid ejection of parasites and other pathogens from the body
Type I hypersensitivity reactions (immediate hypersensitivity
reaction triggered by the interaction of an allergen-specific IgE bound to the FcepsilonRI receptor of mast cells, basophils, and eosinophils. This interaction an allergic reaction that occurs within minutes of exposure to antigen in a sensitized person, as a result of the activation of mast cells by antigen cross-linking specific IgE that was made in response to an initial encounter with the antigen, and which has become bound to Fc receptors on the mast cell. Symptoms can range from the unpleasant but relatively minor, as in hay fever (allergic rhinitis), to the life0threatening reaction of systemic anaphylaxis.
FcERI
receptor present in the surface of mast cells, basophils, and activated eosinophils that binds free IgE with very high affinity. When antigen binds to IgE and cross-links FcERI, it causes cellular activation and degranulation
SIP
receptor that is expressed when naive B cells do not find their antigen. It draws the naive B cells out of the B cell area and out of the lymph node and back into circulation.
Trancytosis
receptor-mediated transport of a macromolecule from one side of a cell to the other
Bad news
recognition of tumor antigens occurs but occurs without activation of immune effector responses
TLR-5
recognizes flagellin which is the protein encoding for the bacterial flaggellin. TLR-5 would activate NFkappabeta, and NFkappabeta regulates transcription. This transcribes chemokines, cytokines, and other mediators that recruit and activate neutrophils and monocytes.
Germ-free mice
reduced capacity to mount immune responses, smaller secondary lymphoid tissues, decreased Igs
Suppression of autoreactive T cells by
regulatory T cells requires them to interact with the same antigen-presenting cell
Gene therapy
relatively selective
Targeted therapy
relatively selective
Mutlivalent antigen cross links IgE antibody bound at mast cell surface causing
release of granule contents
Break down plant fibers in food
release of small molecules that can be used in metabolism and biosynthesis
Surgery
remove tumor cells and tissues physcially
Gut dendritic cells
respond differently to food, commensal microoganisms, and pathogens
Autoimmune Polyglandular disease (APD)
same think as APECED: autoimmune disease caused by a lack of a protein autoimmune regulator (AIRE), which results in the production of T cells reactive to a number of tissues in the body.
immunoreceptor tyrosine-based activation motifs (ITAMS)
sequence in cytoplasmic domains of membrane receptors that are sites of tyrosine phosphorylation and of association with tyrosine kinases and phosphotyrosine-binding proteins involved in signal transduction.
ABO system
set of blood group antigens on red blood cells that have to be appropriately matched between donor and recipient for successful blood transfusion or organ transplantation
B-cell activation requires
signals from the B-cell co-receptor
mucus
slimy protective secretion composed of glycoprotein, proteoglycans, peptides, and enzymes that is produced by the goblet cells in many internal epithelia.
Actively dividing B cells undergo
somatic hypermutation
Eosinophils
specialized granulocytes that release toxic mediators in IgE mediated responses. Most are resident in the connective tissue immediately underlying the epithelia of the respiratory, gastrointestinal, and urogenital tracts.
Subcapsular sinus macrophage
specialized macrophage resident in the subcapsular sinus of the lymph node. it captures complement-tagged antigens from the afferent lymph and holds them at the cell surface. Resemble FDCs-- they have little phagocytic activity and have CR1and CR2 for taking up antigens tagged with C3d or C3b and then holding them on the cell surface
CD34+ cells
stem cells
Somatic mutation requires
stimulation of B cells by specific antigen and interaction with helper T cells
immunogenetics
subfield of immunology that deals with the polymorphism and population genetics of genes and proteins that are important for immune system function
Adjuvant
substances used in experimental immunology and in vaccines to enhance the adaptive immune response to an antigen used for combination vaccines
toxic shock syndrome toxin-1 (TSST-1)
superantigen secreted by Staphylococcus aureus that cause toxic shock, a systemic shock reaction resulting from the overproduction of cytokines by CD4 T cells activated by the superantigen. Activates Vbeta2 gene segment of CD4T cells.
Primary focus
temporary aggregate of proliferating activated antigen-specific B cells and T cells that forms during a secondary lymphoid tissue at the beginning of an adaptive immune response
xenoantigens
term for antigen of the donor tissue when being transplanted into an animal of a different species
cross-match test
test used in blood typing and histocompatibility testing to determine whether donor and recipient have antibodies against each other's cells that might interfere with successful transfusion or transplantation.
Tissue typing
tests to determine potential donors based upon HLA match-use of anti-HLA antibodies
B-cell coreceptor
the B-cell co-receptor comprises three proteins: 1. complement receptor 2 (CR2 or CD21), which recognizes the iC3b and C3d derivatives of the C3b fragments. 2. CD19, which is the signaling chain of the co-receptor. 3. CD81, which binds to CD19 and is essential for bringing it to the B-cell surface
Antigen activated B cells move close to where?
the T-cell and B-cell area to find a helper TFH cell. Naive B cells arriving from the blood via HEV will be attracted to the T-cell are by the chemokines CCL21 and CCL19, and then into a B-cell follicle by the chemokine CXCL13.
To ensure that low affinity antibodies and IgM are not made in secondary response
the activation of naive pathogen specific B cells is suppressed
Vaccina virus
the cowpox virus- causes very mild infection in people, but the immunity produced gives effective protection against both smallpox and cowpox because the two viruses have anti-genes in common. Using the vaccina virus (Jenner) replaces variolation and was responsible for the eradication of smallpox in the 20th century.
agonistic and antagonistic autoantibodies against the insulin receptor
the disease affects the entire body-- systemic autoimmune disease. The cells of patients with antagonistic autoantibodies are unable to take up glucose, which accumulates in the blood, causing hyperglycemia and a form of diabetes mellitus that is resistant to treatment with insulin. In patients with agonistic antibodies, the antibodies mimic insulin and cause the cells to continuously remove glucose from the blood. Blood glucose decreases to an abnormally low level, inducing a state of hypoglycemia and light-headedness caused by insufficient glucose reaching the brain. These conditions can be treated with immunosuppressive drugs and with anti-CD20 antibody to eliminate the B cells making the autoantibodies.
islets of Langerhans
the endocrine hormone-producing tissue of the pancreas, which includes the beta cells that produce insulin
follicle-associated epithelium
the epithelium that over-lies a mucosal lymphoid tissue or organ (over the Peyer's patches and isolated lymphoid follicle), and through which microorganisms are transported-- not well defended, do not contain Paneth or goblet cells.
Secretory component, or secretory piece
the fragment of the poly-Ig receptor that is left attached to dimeric IgA that had been secreted across a mucosal epithelium
atopy
the genetically determined tendency of some people to produce IgE-mediated hypersensitivity reactions (allergic reactions) against innocuous substances
What makes memory B cells more efficient than naive B cells in binding and internalizing antigen for processing and presentation of CD4 Tfh cells?
the high affinity of their antigen receptors.
In the absence of microbiota
the immune system develops abnormally
epitope spreading
the process by which the immune response initially targets epitopes in one part of an antigenic molecule and then progresses to different epitopes.
IgE provides a mechanism for
the rapid ejection of parasites and other pathogens from the body
bone marrow transplantation
the replacement of a person's diseases or functionally deficient blood and immune system by the infusion of healthy bone marrow, which contains hematopoietic stem cells, from a donor.
Sensitivity reaction or allergic reactions
the result of a secondary immune response to an otherwise innocuous environmental antigen, or allergen, causing a wide variety of unpleasant and sometimes life-threatening symptoms. The description 'allergic' is often reserved for reaction involving IgE (type I hypersensitivity reaction); other types of immunological hypersensitivity reaction involve other types of antibody (such as IgG) or effector T cells.
relapse
the return of cancer or other disease after a period of remission in which it seemed to have been successfully
Linkage disequilibrium
the situation when particular alleles of two or more polymorphic genes (for example those of the HLA haplotype) are inherited together at frequencies higher than expected by chance.
Protective Immunity
the specific immunological resistance to a pathogen that is present in an individual during months after either vaccination or recovery from an infection with the pathogen, and which is due to pathogen-specific antibodies and effector T cells produced during the primary response.
What is required for mucosal surfaces to do their job?
thin, permeable barriers to the interior of the body
A1-B8-DR3-DQ2 haplotype
this haplotype is uniquely associated with several common autoimmune diseases, including type 1 diabetes, SLE, myasthenia gravis, autoimmune hepatitis, and primary biliary cirrhosis. It is characteristic of Caucasian populations.
The genes most consistently associated with susceptibility to autoimmune diseases are
those of the MHC or HLA (Human MHC) complex
allograft/ allogenic transplant
tissue graft made between genetically non-identical members of the same species
ectopic lymphoid tissues
tissue resembling secondary lymphoid organs that forms in diseased and inflamed organs that do not normally contain lymphoid tissues, for example in the thyroid in Hashimoto's disease. It also forms in other autoimmune diseases, including rheumatoid arthritis, Graves' disease, and multiple sclerosis, but with less regularity than for Hashimoto's disease.
Type III hypersensitivity
tissue-damaging immune reaction caused by immune complexes formed during the secondary immune response to soluble proteins of non-human origin
Type II hypersensitivity
tissue-damaging immune reaction caused by secondary immune response to small chemically reactive molecules that modify cell-surface components and stimulate the production of specific IgG antibodies
AIRE
transcription factor that controls rare proteins expressed by epithelial cells in thymus
AIRE (autoimmune regulator)
transcription factor who's function is to induce the deletion of thymocytes that recognize peptides cleaved from tissue-specific proteins expressed by one or a small number of cells or tissues. AIRE ensures that these proteins are expressed in the thymus, where their peptide antigens contribute to negative selection of the T-cell repertoire. For children with two defective copies, the normal array of tissue-specific proteins is not expressed in the thymus and so negative selection of the T-cell repertoire is incomplete. transcription factor that causes several hundred tissue-specific genes to be transcribed by a subpopulation of epithelial cells in the thymus, which thus enable to developing T cell population to become tolerant of antigens that normally occur only outside the thymus.
Passive transfer of immunity
transfer of immunity to a non-immune individual by injection of specific antibody, immune serum or T cells
xenotranplantation
transplantation where the donor and recipient are of different species
The receptor FcRn
transports IgG from blood stream into extracellular spaces of tissues
TGF-B associated with
tumor-induced suppression of the immune response
Macrophage-tropic virus
uses CCR5 on macrophages, DCs, and T cells
Lymphocyte-tropic virus
uses CXCR4 on activated T cells requires the highest expression of CD4
Herpesvirus
uses persistence and reactivation of herpes simplex virus to go into latent phase and then activation of infection.
Clinical transplantation
usually involves both a donated organ and a transplant recipient that are stressed and inflamed
Conjugate vaccines
vaccine made from capsular polysaccharides bound to an immunogenic protein such as tetanus toxoid. The protein provides peptide epitopes that stimulate CD4 T cells to help B cells specific for epitopes of the polysaccharide. ex) meningitis vaccine
Allergy is prevalent in countries
where parasites infections have been eliminated
