Immun_Block 7_ALL
Which disease has been eradicated due to vaccinations?
smallpox
Hematopoietic stem cell match
transplant requires perfect match for HLA-A, -B, - C, -DRB1, - DQ (10 match)
Avidity can be enhanced by ...
valency IgG is a monomer and only has 2 binding sites IgM is a pentamer and has 10 antigen binding sites -> results in bigger complex
Explain pathogenesis of rheumatic fever
via molecular mimicry Pt is exposed to pathogen like Streptococcus Progenies, which has specific M proteins on the surface. Immune system starts producing antibodies against M proteins within 3 weeks. Antibodies attack not only the pathogen, but can also attack heart valves and sarcolemma
What antibody is produced after booster shots?
during initial pathogen exposure: - weak immune response - IgM produced during second exposure/booster vaccine: - strong + faster response - IgG
In which part of the body do T cells express both CD8 and CD4?
in cortex of thymus
Acute vascular rejection
(Occurs in xenografts - 4-8 days after transplantation): Mediated by anti-Gal antibody Mechanism: 1. Endothelial activation and coagulation, causing cell damage, thrombosis and eventual graft rejection 2. Humans, apes and Old World monkeys produce anti-Gal antibody, which specifically interacts with alpha-gal epitopes produced by other species. Reaction between Gal epitope (graft) and anti-GAL antibody (human) may recruit complement protein as animal tissues don't have inhibitors of complement activity
Acute rejection
(begins after first week): - mediated by CMI (CD8 & CD4 T cells); antibodies may also be involved Mechanism: 1. CD8 and CD4 T lymphocytes are activated and proliferate; effector mechanism is CTL and DTH 2. Antibodies activate Complement system (classical pathway)
Immunosurveillance theory suggests ... What cells are essential in tumor surveillance?
(by Burnet & Thomas, 1957) = lymphocytes recognize + eliminate aberrant or tumor cells that spontaneously arise in tissues Tumor cells express antigens that are abnormal to immune system - activates lymphocytes -> tumor cells eliminated Sentinel cells, mainly NK cells are essential in tumor cells surveillance, however, other immune cells also play critical role
Treatments of autoimmune diseases
(don't need to know)
Chronic rejection
(occurs months to years after surgery): - mediated by CMI (CD8 & CD4 T cells); antibodies may also be involved Mechanism: 1. It is hypothesized that chronic rejection is result of continued prolonged acute rejection process 2. Granulomas can form in transplanted tissue d/t prolonged immunosuppressive therapy (host immune system is unable to clear pathogens)
Hyper acute rejection
(up to 24 hrs) Antibody mediated - occurs within minutes when tissue becomes vascularized - mediated by pre-existing antibodies to donor's antigens Mechanism: 1. Antibody binds to antigens in graft's endothelium 2. Complement activated + influx of neutrophils 3. Endothelium cells shed lipid particles and promote coagulation 4. Formation of thrombus, ischemia, cell death
What cytokines differentiate CD4 into Th1, Th2, Th17, ThFH and Treg. What cytokines do those cells produce once they get activated?
***keep figure for Step - this figure is wrong in other books
If pt is AB blood type, he/she can get blood from .... and can donate to ... If pt is B blood type, he/she can get blood from ... and can donate to ... Type O pt can get blood from ... and donate to ...
**also need to consider Rh factor
Is expression of cytokines and chemokines regulated?
*Expression of cytokine/chemokines and their receptors is highly regulated - both timing and location expression
What factors are secreted by tumor tissues to suppress T cell proliferation and activation?
- IDO (indoleamine 2,3-dioxygenase) - converts tryptophan to kynurenine- "tryptophan desert" - FAS ligand - inducies apoptosis in T cells through ligation to FAS receptor - CTLA-4 - "off" switch for activated T cells; blocks formation of Immunological synapse binding CD80 (B7) on T cells
What antigens are Tumor antigens?
- any protein produced in tumor cell that has abnormal structure (mutation) acts tumor antigen!!! TSA - tumor specific antigens - present ONLY on tumor cells Abnormal products of ras and p53 genes
Principle of direct Coombs test
- blood sample from patient taken - Coombs reagent (antihuman antibody) is added - Coombs reagent will recognize Fc portion human immunoglobulin and will start causing clumping = +reaction
What are the immunologically privileged sites in the body?
- immune system cannot access these regions - antigens from these sites have never been exposed to immune system
What does each region of thymus contain?
- located above the heart Subcapsular Zone (upper region): - immature T cells - don't have any T cell receptors on their surfaces - not differentiated into CD4 or CD8 yet - don't express TCR or CD3 yet Cortex - express TCR and CD3 - express both CD4 and CD8 - should be able to bind strongly w/ MHC I and II - if there's weak binding, they are eliminated via apoptosis => POSITIVE SELECTION Medulla - differentiate into CD8 or CD4 - once differentiated, get presented with self antigen and if they bind strongly they are eliminated => NEGATIVE SELECTION
What are cytokines? What are their important features?
- low molecular weight proteins/glycoproteins (30KDa) - important in cell signaling and helping in communication between immune cells like B-cells, T-cells, macrophages, dendritic cells neutrophils, endothelial cells and CT cells - most are soluble molecules, some are membrane bound (ex. TNF) - High affinity for receptors - Active in picomole amounts
Central tolerance occurs during .... in ....
- occurs during lymphocyte (T & B Cells) maturation in primary lymphoid organs (thymus & bone marrow) Body presents immature lymphocytes with self-antigen Immature lymphocytes which react with high affinity to self-antigen are deleted (apoptosis) - APC presents self-antigen via MHCI or II Immature lymphocytes which react with low affinity are positively selected to mature
Live attenuated/modified vaccines are made from ... Who should get these?
- pathogens are active but have reduced virulence - colonize/infect and replicate, but do not cause disease (reduced virulence) - generate robust immunological response If given to <1 year old -> maternal Ab may kill pathogen
Agglutination is used to determine
- presence of pathogen/antigen in patient's serum - presence of antibody to antigen in patient's serum
What is difference between autocrine, paracrine and endocrine action of cytokines? Give one example of each
1) Autocrine Action: - act on same cell that produces cytokine Ex. Th1 (can also be made by Th2) is the major cell that produces IL-2. IL-2 then acts on the same Th1 to induce proliferation and differentiation 2) Paracrine Action: - affect other nearby cells Ex. IL-7 in bone marrow act on B-cells progenitors 3) Endocrine Action: - affect many cells systemically (away) via bloodstream Ex. Interferons and TNF-alpha produce acute phase response during inflammation
Once cytokine binds to the receptor on a cell, what effects can be seen in that cell?
1) Cell may prepare to divide 2) Undergo growth and differentiation 3) Secrets its own cytokine
What are the four causes for loss of self-tolerance?
1) Exposure of normally inaccessible self antigens: - post trauma or infection, previously unseen Ags may emerge (from immune privileged sites like brain, eye, testes, uterus (fetus) Ex: physical trauma to one eye initiates autoimmunity that can destroy vision in both eyes (Sympathetic Ophthalmia) - with injury antigens are released and picked up by dendritic cell, which take them to lymph nodes. Lymph nodes contain B and T cells. T cells get activated and then activate B cells. Once B cells are differentiated into plasma cells they start producing antibodies. Effector cells, like B cells, T cells, antibodies, will come back to the eye to control infection and attack antigen not only in one but both eyes. ***both eyes have the same antigens. If there're antibodies or effector T cells that act against antigen in one eye, they will also attack the second eye 2) Self Antigen Modification: - normal self antigens may be modified by factors such as viruses, drugs, genetic mutations so they are no longer recognized by immune system as self-antigen 3) Chronic Inflammation - can cause significant tissue damage, which exposes/releases self-antigen - linked to increase in autoimmunity Autontibody-mediated inflammation can lead to further autoreactive B-cell activation and this leads to further chronic inflammation pic: tissue damage results in release of antigens that get taken up by APC (ex. B cell). B cell then activates T cell, which then acts to activate B cells and make them differentiate. Plasma cells produce antibodies, which go back and attack the tissue. This leads to even more release of antigens. 4) Molecular mimicry (Cross reactions): - infectious agents appear similar to self-antigens (reaction between streptococcal antigen & myocardium in rheumatic fever) pic: we share some antigens with pathogen. Ex. some of the antigens on bacteria are similar to antigens in our organs like heart. Antibodies against antigens on bacteria cross-react and attach heart tissue -> rheumatic fever
Problem 2
1. A+ 2. B+ 3. AB+ 4. O-
What are the clinical applications of agglutination essay?
1. Direct detection of bacterial, fungal and parasitic species in pt's sample 2. Diagnosis of rheumatoid arthritis: detection of Rheumatoid Factor (RF) 3. Diagnosis of typhoid fever (Widal Test): detection of S.enteritica Sp. Typhi 4. Determination of viral infection and timeline (kinetics) of infection (IgM or IgG) - if only get IgM in sample, that means pt is in early stage of disease - if detect only IgG and no IgM -> pt in later stage of disease or received vaccine to antigen 5. Blood typing (hemagglutination) 6. Combs test pic: Rt - negative; Left positive rxn
What factors contribute to Autoimmunity?
1. Genetics: - defects can lead to failure of intrinsic tolerance - autoimmune conditions run in families Certain autoimmune diseases affect individuals with of specific HLA allotypes Ex. HLA-DR3, HLA-DR4 -> insulin dependent diabetes mellitus ------------------ 2. Environmental exposure: - pollution, carcinogens, hormonal status etc. - may be due to infection or damage Molecular mimicry involved in infection - viral or bacterial gene products may resemble self-antigens - present antigenic epitopes that are cross reactive
What are the types of vaccines?
1. Live vaccines 2. Attenuated live vaccines 3. Inactivated (killed vaccines) 4. Subunit 5. Toxoids 6. Conjugated
Problem: What would be the result for this serotype? How does AB+ look like?
1. O+ 2. O- 3. A+ 4. A- 5. B+ AB+ => all 3 will have positive agglutination
Most effective vaccines generate antibodies that ....
1. Prevent toxins from binding their receptors - antibodies neutralize toxins by binding to them and not letting them bind to receptors on the cell 2. Bind the pathogen and prevent infection - viruses usually get neutralized by production of antibodies
What factors contribute to graft rejection?
1. Surgical complications 2. Ischemia-reperfusion injury 3. Rejection a. Acute b. Chronic 4. Infections 5. Post-transplantation lymphoproliferative disorders (PTLDs)
What is anergy induction?
1. T-cells become unresponsive to antigen stimulation d/t inadequate activation of T-cells During normal T cell response: - APC presents antigen on MHCII to TCR - co-stimulatory signal between B7 (on APC) and CD28 (on T cell) are needed - if both signals happen -> T cell is activated During Anergy: - CD28 on T cell is replaced by CTLA-4 (cytotoxic T lymphocyte antigen). CTLA-4 binds with B7. (co-stimulatory signal is needed) 2. TCR signaling without co-stimulation CTLA-4 binds B7 (CD80/CD86) molecules but has negative effects, unlike CD28 which provides costimulatory signal for T cell activation - CTLA-4 binding B7 proteins transmits inhibitory signal - different signaling pathway is activated than when CD28 binds B7 proteins (CD80/CD86) - CTLA-4 signaling pathway shuts down T-cell activity 3. CTLA-4 binds more avidly to B7 than CD28
What are the 4 effects of autoimmunity?
1. Tissue destruction: - IDDM (Insulin dependent DM): CTLs destroy insulin producing beta cells - Hashimoto's Thyroiditis: destruction of thyroid by thyroid-specific antibodies -> Hypothyroidism 2. Ab stimulates inappropriate function: - Grave's disease: Ab binds to TSH-receptor -> Hyperthyroidism 3. Ab blocks normal function: - Myasthenia gravis: Ab binds ACh receptors 4. Ag-Ab complexes affect function: Rheumatoid arthritis: Ab complexes deposit in joints -> inflammation
Mechanisms of peripheral T cell tolerance
1. clonal anergy 2. clonal deletion 3. suppression - mechanisms to get rid of self-reactive T cells
Kidney transplant rejection
= T cell mediated A: patchy distribution of infiltration cells B: predominance of lymphocytes in infiltrate C: plasma cells & eosinophils D: tubular invasion of lymphocytes
What is tolerance?
= ability of distinguish between self and non self cells and tissues All individuals are tolerant of their own antigens (self-tolerance) Breakdown of self-tolerance = autoimmunity
Colony Stimulating Factors (CSF) function and examples
= cytokines that act on stem cells in bone marrow to stimulate growth and differentiation into specific types of blood cells Include: - Macrophages CSF (Monocyte-CSF/CSF1) - Granulocyte CSD/CSF3) - Erythropoietin (EPOp)
What are adjuvants and why they added in some vaccines?
= ingredient of vaccine that help create stronger immune response Adjuvants help vaccines work better 1. Aluminum gels or aluminum salts; used in vaccines since 1930s: - Hepatitis A - Hepatitis B - Diphtheria-tetanus-pertussis - Haemophilus influenzae type b (Hib) 2. Monophosphoryl lipid A has been used since 2009 in one vaccine in US (HPV, cervarix) pic: effects of adjuvants on antibody responses of mice to egg albumin pic: injecting antigen in saline, antibody titer is small - injecting antigen+adjuvant leads to much higher production of antibodies
Tumor Necrosis Factor (TNF) function
= large superfamily of cytokines (19 different ligands and 29 different receptors in human) TNF-alpha = major "inflammatory" cytokine - involved in activating immune cells during infection and inflammation Play important role in death of tumor cell
What is active immunization and what are the types?
= refers to immunity produced by body after exposure to antigens Naturally: - following exposure to infection (virus, bacteria) Artificially: - by vaccination: attenuated organisms, killed organisms, toxoids etc
What is vaccine? Vaccines are usually prepared from ....
= substance used to stimulate production of antibodies and provide immunity against one or several diseases - B-cells and T-cells responses without overt infections - Protection via immune memory Vaccines are usually prepared from: 1) causative agent of disease 2) products of causative agent
Toxin neutralization Why is it important?
Ab attaches to toxin Physical binding of antibody (IgG is most plentiful) may prevent protein toxin from binding to its receptor site and thereby inhibit toxic activity Many diseases are caused by toxins of different microorganisms ex. Tetanus, Cholera etc.
Myasthenia Gravis cause
Ab blocks normal function: Myasthenia gravis: Ab binds ACh receptors - muscle activation is inhibited
Which of the following autoimmune diseases affect the nervous system? A. Myasthenia gravis B. Mixed essential cryoglobulinemia C. Graves' disease D. Pemphigus vulgaris
A. Myasthenia gravis
Graves Disease
Ab stimulates inappropriate function: Grave's disease: Ab binds to TSH-receptor -> Hyperthyroidism Autoimmune B cells make antibodies against TSH receptor that also stimulate thyroid hormone production. Thyroid hormones shut down TSH production, but have no effect on autoantibody production, which continues to cause excessive thyroid hormone production
What is the role of Complement system in transplant rejection?
Activation of complement cascade by donor-specific alloantibodies (DSAs) activates classical pathway Complement activation might cause injury in transplanted tissue by: - Anaphylatoxins - enhance cellular infiltration and inflammation - Migration of MQ, DCs & CTLs to grafted tissue and direct damage to allograft
What is affinity and avidity binding in antigen-antibody interactions?
Affinity = quality of fit between antigen and antibody - antigen binds to N-termins of antibody at CDR (complementarity determining regions) pic: well balanced fit, all AA interact (Lt) (Rt) low affinity binding; easier destroyed Avidity = overall strength of Ab-Ag complex
In peripheral tolerance what mechanisms silence potentially autoreactive T cells?
Anergy => unresponsiveness Deletion => by activation-induced cell death Suppression => block in activation via T regs
AIRE genes are responsible for ... Mutation in AIRE Genes lead to ...
Autoimmune regulator (AIRE) - responsible for expression self antigens by epithelial cells and dendritic cells in medulla of thymus Mutations -> autoimmune disease due to poor presentation of self antigens by epithelial or dendritic cells AIRE genes are important for maintaining tolerance and avoid autoimmune diseases
Differentiate autoimmunity from immunity, immunodeficiency, hypersensitivity and immunosuppression
Autoimmunity = responses against its own healthy cells and tissues Immunity = ability to resist infection/toxin by action of specific antibodies Immunodeficiency = failure of immune system to protect body against infection Hypersensitivity = undesirable reactions produced by the normal immune system, including allergies and autoimmunity Immunosuppression = partial or complete suppression of the immune response of individual
What is autoimmunity?
B and T-cells recognize own cells as foreign cells - attack against own cells
Which of the following is not a type of cytokine? A. Chemokines B. Hormones C. Interferons D. Lymphokines E. Interleukins
B hormones
The patient in the previous question tells you she is pregnant. Does her risk from this vaccine increase? A. Yes B. No
B. No - since vaccine is recombinant and not live attenuated - live attenuated would be more risky
What are agglutinins? Give examples
Binding of antibody to antigen -> precipitation of Ab:Ag complex - can be visible to naked eye Agglutinins = antibodies that can precipitate antigen - IgM -> d/t its high valence; particularly good agglutinin Note: other substances that cause particles to coagulate from fluid to solid state are also called agglutinins (lectins, WGA, Ricin, some viral antigens)
Immunization is designed to increase concentrations of ....
antibodies and/or effector Tcells, which are reactive against infection Immunization procedure called vaccination Immunizing agent called vaccine
What are the principles of blood typing?
Blood antigens are carbohydrates linked to cell membrane proteins or lipids There are 2 blood antigens: A & B - based on RBC cell surface carbohydrate content Group AB - both antigens present Group O - RBC have neither of two antigens D antigen - Rh (Rhesus ) factor ABO test - antibody (immobilized on surface) is mixed with antigen = blood Positive test = agglutination of particulate antigen *Control well has no antibody! pic: Top -> blood sample is placed on ring; ring has series of immunoglobulins. Group Type is O- since there's no agglutination for A, B or Rhesus #1 - immunoglobulin will recognize factor A #2 - immunoglobulin will recognize factor B (anti-B antibody) #3 - will recognize Rhesus factor #4 - control - shows how no agglutination sample looks like Bottom: Group type is A+ since agglutination in A and Rhesus
What is the difference between CD4 and CD8?
CD8 = role in controlling viral infection + tumor cells CD4 = produce cytokines, activate and direct other cells
How does host respond to tumors?
Cell-Mediated Immunity - effector cells (T cells, NK, MQ) have effective tumoricidal abilities Humoral - no significant protection against tumor growth - most antibodies can't recognize TAAs - shed TAAs may be captured by these antibodies as prevent access to tumor tissue - blocking antibodies can ↑tumor growth - Cytotoxic antibodies - directed against tumor cells play minor role Cytotoxic antibodies - when bound to antigen, activate complement pathway or NK cells (ADCC) Blocking antibodies - when bound to antigen, block another immune reaction. May induce partial immune tolerance
Differentiate central from peripheral tolerance. What mechanisms are related to each?
Central tolerance -> occurs via clonal deletion in primary lymphoid organs Peripheral -> via anergy, suppression, deletion
Differentiate between positive and negative selection. At which parts of thymus they do they occur?
Cortex => negative selection Medulla => positive selection Positive selection: - double-positive thymocytes (CD4+/CD8+) migrate deep into the thymic cortex, where they are presented with self-antigens expressed on MHC molecules on surface of cortical epithelial cells - thymocytes that interact with MHC-I or MHC-II survive Negative selection: - in medulla, they are again presented with self antigen presented on MHC complex of medullary epithelial cells - thymocytes that interact too strongly with self-antigen receive apoptotic signal This process is important component of central tolerance and serves to prevent formation of self-reactive T cells that are capable of inducing autoimmune diseases
What was the first vaccine used on a smallpox virus?
Cowpox vaccine
What is the difference between cytokines and chemokines?
Cytokines => direct growth, development, maturation, activation and life-span of immune cells Chemokines (Chemotactic Cytokine) => subset of cytokines - direct movement of WBCs like neutrophils in the body, tells them where to go
Cytokines and chemokines change cell behavior by altering ...
Cytokines bind to specific receptors on target cells and send signals inside the cell, leading to gene transcription Cytokines and chemokines change cell behavior by altering function of protein in cell and by changing expression of specific gene by the cell Different cytokines have opposing effects, some turn responses up and some down
Chronic diseases in which immune response is targeted toward autologous entities of one's body are known as _____. A. Hypersensitivity reactions B. Innate immune reactions C. Allergic reactions D. Autoimmune diseases
D. Autoimmune diseases - own cells attack own cells
In central tolerance, immature lymphocytes with high affinity receptors for self-antigens are deleted. What is this process called? A. Hypersensitivity reactions B. Both Positive and Negative selection C. Positive selection D. Negative selection
D. Negative selection
You have a patient who is a researcher who will be handling blood samples. She wants to get vaccinated against Hepatitis B (which is transmitted through blood). The HepB vaccine is produced by having yeast produce a protein from the outer surface of the virus, and then purifying that protein. What type of vaccine is this? A. Attenuated vaccine B. Whole agent inactivated vaccine C. Toxoid vaccine D. Recombinant subunit vaccine
D. Recombinant subunit vaccine
48-year-old man has had chronic cough with fever for 2 months. On physical examination his temperature is 37.9°C. A chest radiograph reveals a diffuse bilateral reticulonodular pattern. A transbronchial biopsy is performed and microscopic examination shows focal areas of inflammation containing epithelioid macrophages, langhans giant cells, and lymphocytes. Which hypersensitivity is best described by these findings? A. Type I hypersensitivity B. Type II hypersensitivity C. Type III hypersensitivity D. Type IV hypersensitivity
D. Type IV hypersensitivity - because of lymphocytes, delayed response - no antibody relationship
Direct vs Indirect agglutination
DIRECT: antibody reacts directly with pathogen (antigen) - antibody can directly capture and agglutinate antigen INDIRECT (passive): there's artificial carrier of rx between antibody and antigen. Ex: latex beads coated with antibody or antigen - RBCs can also be used in indirect pic: latex bead is covered with antigen. If serum has antibody that recognizes antigen, clumping will occur = positive test pic: latex bead can be covered with immunoglobulin (any immunoglobulin even IgG). If the sample has antigen, antibody coated bead will clump antigen (or epitope, particle etc)
Vaccination schedule for 0-6 years old
DTaP = PEDIATRIC = 6 weeks to 6 y.o. Tdap = adult = booster of DTaP
Differentiate DTaP and Tdap in terms of relative concentrations of each antigen, and who gets vaccinated with each. What happens if they are mixed up?
DTaP = pediatric = 6 weeks - 6y.o. - to three deadly diseases caused by bacteria: diphtheria, tetanus, and whooping cough (pertussis). Tdap = adult booster - reduced dose of the diphtheria and pertussis vaccines
Autoantibodies Against Receptors can activate (Agonist) or destroy (Antagonist) receptor. Which diseases (Graves, Myasthenia gravis, Insulin-resistant diabetes, hypoglycemia) exhibit activation and which show destruction of receptors?
Graves and Hypoglycemia: = agonist reaction => activation of receptors MG and Insulin-reistant DM = antagonist => destruction of receptors
Principles of Coombs test Direct vs Indirect
Direct = used to detect antibodies stuck to surface of RBC Indirect = tests for presence of free-flowing antibodies that can react with RBC
When is direct Coombs test used?
Direct used in: - Alloimmune Hemolytic disease - Autoimmune hemolysis AIHA = autoimmune hemolytic anemia
Do mature lymphocytes come in contact with new or already seen antigen?
During maturation, lymphocytes cannot be presented with every self-antigen Some antigens are found in low concentrations in specific locations New antigens are formed during life Therefore, lymphocytes come in contact with new antigen
What is the composition of vaccine for diphtheria? A. Carbohydrate B. Inactivated bacteria C. Live attenuated bacteria D. Protein-conjugated carbohydrate E. Toxoid
E. Toxoid - sometimes toxoids are used to increase efficacy of polysaccharide vaccines
What type of vaccine is used on encapsulated bacteria?
Encapsulated bacteria needs conjugated vaccines to have stronger immune response Examples: - H. Influenza type B (Hib) - Neisseria meningitidis - Streptococcus pneumoniae
What is the only anti-inflammatory cytokine?
IL-10
What is the last pre-transfusion test?
Final step of pre-transfusion compatibility testing for presence of irregular antibodies (any antibodies outside of ABO system); errors in ABO grouping, and clerical errors in patient identification and result recording. Irregular antibodies can be produced d/t: - repeated blood transfusions, injections, maternal and child blood group incompatibility in pregnancy, immune-stimulating of blood products or some non-perceived stimuli **If pt had multiple blood transfusions, it's likely pt developed immunity to some other factors that could be present on RBC (also serum byproducts can cause this) ***Maternal incompatibility in pregnancy has to do with Rh
What are 3 roles of INF alpha and beta (Type I) in controlling viral infection?
Functions of INF alpha and beta: 1 - protect uninfected neighboring cells by activating genes that induce destruction of mRNA and inhibit translation -> virus won't replicate and multiply once neighboring cells are affected 2 - increase expression of MHC I (MHC I present antigen to CD8) This helps to recruit more CD8 and control viral infection 3 - activate NK cells to kill virus-infected cells KNOW at least the ones above!
GVHD (graft versus host disease) results from ...
GvHD - resulting form cause other than bone marrow transplant Thymus transplant (cause recipient cells act as donor T cells). - because of negative selection to donor an not recipient's antigens in donated thymus Transfusion associated GvHD - donor lymphocytes attack recipient's lymphoid tissue - occurs in immunocompromised patients, or in blood donations from close-relatives (parent, sibling, child) TAMA (thymoma-associated multiorgan autoimmunity): - patient's own thymus produces self-directed T cells, d/t it's inability to eliminate self-reacting T cells
Clinical applications of hemagglutination assay
HA (hemagglutination assay) - RBCs are used to detect presence of Influenza virus Most frequent use of this test is in Influenza vaccine production HA can be also used to detect mumps and rubella viruses, which also cause agglutination of RBCs pic: assay is used to test amount of virus in vaccine - serial dilution of virus in vaccine (dilutions of virus are mixed with RBCs 1/8-1/32 = good agglutination 1/64 => weaker agglutination = so probably TITER 1/28 and 1/256 => no agglutination - we want to see at which point the virus is still viable to cause hemagglutination We want to have vaccine that will be effective and cause production of neutralizing antibodies and so vaccines are tested before administered to population
What is the difference between hemagglutination assay and hemagglutination inhibition assay
HIA tests for presence of neutralizing antibodies in pt serum Control rx = shows agglutination Test rxn: pt serum is tested to see if there are neutralizing antibodies that may react with virus and neutralize it - no agglutination rxn
Current approaches to match graft donor & recipient
HLA (MHC) class I and class II compatibility - Humans express 6 alleles of HLA I molecules and ~8 classes of HLA II; together ~14 alleles HLA I (A, B, C) = 6 (1 allele from each parent) HLA II = DQ, & DP - 1 from each parent; DR - 1 or 2 - from each parent - HLA match for transplant is based on 8 or 10 HLA markers (alleles) that are most representative in population Maximum number of HLA markers considered for HLA typing is 10 (HLA-A, -B &-C; DRB1 & DQ) ****The more markers people share, the better HLA match
Which allotypes are associated with type 1 DM?
HLA-DR3, HLA-DR4 Type 1 DM = insulin dependent
Using Hashimoto's thyroiditis and Grave's Disease as prototypical autoimmune diseases, explain how autoantibodies can cause hyperactivity or hypoactivity in a target organ
Hashimoto: - CD4 cells can activate CD8 cells (CTL), which kill thyroid cells via apoptosis - CD4 can activate B cells, which differentiate into plasma cells and produce antibodies. Antibodies attack thyroid cells and lead to destruction of thyroid gland => Hypothyroidism Graves: Autoimmune B cells make antibodies against TSH receptor that also stimulate thyroid hormone production. Thyroid hormones shut down TSH production, but have no effect on autoantibody production, which continues to cause excessive thyroid hormone production => Hyperthyroidism
Describe role of MHC in autoimmunity (example of a genetic contributing factor)
Having some MHC molecules increases the risk of autoimmune diseases more than having others. Certain autoimmune diseases affect individuals with of specific HLA allotypes Ex. HLA-DR3, HLA-DR4 -> insulin dependent diabetes mellitus
What is herd immunity, how does it work? What is the overall percentage of people who need to be vaccinated to protect the population at large from a vaccine-preventable epidemic?
Herd immunity does not protect against all vaccine-preventable disease Best example of this is tetanus, which is caught from bacteria in environment, not from other people who have the disease - No matter how many people around you are vaccinated against tetanus, it will not protect you from tetanus
Classification of chemokines based on their function
Homeostatic Chemokines: - control migration of cells during normal development and maintenance of tissues and lymphoid organs Inflammatory Chemokines: - produced in response to infection or injury - direct migration of leukocytes into infected or damaged site Angiogenic Chemokines: - some chemokines promote development of blood vessels (pro-angiogenic) - others prevent development of blood vessels (anti-angiogenic)
What cytokines differentiate CD4 into Th1? What cytokines are produced by Th1?
IL-12. INF-gamma induce differentiation Th1 produce: IL-2, INF-gamma, TNF-alpha
CD4 cells get differentiated into Th2 under the influence of ... cytokines What cytokines are produced by Th27?
IL-4 induce differentiation Th-2 produce: IL-4, IL-5, IL-10
Which cytokine acts on liver to induce production of acute phase proteins?
IL-6
CD4 cells get differentiated into Tfh cells under the influence of ... cytokines What cytokines are produced by Tfh?
IL-6, IL-21 induce differentiation Tfh produce: IL-21 function: activate B cells; maturation of antibody response
CD4 cells get differentiated into Th17 under the influence of ... cytokines What cytokines are produced by Th17?
IL-6, TGF-beta, IL-23 induce differentiation Th17 produce: IL-17, IL-6 function: bring neutrophils to site of inflammation
What cytokines cause fever?
IL1-beta, IL6, TNF alpha
Investigators developing a new peptide vaccine against Mycobacterium tuberculosis are testing the vaccine in mice. They analyze the cytokines produced in response to immunization as a correlate of protection. Induction of which cytokine by immunization would suggest a poor outcome because of exacerbation of disease? A. Interferon-γ B. Interleukin-1 (IL-1) C. Interleukin-2 (IL-2) D. Interleukin-3 (IL-3) E. Interleukin-4 (IL-4)
IL4 because it will inhibit Th1
When is the indirect Coomb's test used?
IgG can cross placenta
What is passive immunization? What are the types?
Immunity can be acquired, without the immune system being challenged with an antigen Naturally: - trans-placental transfer of maternal IgG Abs to developing fetus - transfer of IgA Abs in milk during breastfeeding of newborn Artificially: - injection of immunoglobulin after diagnosis of exposure to toxin/virus - short-term preventive procedure ex. if one is traveling to endemic area like Africa where Yellow fever is present, vaccine can be given but need 3-4 weeks for antibodies to develop. This type of vaccine may not be helpful and instead passive immunization of immunoglobulin will give quick protection ***In diphtheria and tetanus passive immunization is given as prophylaxis or tx In rabies it's given post-exposure
Subunit vaccines are made from .... How can they be made? What are the chances of adverse reactions?
Instead of entire microbe, subunit vaccines include only antigens that best stimulate immune system In some cases, these vaccines use epitopes - very specific parts of antigen that antibodies recognize and bind to Can contain 1 - 20 or more antigens Because subunit vaccines contain only essential antigens, chances of adverse reactions to vaccine are lower Ways of making Subunit vaccines: 1) Grow microbe in lab and then use chemicals to break it apart and gather important antigens 2) Manufacture antigen molecules from microbe using recombinant DNA technology. Vaccines produced this way = "recombinant subunit vaccines"
A 5-year-old boy with immunodeficiency is extremely susceptible to severe disease caused by fungi and enveloped viruses, especially herpesviruses. What deficiency is consistent with this disorder? A. Complement C3 B. Complement C5 C. Interferon-alpha D. Interleukin-1 (IL-1)
Interferon alpha and beta are needed to control viral infections
What antibodies are produced during primary and secondary immune response? Why?
In primary immune response: - APC like B cell, which have BCR needed to bind with pathogen. Once antigen binds, positive signal is sent to B cell and it gets activated, becomes plasma cell and starts producing IgM antibodies. ------------ In secondary immune response: - on second exposure with the same pathogen with the same antigen, antibodies that are already present d/t primary exposure will bind to antigen and Fc portion of antibody binds to Fc-gamma R2B1 receptor on B cell. B cells won't get activated and will not produce IgM antibodies (negative signal). Memory B cells bind to antigen on pathogen and this sends positive signal to memory cell , which will differentiate into plasma cell and start producing IgG
People with IL-12 receptor deficiency are at highest risk for ...
Increased susceptibility to intracellular infections: - Disseminated Salmonella - Disseminated TB mycobacterial infections - Disseminated Bacillus Calmette-Guerin (BCG) after vaccine IL-12 triggers differentiation of Tho to Th1 cells Activated Th1 cells produce IFN-gamma - Important for response to intracellular infections Children born without IL-12 receptors have impaired Th1 responses & low IFN-gamma levels Treatment: IFN-gamma INF-gamma will induce macrophages to kill mycobacteria
Which cytokines inhibit Th2 responses? Which cytokines inhibit Th1 responses?
Inhibit Th1: IL-4, IL-10 - Th1 produce INF gamma, which inhibits Th2 response Inhibit Th2: INF-gamma - Th2 produce IL4 and IL10, which inhibit Th1
Live attenuated vaccines are available against ...
Know: 1. MMR 2. Oral polio vaccine = called Sabin - not used in US since there was incidence of it causing disease 3. against bacteria Typhoid BCG (against TB) - not used in US; but used around the world to vaccinate children
What are the subsets of cytokines?
Interleukins => made by T-cells (IL1, IL2 etc) Lymphokines => made by lymphocytes Interferons (IFN) => involved in antiviral responses; control viral infection Tumor Necrosis Factors (TNF) => produced by mast cells, macrophage and T-cells, they are membrane bound (cause tumor death) Transforming Growth Factors (TGF) Colony Stimulating Factors (CSF) => for growth and differentiation of immature leukocytes in bone marrow Chemokines => promote chemotaxis (attract immune cells)
Ischemia vs Reperfusion
Ischemia - lack of arterial blood flow through organ Reperfusion - restoration of arterial blood flow in ischemic organ
Molecular basis of transplant rejection
MHC molecules are alloantigens 10% of T cell repertoire are allospecific to alloantigens When donor (D) cells are transplanted into recipient (R); recipient lymphocytes will recognize donor cells as "non-self" through MHC mismatch and trigger immune response = graft rejection Alloantibodies may also trigger reaction = function of complement
What cells of innate and adaptive immunity produce cytokines? Majority of cytokines and chemokines are produced by ....
Majority of Cytokines and chemokines are produced by Macrophages, Dendritic cells and T-lymphocytes
Classification of Cytokines based on their function
Mediators and Regulators of Innate Immunity: - IL-1, TNF-alpha, IL-6, IFN-gamma etc - act on endothelial cells and leukocytes to stimulate early innate responses Mediators and Regulators of Adaptive Immunity: - IL-4, IL-5 , TGF-beta etc - act on lymphocytes to stimulate and regulate adaptive responses to specific things Stimulator of hematopoiesis: - IL-3, IL-7, GM-CSF etc - act on bone marrow to stimulate growth and differentiation of leukocytes and lymphocytes
What are mitogens? Give examples
Mitogens are often used to stimulate lymphocyte to assess immune function The most commonly used mitogens in clinical laboratory medicine are: 1. Phytohaemagglutinin (PHA) - common 2. Concanavalin A (Con A) 3. Lipopolysacchride (LPS) 4. Pokeweed Mitogen (PWM) Mitogens are used to see if vaccine is working or not. Ex. if you vaccinate a group of people and you see they are not responding to vaccine. To see If T and B cells are working, you can stimulate them with mitogens in the lab and see if they are functional or not.
Define molecular mimicry and describe its role in autoimmunity induction (example of an environmental contributing factor)
Molecular mimicry is one of the leading mechanisms by which infectious or chemical agents may induce autoimmunity. It occurs when similarities between foreign and self-peptides favor an activation of autoreactive T or B cells by a foreign-derived antigen in susceptible individual.
Why are we concerned with ABO blood testing in a patient that never had blood transfusion, thus should not be immunized?
Molecules of ABO blood type are based on carbohydrate chain made of 4-5 simple sugars, and so are not unique. These antigens are present also on surface of saprophytic bacteria (in the gut), viruses and food we ingest. Before age of 1 y.o, person will produce antibodies to these sugars that are absent from his/her own RBCs, and becomes immunized to non-self blood type through this mechanism Remember!! - antibodies to carbohydrates are generated through TI mechanism of antigen presentation; and are primarily of IgM group (carbohydrates are not presented via MHC molecules; therefore antibodies to carbohydrates are generated through T cell independent mechanism and antibodies being produced are primarily IgM, which are good agglutinins) - thus agglutination will occur almost immediately if blood type is not perfectly determined before transfusion (if not good blood match)
Interleukins are made by ... What are the key roles of IL-1, IL-2, IL-4, IL-5, IL-15, IL-10?
More than 35 different interleukins identified in humans - made by WBCs to regulate function of other immune cells Key roles: IL-1 = inflammation, induce fever IL-2 = T-cell growth IL-4 = B-cell growth IL-5 = Eosinophil growth IL-15 = NK cell growth IL-10 = regulatory/immunosuppressive (suppress T helper cells)
What are the two modes of organ transplantation?
Moving of organ/tissue from donor to recipient - allografts - donor and recipient are from same species - Isograft (syngeneic graft) - donor and recipient are genetically identical (identical twins) - xenografts - tissue from different species (skin, bone, heart valve tissues - xenotransplant - organ from different species (temporary solution to keep patients alive) Moving tissue within same person's body = autograft - Skin (burn victims) - Muscle - Hair
For which diseases we don't have effective vaccines yet?
Need better vaccine for Measles because current vaccine is heat sensitive and cannot transport it easily in hot climates TB vaccine has many disadvantages: - can cross-react with PPD antigen and this compromises PPD used in diagnosis - efficacy varies: some areas it gives good protection in others doesn't - can't be given to immunocompromised Need better vaccine for TB and Measles; other diseases listed don't have vaccine currently
... selection is important for avoiding autoimmune diseases
Negative selection
Which selection is important to avoid autoimmune diseases? Where does it happen?
Negative selection (T cells that strongly bind to self antigens are eliminated) In medulla of thymus Only select T cells that: - bind to self MHC I and II - don't bind self antigen T cells that survive will maintain tolerance in our body
General Properties of Cytokines
Once cytokine is released, it can bind to receptor on another cell Binding causes internal cell signal and alters cell activity
What are the examples of inactivated vaccines, what antibodies do they generate?
Polio => Salk = inactivated vaccine Generate a lot of IgA, which are needed in mucosal surfaces of GI
GVHD (graft versus host disease)
Reaction that develops after allogeneic bone marrow transplant and is initiated by grafted tissue In nutshell: immunocompetent cells that are transplanted to immuno-incompetent host recognize host as non-self Mechanism: 1. afferent phase: presentation of antigens and activation of APCs 2. efferent phase: activation, proliferation & migration of effector cells (CD8 T cells) 3. effector phase: activated immune cells migrate to various organs causing multi-organ failures
What are the conjugated vaccines and what are the examples?
Polysaccharide antigens - No T-cell stimulation (T cells can only recognize peptides. B cells won't be activated leading to poor B-cell memory - weak immune response -> weak protection Conjugated to peptide antigen - B-cells generate antibodies to polysaccharides - protein antigen presented to T-cells - T-cells in response will boost B-cell response - Strong immune response -> strong protection Examples: - H. Influenza type B (Hib) - Neisseria meningitidis - Streptococcus pneumoniae ****Encapsulated bacteria needs conjugated vaccines to have stronger immune response
Positive vs Negative selection in central tolerance
Positive Selection = ensures that mature T-cells recognize non self-peptide/MHC complex Negative Selection = ensures that autoreactive T cells are killed before released from thymus
Practice 4
Pt samples are serially diluted Pt A: - samples form pallet = no agglutination That means neutralizing antibodies in pt serum can neutralize virus and blood cells via gravity fall to the bottom of well pt A 1:128 = agglutination => so titer is 1:128 - that means sample was diluted too far and the antibodies won't neutralize virus - at this titer pt is infected Pt B: - agglutination in every dilution - there're no antibodies in pt serum to neutralize virus - Pt not infected Pt C: - palet forms in dilutions 1:1 - 1:32 That means pt is infected because in the dilutions there were still enough antibodies to cause virus neutralization 1:64 antibodies are diluted too much titer = 1:64
Quantitative agglutination test is used to measure ...
Qualitative agglutination = previous tests described => give yes/no answer Quantitative = measures level of antibodies that particulate antigen(s) in pt's serum - via hemagglutination - serum sample may be diluted serially - maximum antibody dilution (terminal dilution) that gives visible agglutination is called = TITER
Polio vaccine types
Salk vaccine, which is inactivated and the one used in the US. Sabin vaccine, which is an oral vaccine and used in other countries, carries risk of causing polio.
What test can help determine if there's any antibody in pt or donor's serum that could react with RBC upon transfusion?
Several categories of cross-matching: 1. Major cross-match - involves testing pt's serum with donor cells to determine whether pt has antibody which may cause hemolytic transfusion reaction of donor cells how: pt serum is matched with donor's RBC; if there's reaction and agglutination happens => NEGATIVE MATCH (blood can't be used in transfusion) 2. Minor cross-match - involves testing pt cells with donor plasma to determine whether there is antibody in donor's plasma directed against antigen on pt's cells how: donor's serum mixed with pt's cells. If agglutination -> Negative match 3. Electronic cross-match - computer-assisted analysis using data, from donor unit (where donor's blood is tested prior to donation) and testing done on blood samples from recipient. This includes: - ABO/Rh typing of unit and of recipient + - antibody screen of the recipient.
Minimum HLA matching recommendations
Solid organs - Kidney (HLA - A: -B: - DR) match - Heart & lung (HLA - DR) - standards are lower due to rapid tissue ischemic injury - Liver- ABO compatibility Liver is more tolerant to ABO blood group incompatibilities than other solid organ transplants. This approach is used in desperate situations (fulminant hepatic failure) - Hematopoietic stem cells transplant requires perfect match for HLA-A, -B, - C, -DRB1, - DQ (10 match)
What mechanisms help tumor cells escape immune system?
Suppression of MHC I expression Antigenic masking of tumors - lack of suitable antigenic component to be recognized by circulating lymphocytes - Lack of co-stimulatory signaling (defective immunological synapse) Immunosuppressive microenvironment via inhibitory cytokines: - TGFβ -has 3 functions: controls proliferation, induces cellular differentiation or promotes apoptosis. In tumors synthesis TGFβ↑: promotes immunosuppression of surrounding cells, angiogenesis in tumor tissue and changes proinflammatory status of effector T cells to anti-inflammatory suppressor T cells - IL-10 - anti-inflammatory - downregulates expression of TH1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages Tumor antigen shedding induces tolerance to tumor antigens by: - depletes parent cell of tumor antigen and makes them invisible to host immune surveillance system - TSAs & TAAs adsorb circulating antibodies -> neutralizes their anti-tumor effect - Membrane vesicles shed from tumor cells include promotors of coagulation => induce clotting near tumor + form barricade to isolate tumor from host immune system
What is suppression?
T-Regulatory cells found in thymus and peripheral tissues, inhibit (suppress) functions and activation of autoreactive effector T-cells - CD4 differentiates into Treg under influence of TGF-Beta cytokine Such immune response inhibition makes autoreactive T-cells unable to attack self antigens
Can normal cells express tumor antigens?
TAA - tumor associated antigens are present on some tumor cells, but also some normal cells
CD4 cells get differentiated into Treg under the influence of ... cytokines What cytokines are produced by Treg?
TGF-beta induces differentiation Treg produce: TGF-beta Function: suppress immune responses
What is the role of cytokines produced by Th1 and Th2 cells?
Th1 cells: IL-2: - mostly produced by Th1 cells (can also be made by Th2) - they are T-cell growth factor - stimulate growth of CD4, CD8 T-cells - activate B-cells and NK cells IFN-gamma: - activate macrophages (phagocytosis/killing) - activate Th1 cells - suppresses Th2 production - cells under influence of INF-gamma produce more MHC I and II proteins ----------------------------------------------------- Th2 cells: IL-4 (Major Th2 cytokine): - activate Th2 cells - suppresses Th1 production - promote IgE production (allergies, parasitic infection) IL-5: - activates eosinophils (helminth infections) - help with class switching and promote IgA production (GI bacteria -> IgA acts at mucosal surface) IL-10: - inhibit Th1 production - only "Anti-inflammatory" cytokine - No pro-inflammatory effect!!!
How does the body decide whether it needs Th1 or Th2 responses?
Th1 versus Th2 varies by infection Th1 important for many intracellular infections ex. M. tuberculosis: - Intracellular infection (macrophages); M.tuberculosis survives inside macrophages and antibodies cannot enter macrophages to control infection - antibodies not effective - need strong Th1 response ex. Listeria monocytogenese: - facultative intracellular organism - weaker (relatively) Th1 response in certain populations - newborns/elderly: Risk for listeria meningitis - pregnancy: Granulomatosis infantiseptica
Practice question: Calculate serum antibody titer for each patient
This is a Quantitative agglutination test Pt 6: - Prozone in 1/2 and 1/4 dilutions -> too many antibodies that couldn't cause cross linking and agglutination - 1/8 - 1/128 => equivalence state Maximum dilution that gives agglutination = Titer
What Innate immunity factors contribute to ischemia reperfusion injury?
Transplanted tissue releases DAMPs and PAMPs (if bacteria are present) mobilize expression of TLRs on endothelium Ligation of TLR4 with DAMP(s) causes activation of endothelium and secretion of proinflammatory cytokines Induction of local inflammatory reaction causes migration and influx of leukocytes into transplanted tissue and the following: - Phagocytosis & presentation of antigens in local Lymph nodes - humoral response - CMI - CTL (mediated)
What process prevents tumors being infiltrated by immune cells & pro-inflammatory signaling?
Tumor cells lower expression of MHC molecules to avoid Tumor-associated antigen (TAAs) presentation to CD8+ T cells IFNγ stimulates tumor cells to express MHC I, process, present TAAs. Immune cells infiltrate tumor tissue IFNγ exerts following effects on tumor cells: - blocks tumor proliferation - blocks angiogenesis - increases apoptosis
What's the reason tumor and cancer start forming?
Tumor starts with failure of immune system to eliminate aberrant cell Cancer starts with failure of immune system to eliminate / contain malignant tumor
Insulin-Dependent Diabetes Mellitus (IDDM) 1 is caused by ...
Type 1 DM (Insulin is stained brown) Insulin is produced by beta cells of pancreas. If effector T cells (CTL = CD8) destroy beta cells and there will be no insulin production. - alpha cells still make glucagon - delta cells still make somatostatin
In hemagglutination by Influenza, what surface proteins of Influenza can agglutinate RBCs?
Viruses that can react with RBC: EBV, CMV, Influenza Influenza viruses express surface proteins neuraminidase(N) & hemagglutinin (H), that have can bind and agglutinate RBCs pic: if virus is present, agglutination happens if no virus, no agglutinaiton hemagglutinaiton assay sin't used to detect virus, but is used viral content in preparation of vaccine
Cytokine Receptors
a) Ig super family (Rare) => unique receptors; disulfide bonds link folded protein IL-1 and Monocyte-CSF can bind b) Class I- hematopoietin => receptor has 4 domains (upper 2, where cytokines bind, have conserved Cysteine regions; lower 2 have WSXWS protein motifs, which are absent in Class II) - most cytokines can bind c) Class II-interferon => lower domains don't have WSXWS protein motifs, otherwise look like class I - all 4 domains have conserved Cysteine regions - Interferon alpha, beta, gamma can bind + IL d) TNF receptors => 4 domains are arranged in chain - each domain has 3 conserved regions - bind TNF-alpha and beta e) Chemokines receptor family => G-protein coupled receptors (7-transmembrane) - bind IL-8 and others
What are the differences between pleiotropy, antagonism, synergy and cascading?
a) Pleiotropy = one cytokine has different effects on different cells b) Cascading = Cytokines acting sequentially - like feedback loop Ex. macrophages produce IL-12, which acts on naive Tho cells to differentiate into Th1 cells. Th1 cells will start producing INF-gamma, which then will activate macrophages (macrophages help T cells to get activated, and in response Th1 cells produce INF-gamma to activate macrophages further esp. during intracellular infections) c) Redundancy = 2 or 3 cytokines stimulate one cell - different cytokine has the same effect on ONE cell d) Synergy = 1st cytokine stimulates cell and 2nd cytokine increases the effect - one cytokine helps another cytokine to achieve maximum effect Ex. INF-gamma and TNF help each other to increase expression of MHCI e) Antagonism = 1st cytokine stimulates cell but 2nd cytokine inhibits or decreases the effect ex. IL-4 acts on B cell to class switch, but INF-gamma inhibits IL-4
Why is rabies generally given post-exposure and as a combo human rabies Ig + human diploid cell vaccine (Ag)?
active immunization in form of vaccine is given to give a person long-term immunity and let their body produce antibodies + passive immunization in form of immunoglobulin is given to give immediate protection - can't wait 3-4 weeks for body to produce antibodies
Hashimoto's Disease is caused by ..
antibodies are produced against thyroglobulin - destruction of thyroid gland's hormone secreting capacity pic: - CD4 cells can activate CD8 cells (CTL), which kill thyroid cells via apoptosis - CD4 can activate B cells, which differentiate into plasma cells and produce antibodies. Antibodies attack thyroid cells and lead to destruction of thyroid gland => hypothyroidism
Alloantibody
antibody that occurs naturally against foreign tissues from person of same species
The immune response to graft is mediated by ...
both arms of the immune system Innate immunity (early response) - Ischemia re-perfusion injury Adaptive immunity (CMI) - CD8 T cell cytotoxicity - CD4 T cells (Delayed Type Hypersensitivity = DHT) The consequence of immune response to transplanted organ is graft rejection
What type of immunity results from vaccination? What type of immunity is from preformed antibody administration?
artificially acquired active immunity ACTIVE immunization = vaccines PASSIVE immunization = preformed antibody administration
Activated macrophages produce CXCL8 that helps in .... a. activates macrophages b. induces T cell proliferation c. attract neutrophils to the site of infection d. attract macrophages to the site of infection
attract neutrophils to the site of infection
Breakdown of sells-tolerance leads to ...
autoimmunity
Toxoid vaccines are prepared by .... What are the examples?
by detoxifying exotoxins of some bacteria rendering them antigenic but not pathogenic Adjuvant (e.g. alum) needs to be added to increase potency of vaccine Antibodies generated are against toxin (antibodies neutralize toxic moiety produced during infection rather than act upon organism itself) Toxoids are highly efficacious and safe immunizing agents pic: toxin is modified to toxoid by treating it with a chemical. Toxoid vaccine gives protection without causing disease Example: - Diphtheria - Tetanus ***Against Toxins **toxoids can be conjugated with polysaccharide vaccines
Innactivated (killed) vaccines are produced by ...
by killing disease-causing microbe with chemicals, heat, or radiation - pathogen killed but antigens remain intact - cannot replicate or cause disease - strong humeral responses (antibodies) - generally requires 3-5 doses since titer of antibodies decreases with time so booster shots are needed Induces weak immune responses -> booster shots
Interferons are produced by ... What are the functions of Type I and Type II interferons?
by many infected body cells cells (not just immune cells, ex. endothelial, CT cells) in response to infections More than 20 different interferons identified in humans Type I interferons (IFN alpha and beta) => viral infections Type II interferon (IFN-gamma) => intracellular pathogens Ex. mycobcateria (TB)
CXCL2
chemokine produced by TH1 cells - stimulate and proliferate T cells
What is hemagglutination?
clumping of RBCs If erythrocyte is antigen used for reaction with antibody, agglutination is called hemagglutination
Presence of tumor-associated antigens in the serum of patients is being used for
diagnostic and prognostic purposes Ex: - in colorectal carcinoma (CRC) pt, levels of carcinoembryonic antigen (CEA) in serum has clinical relevance and is used as prognostic maker
Antigen-binding sites are located in ... regions
complementarity determining regions (CDRs) of V segments of H and L chains - this is where epitope is captured - binding is noncovalent interaction between adjacent AA (ionic interactions between adjacent AA; attraction of opposite charges; H bonds; hydrophobic interactions => determine strength of Ab-Ag reaction_)
How do immune cells communicate with each other?
cytokines
What are the subtypes of CD4? What makes CD4 differentiate into other cells?
cytokines direct differentiation
What describes a vaccine that can prevent the most common cause of severe viral gastroenteritis in infants? a. inactivated vaccine b. subunit vaccine c. toxoid d. live attenuated vaccine
d. live attenuated vaccine
Peripheral tolerance occurs in ... and it's main purpose is ....
in immune periphery (after T and B cells egress from primary lymphoid organs) Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease During maturation, lymphocytes cannot be presented with every self-antigen. - some antigens are found in low concentration in specific locations - new antigen are formed during life Therefor, lymphocytes come in contact with new antigen throughout life and they shouldn't react with self-antigens (that's why peripheral tolerance is needed)
Live vaccines are made from ... What is the only live vaccine?
made from live infectious agents without any amendment ***only live vaccine is "variola" small pox vaccine, made of live vaccinia cow-pox virus which is not pathogenic but antigenic, giving cross immunity for variola antigenic = microorganism wasn't able to cause disease, but can induce immune response
Modern vaccines are created from ...
killed bacteria or viruses, or fragments of proteins from these microbes. - proteins are recognized as antigens by our immune systems. This causes mild immune response. Goal: produce Memory T-cells and B-cells that will fight off illness if it is encountered again
What cytokines are produced by macrophages and what are their effects?
know entire chart! know function, local and systemic effects; which ones cause fever
Give examples of natural and artificial active and passive immunity
know!
Passenger leukocyte theory
leukocytes within transplanted organs sensitize recipient's alloreactive T cells PLS (passenger leukocyte syndrome) type of graft-versus-host disease results in immune-mediated hemolysis
Effective vaccines induce ... What is required against pathogens that enter via mucosa? Which pathogens can enter body through mucosal surfaces?
long-lasting memory T and B- cell responses Since vaccinations ideally need to induce host defense at point of entry, stimulation of mucosal immunity is important requirement for effective vaccines against pathogens entering via mucosa Examples of pathogens that infect via mucosa include: - Bordetella pertussis - Influenza viruses - Enteric microbes: Vibrio cholerae, Salmonella typhii; Shigella
Antibody TITER in hemagglutination assay
maximum serum dilution that forms agglutination as numerical value pic not from lecture
Autoimmune disorders are more prevalent in .... (males/females)
more common in females (3x more than men) - can also be related to stress, hormones (estrogen), pregnancy Age of onset 20-40 years old
What is the prozone effect?
negative at low serum dilution, but positive at higher dilution -- seen in Pt with very high AB levels that are unable to cross-link --> no agglutination When concentration of antibody is high, all epitopes may be saturated with antibodies and no cross-linking occurs and there is no agglutination => PROZONE EFFECT - no possibility to form agglutination since a lot of antibodies But when serum sample is diluted, cross-linking becomes possible and agglutination occurs = EQUIVALENCE state - diluted enough to be able to react with epitopes This situation can give false negative result; to avoid this, laboratories test each sample through wide range of serial dilutions POST-ZONE => no agglutination - antibodies are diluted to the point that can't form cross-linking
What is deletion?
process of deleting or killing autoreactive cells = apoptosis = programmed cell death
Principle of indirect Coombs test
pt serum is tested when you suspect antibodies may are reacting with RBC - Pt serum is mixed with RBC of donor - Coombs reagent is added - Clumping = +reaction
Advantages and disadvantages of passive immunity
no memory since preformed antibodies are given and there's no exposure to antigen Can lead to serum sickness because antibodies that are there can form antigen-Ab complex
What are the therapeutic effects of IL-2, Interferon alpha, beta and gamma, TNF-alpha, and CSF?
not on exam; just know which cytokines are used therapeutically
Explain hemagglutination
pic: shows side and top view Lt pic: +agglutination - antibody recognizes antigen on RBC and agglutination happens - from the top will see red-colored well Rt: -agglutination - RBCs gravitate to the bottom - form small-like pallet that can be seen from the top
Effector and memory B and T cells are produced during ... immune response
primary Effector cells control infection Memory cells are needed for future protection against same pathogen
