Immunology test 3
Leishmainia
*** The triad of canine vector-borne diseases: three way interation between the infectious agent, vector, and host immune system -vector salivary proteins injected into dermal microenvironment make favorable environment in the host macrophages: this allows for infection of co-feeding naive vectors and promotes ***Th2 above he host protective Th1-regulated cellular immne response *** Plasticity of CD4 T cell subsets - murine model of leishmaniosis; sterilizing immunity is prevented by the action of T cells with regulatory function
Vaccine and vaccination
- a preparation of living or inactivated pathogens used as an antigen. -administration of a living or inactivated pathogen to induce an immune response
iLC 2&3 combat helminths
- iLC3 - promote formation of peyers patch by releasing cytokines and increasing adhesion molecules that both attract cells to form the immune rich environment -iLC2 - in peyers patches promotes anti-helminthic immunity by releasing cytokines that can increase mucus secretion and contract intestinal smooth muscle
Il7 and IL15
- these cytokines provide survival signals for memory T and B cells -maintenance of memory cells does not require the persistence of the original antigen
Vaccination / Small pox
-1850-1979 1 billion people died from smallpox virus -Vaccination programs reduced virus spread and eradicated worldwide in 1979 -2 immunizations close t osmallpox virus induces secondary immune response w/ memory -1/2 population in USA has been vaccinated; neither group has been exposed to the virus -*** Comparison reveals persistence of immunological memory in the absence of antigen
Gene rearrangement by Trypanosomes
-African trypansomes have antigenic variation that allows them to escape from adaptive immunity (also salmonella and n. gonorrhoeae) -There are many inactive trypanosome VSG genes but only one site for expression; Inactive genes are copied into the expression site by conversion; many rounds of gene conversion can occur, allowing the trypanosome to vary the VSG gene expressed: this results in a dramatic cycling of parasites within the infected person
Recombination allows flu virus to escape from immunity ????
-Appearance of the new antigens as a result of genetic recombinations between two or more viral strains - antigenic shift (more dramatic than drift) -A second host is infected with a human and avian strain; recombination of viral RNA in the secondary host produces virus with a different hemagglutinin; no cross-protective immunity in humans to virus expressing a novel hemagglutinin
BVDV ????
-Bovine viral diarrhea viruses -development of the fetal calf depend on the timing of infection -the infectious agents that cause this disease may occur as two biotypes: non-cytopathic and cytopathic [whether or not they exhibit visible changes in cell culture]
Autoimmune diseases
-Breaking T cell tomerance is a feature of autoimmune disease -Incomplete deletion of self-reactive T cells in the thymus: APECED -Insufficient control of T cell co-stimulation: CTLA-4 deficiency -Lack of Treg cells, deficiency in FOXp3: IPEX
iLCs
-Cells that have lymphoid progenitor and morphology but respond rapidly and robustly in a non-specific manner -Likely goes from the lymphoid precursor through an iLC precursor -Distinct from lymphocytes because they have limited receptor rearrangement -Roles of tissue defense, repair, immune homeostasis and contributing or initiating adaptive immune responses -iLC regulation of adaptive immunity -cytokine production: rapid and sustained "first responders"; could stimulate T cell differentiation and/or immune homeostasis NK cells produce IFN-gto induce TH1 responses ILC2 cells produce IL-4 to induce TH2 responses • ILC2 cells produce IL-13 to induce DC homing to lymph nodes, which can also induce TH2 responses • NK cells can kill immature DC (lack of MHC class I expression); "prunes" excess immature DC population -Direct cell interactions: iLCs 2 and 3 express MHC class II
How tumors are eliminated by the immune system
-Combination of innate and adaptive immunity -Innate: NK cells and γδT-cells: Recognition of MIC (MHC class I related-chain) by innate lymphocytes expressing the activating receptor NKG2D. MIC expression; cell infection, proinflammatorycytokines, DNA damage. Tumor-specific antibodies: recognize surface-expressed tumor antigens. Antibody-dependent cell-mediated cytotoxicityby NK cells. -Adaptive: CD4+ effector helper T-cells (activation of cytotoxic t cells); a). Required for protective antibody responses (T-cell help). b). Required for activation of naïve CTL. c). Macrophage activation -production of reactive oxygen species at the tumor. CD8+ CytotoxicT-cells; CTL-mediated killing of tumor cells. Secretion of IFN-γ: Increase MHC expression; Inhibit angiogenesis; Induce apoptosis of some tumors
Features of Mucosal Immunity
-Combined area of the mucosal surfaces > skin -Three quarters of the body's lymphocytes are in secondary lymphoid tissues serving mucosal surfaces, and a similar proportion of all antibodies made by the body is secreted dimeric IgA -GI tract has continuous contacts with large populations of commensal microorganisms and substantial quantities of proteins derived from the animals and plants (food) -***The major challenge for the mucosal immunity is to make immune responses to eliminate pathogens, limit the growth and location of commensal microorganisms, and do not attack the food!
Bridging
-Connecting innate to adaptive - the adaptive response depends on innate cells for initiation: antigen presenting cell to T cell (DC, MP, Bcell) -Cells that possess innate and lymphoid characteristics: the in-betweeners (gammadelta, B-1, NKT, Innate-like T cells)
NOD-like receptors ***
-Cytoplasmic NOD-like receptors are signaling PRRS -endothelial cell enterocyte have innate immune ftn respond to bacterial products -binding of PAMPS to signaling PRRS promotes cytokines, chemokines and defensins to be secreted that are crucial to initiating innate immunity and adaptive immunity
Gut-joint disease axis
-DCs activated by PAMPS and DAMPS can express CD1d and MR1 -> iNKT and MAIT -> cytokine and inflammation -activation of iNKT and MAIT cells by self antigens from damaged cells or by microbial derived products
Methods of Tissue Damage by Pathogens
-Exotoxin Production: strep,staph, c.tetani -Endotoxin Production: e.coli, salmonella, shiella, pseudomonas, y.pestis -Direct cytopathic effect: variola, flu, herpes - Multicellular Organisms: giardiasis, roundworms, nematodes, gapeworms etc.
FcRn
-FcRn transports IgG from the blood stream into the exracellular spaces -Procses - fluid-phase endocytosis of IgG from blood by endothelial cells of the blood vessel; acidic pH of endocyticvesicel causes association og IgG with FcRn which protects it from proteolysis; When it reaches the basolateral face of the endothelial cell, the basic pH of the extracellular fluid dissociates from FcRn
Mucosal Barrier
-First arm of the innate immune response -Goblet cells together with antibodies, defensins and other antimicrobial molecules, release protective agents that bombard pathogenic microorganisms to produce a hostile environment reducing their chances of reaching the host epithelium -Mucins are the essential anti-parasitic effectormolecules over and above their importance in mucus structural integrity -The interplay with this "first line of defense" is clearly more dynamic than previously appreciated -Opening up potentially new therapeutic approaches that aim to protect this barrier and maintain its function that ultimately may serve to reduce gastrointestinal infections and regulate inflammatory conditions in general
GALT
-Gut associated lymphoid tissues -lamina propria; mesenteric lymph nodes; palatine tonsils; adenoids; lingual tonsils; Peyer's patches [connection to lymph and blood system]; M cells; isolated lymphoid follicles; intestinal epithelium
Features of Helminth-Induced Immune response
-Helminths-infected populations exhibit lower levels of immunological diseases such as TH1-related autoimmune diseases or aberrant TH2-related diseases -Allergy being an expanding problem of developed and industrialized countries, while helminth infection being a feature in developing countries -***Unique evolutionary dialogue with their hosts immune system due to the 1) longevity within the host; 2) complex life cycles; 3) multicellularnature -Induce very different immune responses compared to other pathogens -Initiation of TH2 type immunity involving response to helminth infection, as well as allergic reactions • -***TH2 type immune responses: inflammation, wound repair, resistance to helminths -***Key players: DCs, CD4+ TH2 cells, IL-4, 5, 9, 10, 13, IgE, chemokines leading to recruitment and infiltration of eosinophils,basophils, mast cells, and expansion of alternatively activated macrophages (AAM) -***Helminths are master regulators of immune responses inducing a "modified TH2 type response" to limit a possible detrimental TH2 immunity, thus restraining the extreme symptoms: allergyor in aspects of helminth diseases such as fibrosisin Schistosoma mansoni -These mechanisms can lead to attenuation of pathology, tolerance and ultimately persistence of the worm assuring long-term survival of the parasite within the host, sustain parasite feeding, completion of the life cycle, and successful reproduction -Overall: helmimths induce protective TH2 immune response, induce immunoreglation via modulation of immue cells, allergic inflammaiton may be surpressed by a spill over effect of immunomodulatory mechansims by helminths -b cell produces il10 and inhibitory antibodies-but helminth survives -helminths can dampen allergic reactions
Tumor cell necrosis
-How adaptive immunity is activated -Tumor cell necrosis in an environment of low oxygen (hypoxia) and nutrient starvation. -Tumor cell necrosis results in the release of common intracellular proteins such as heat-shock proteins (Hsp70) and high mobility group proteins (HMGB1). -These kinds of proteins are recognized by TLR on macrophages (inflammatory cytokines) and immature dendriticcells (adaptive immunity). -Tumor antigens will be presented by DC expressing the costimulatory molecule B7
IgG suppresses naive B cells
-IgG antibody uppresses the activation of naive B cells by cross-linking the BCR and FcgR on B cells -Primary response: Naive B cell binds to pathogen-> Naive B cell is activated and becomes antibody producing plasma cell -> production of low affinity IgM antibodies - Secondary Response: Naive cell binds pathogen coated with specific antibody -> a negative signal is giben to the naive B cell to prevent its activation -> No production of low affinity IgM antibodies; ALSO Memory B cell binds pathogens coated with specific antibody -> Memory B cell is activated and becomes an antibody-producing plasma cell -> Production of high-affinity IgG, IgA, and IgE antibodies
Mothers to young: protective antibodies
-IgG isotype is selectively distributed in the body and transported from the maternal to the fetal circulation by ***FcRn*** in the placenta. -Dimeric IgA predominates in the secretions of mucosal epithelia and passed to the fetus by transcytossi mediated by poly-Ig-receptor (milk)
Genetic and env factors predispose autoimmune disease
-Infections as environmental factors that can trigger autoimmune disease -Autoimmune T cells can be activated in a pathogen-specific or non specific manner by infection -Senescence of the T cell population can contribute to autoimmunity -Genetic: different MHC I and II allotypes are correlated with different disease susceptibilities, presenting autoantigens to tolerance-breaking T cells, HLA acccounts for half of genetic predisposition autoimmune disease. Other genetic factors include proteins involved in thymic selection and in the control of T cell activation -Environmental: Damage the integrity of tissues and stimulate the adaptive immune response. Trauma, chemicals, irradiation, certain foods, all of which may also be accompanied by some form of infection
HLA
-It is the dominant genetic factor affecting susceptibility to autoimmune disease -autoimmunity is initiated by disease-associated HLA allotypes presenting antigens to autoimmune T cells -Animal MODELS of autoimmune disease demonstrated that autoreactive T cell clones can transfer disease -hla-b27 - associated with the most serious diseases: arthritis
Periscopes
-Mature DC's can extend processes across the epithelial layer to capture antigen from the lumen of the gut
Naive T cell encounters antigen
-Most activated T cells become effector cells -Some activated and/or effector cells become long-lived memory cells
Sabotage or subersion of immune defense mechainsims
-Mycobacterium phagocytosed prevents fustion of phagosome with lysosome which protects itself from the lysosomal enzymes, it survives and flourishes withing the cells vesicular system -Salmonella changes selective phagocytosis into nonselective macropinocytoss thus avoiding fast and effective antigen recognition -Listeria escapes phagosome in the cytosol and grows and replicates (cytotoxic eventually terminate) -Toxoplasma creates its own vesicle environment which prevents binding to MHC Trepnema and schistosome coat themselves with human proteins thus evading specific antibodies
Mutation allows flu virus to escape from immunity
-Point mutations in the hemagglutinin and neuroaminidase viral genes result in antigenic DRIFT -Neutralizing antibodies bind to hemagglutinin of virus v and prevent binding in person P; however, in person Q mutation alters the hemagglutinin and the neutralizing antibodies against virus V in person P do not block virus V to cells
anti-MHC antibodies
-Pregnancy is the one natural situation that leads to the production of anti-MHC antibodies -Paternal HLA isoforms that differ from the mother's HLA type have the potential to stimulate an alloreactive immune response -Mother and father usually differ in HLA class I and 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
Genetic variations within pathogens
-Protective Immunity to Streptococcus pneumoiae is serotype-specific (90 known serotypes - differ in their capsular polysaccharides) -Antibodies against macromolecules on the surface of pathogens are the most important source of long-term protective immunity to many infectious diseases -Some species of pahtogen evade such protection by having many different strains that all differ in antigenic macromolecules on their outer surfaces
Rare inherited immunodeficiency syndromes
-SCID - RAG1 or RAG2 - no gene rearrangments in b and t cells - all types of infection -Omenn syndrome - Rag 1,2 or artemis - impaired RAG function - all types of infections -Bare lymphocyte syndrome - TAP1 or 2 - Low MHC class I expression - respiratory iral infections -Complete Digeorges syndrome - not known - absence of the thymus and T cells - all types of infection -Autoimmune polyendocrinopathy candidiasis extodermal dystrophy - AIRE - reduced T cell tolerance to self antigens - autoimmune diseases -IPEX - FOXP3 - lack of t regs and peripheral tolerance
Secretory IgA
-Secretory IgA can bind pathogens in several locations -IgA can export toxins and pathogens from lamina propria while being secreted; can neutralize antigens internalized in endosomes and toxins on gut surface; binds pathogen on M cell and takes to lymph tissue (full pathogen and antigen from M cell endosome)
Models of Inflammation
-Species - cow, horse, rats, mice -Sex - male, female -Inflammogen/Disease State - what are you studying? inflammation? Or inflammation due to a disease? Ex.mice w/ LPS to verify inflammatory response;
CCR7
-T cells differentiate into central memory and effector memory subsets distinguished by differential expression of the chemokine receptor CCR7 -memory cells that express CCR7 remain in the lymph tissue
Mycobacterium
-TB and Leprosy -taret antigens for effector T cells (iNKT) that have limited range of alpha beta TCR that recognize lipid antigens presented by CD1 group of MHCI like proteins and the effector T cells secrete inflammatory cytokines and kill infected cells and memory cells
Hypothesis
-Testable -Testable: Cannabinoid compounds will suppress inflammation in dogs through inhibition of interleukin-6 production. -Not testable: Cannabinoid compounds are anti-inflammatory because they inhibit all cytokines. -Simple -Succinct -Specific -Often is stated in a single sentence -Is not always the "right" answer: If you do not prove your hypothesis, you accept the null hypothesis -Should have an overarching hypothesis for the project and a hypothesis for every experiment
Nematode expulsion
-Th2 mediated change in mucus production during intestinal dwelling nematode expulsion -***This effector mechanism acts in concert with other immune-mediated host responses to expel the worm from its intestinal niche
Passive immunization with anti-Rh Ig ????
-This prevents haemolytic anemia of the newborn -First pregnancy of Rh- mother carrying a Th+ fetus: Primary immune response, IgM plus low amounts of low-affinity IgG -> Minor destruction of fetal erythrocytes by anti-Rh IgG -> healthy newborn baby -Second and subsequent pregnancies of Rh- mother carrying a Rh+ fetus: Secondary immune response, abundant, high-affinity IgG transcytosed to fetal circulation -> Massive destruction of fetal erythrocytes triggered by anti-Rh IgG -> Anemic newborn babies -First and subsequent pregnancies of Rh- mother carrying a Rh+ fetus and infused with anti-Rh IgG -> Fetal erythrocytes are not destroyed-> healthy newborn babies -Pregnant RhD-women are infused with purified human RhD-specific abs (RhoGAM) during the 28th week of pregnancy. -The mothers immune system is tricked into responding to the primary RhD antigen exposure as through it was a secondary exposure
Transfer of disease
-Transfer of disease by immune effectors: antibodies to the thyroid-stimulating hormone receptor (TSH) -Temporary symptoms of antibody-mediated autoimmune diseases can be passed from affected mothers to their newborn babies -Example: Mother with graves disease makes anti-TSHR antibodies; During pregnancy, antibodies cross the placenta into the fetus; Newborn infant also suffers from Graves disease; Plasmapheresis removes maternal anti-TSHR antibodies and cures the infant's disease
IgG -fetus
-Transient decrease in levels of IgG in the first year of life -Newly synthesized IgG begins after birth -IgA will begin to be synthesized IgA shortly before birth -Ordered of Ig synthesized: IgM, IgA, IgG
Autoimmune hemolytic anemia
-Type II (antibody against cellsurface or matrix antigens) -Auto antigen - Rh blood group antigens, I antigen -Consequence - destruction of red blood cells by complement and phagocytes, anemia -Three mechanisms destroy erythrocytes in *autoimmune hemolytic anemia*: -Erythrocytes bind anti-erythrocyte autoantibodies -FcR+ cells in spleen -> phagocytosis and erythrocyte destructuin -Complent activation and CR1+ cells in spleen -> phagocytosis and erythrocyte destruction -Complement activation and intravascular hemolysis -> lysis and erythrocyte
Myasthenia gravis
-Type II (antibody against cellsurface or matrix antigens) -Signaling from nerve to muscle across the neuromuscular junction is impaired; acetylcholine receptors are internalized and degraded which impairs muscle contraction -antagonist of acetylcholine receptor which causes progressive muscle weakness
Systemic lupus erythematosus
-Type III (immune complex disease) -Rheumatic disease caused by autoimmunity -autoantigen- nucleosomes (double stranded DNA and histones) -Pathogenic antibody ; IgG recognizing nucleosomes - Disease risk genes: polymorphisms in genes associated with SLE; loss of function in Fc and C3b, CD3 zeta receptor genes -Environmental association - Possible epstein-barr virus infection - molecular mimicry -Pathogenic mechanisms - Type III hypersensitivity; ;arge amount of small immune complexes are formed becasue of auto antigen and autoantibody, they develop in capillaires and become trapped in the basement membrane -Mechanism of autoantigen accumulation: Possible defects in the clearance of apoptotic cells: Macrophages from SLE patients have a reduced capacity to engul apoptotic cells in vitro
Type I Diabetes (IDDM)
-Type IV (t cell-mediated disease) -T cell responses and antibodies are made against insulin and other specialized proteins of the pancreatic beta cell islets of langerhande (clumps of alpha glucagon, Beta insulin, and somatostatin endocrine cells)
Immunological memory
-Vaccine-induced memory lymphocytes will not prevent re-infection, but can prevent disease or at least reduce severity of disease. -Vaccine-induced memory lymphocytes circulate through secondary lymphoid tissues.
iNKT
-alpha beta TCR w/ limited diversity -recognize microbial lipids by CD1 proteins -secrete large amounts of cytokines (there are iNKT subsets) -no memory, and rapid respond to infection -CD1 Antigen presentation: -MHC-like gene but is outside the MHC region -structure - MHC1 b/c uses B2 microglobulin -Behavior - MHCII for ligand binding (engages ligand in vesicle) -Bind hydrophobic channels that bind hydrocarbon alkyl chains
MAIT
-alpha beta TCRs w/ limited diversity -recognize vitamin B2 metabolites by MR1 proteins (non classical MHC type protein) -large amounts of cytokines -no memory, respond to infection -stimulation via TCR and via IL18
Viral self-defense strategies
-capture of cellular genes enxoding cytokines and receptors and diverting the immune response -synthesis of proteins that inhibit complement fixation -synthesis of proteins that inhibit antigen processing and presentation
Helminths and altered immunity
-cellular signals during helminth infections can skew the immune response to favor viral spreading - helminth activates Th2 cells to release 1l4,1l13 which ligate il4r on M2 macrophages harboring latent herpes and Il4r activates STAT6 which initiates viral replication. M2 can also inhibit virus specific Tcells = the virus is not controlled
Canine Parvo & Wolves
-excluded island in Cananda w/ wolves and moose -an ongoing study to monitor population has found they are not balanced - w/ peaks and plummets -parvovirus killed almost all wolves - w/ a limited number of MHC molecules due to isolation and inbreeding
Hemolytic disease of the newborn
-fetus in immunological distress -Immune complex-mediated inhibition of naive B cells is used to prevent hemolytic anema of the newborn (passive immunization with anti-Rhesus IgG)... must check rhesus + and -
Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC)
-helminths cant be killed by phagocytosis - external is resistant to attack and is too big -IgE coats parasites, FceRI of eosinophil and mast cells will recognize IgE and signals eosiniphils to degranulate
Autoimmune response
-immune response that causes autoimmune disease and it produces the state of autoimmunity -presece of autoantibodies, autoimmune T cells and autoantigens -the damaging responses are due to a variety of immune effector mechanisms *** -autoimmune diseases are caused by loss of tolerance of self antigens ***
Key points of Immunity in the fetus and newborn
-immune system is fully formed at birth. all acquired immune responses are primary responses. -newborn mammals obtain Ig from their mother by direct transfer across placenta or by ingestion Ig reach colostrum immediately after birth -Failure of passive transfer may result in newborn suffering from overwhelming infections -milk provides constan Ig (IgA), which helps protect the newborn against intestinal infections
Innate-like Lymphocytes
-impact adaptive immunity -located in many tissues - esp barrier sites -similar to lymphocytes except: limited receptor rearrangement, no clonal expansion when stimulated, react promptly to infection-capable of producing substantial amounts of cytokines -includes iNKT, MAIT and other iLCs
Inactivated (killed) vaccines)
-inactivated pathogen vaccine - polio -virus-like particle vaccine - HPV -subunit vaccine - Hep B, targets hep B surface antigen -inactivated bacterila exotoxins - diptheria, tetanus Conjucate - thymus dependent angitge to thymus independent antigen; generate high affinity IgG to capsular polysaccharides - strep, flu, neisseria *** General characteristics of killed vaccines: -Killed vaccines generally result in an antibody response -Very poor inducer of cytotoxic T cells
Survival strategies of intraceullar parasites
-interfere with antigen uptake mehcainisms (avoiding fast and effective antigen recognition) -create their own vesicle environment which prevents binding to MHC and presentation to T cells -Prevent fusion of phagosomes with the lysosomes which protect from lysosomal enzymes -Escape from the phagosome into the cytosol, grow and replicae
Cytomegalovirus Infection
-latent virus that usually remains quiescent but goes through periods of activation that are then quelled by the immune response -increase in viral load triggers a rapid increase in specific effector T cells -numbers fall back once virus is under control which leaves long-lived virus specific memory T cells
M Cells in GALT
-microfold or multiifenestrated are specialized to transport microorganisms to GALT -Different from DC - can transport but cant process antigen - only transcytosis -M cells btw enterocytes and close to DC endocytose antigens from lumen and antigens are released below to be taken up by APC (dendrites can span through gut wall)
Superantigens
-most powerful T cell mitogens ever discovered -concentrations of less thatn .1 pg/ml are sufficient to stimulate the T lymphocytes in an uncontrolled manner - fever, shock, death -Result in massive systemic release of proinflamm cytokines such as tnf alpha il1b and t cell mediators (Il2) which can lead to fever and shock -bind DIRECTLY to MHC (not a peptide) -Mode of stimulation: -does not prime an adaptive immune response specific for the antigen -stimulates large numbers of T cells - causes a massive production of cytokines by CD4 - contributes to microbial pathogenicity
B-1 B cells
-natural antibodies -derived during fetal development; decreased freq with age; become adult B cell pool -express CD5 (no exclusive, T cells also express) -Ftn: produce **IgM-reactive against self carbs, foreign on bacteria, do not require T cell help to produce antibodies -Can also produce cytokines
Mechanisms that contribute to immunological self-tolerance
-negative selection in the bone marrow and thymus -expression of tissue-specific proteins in the thymus -no lymphocyte access to some tissues -suppression of autoimmune responses by Tregs -induction of anergy in autoreactive T cells
Attenuated live vaccines
-propagate virus in cells of non-human animal species. Select mutants that have lost tropism for target tissues. -When used as a vaccine the attenuated viruses generally replicate at the site of inoculation. -example - sabin vaccine for polio (1960) - live portion may revert back to virulence *** General charcteristics of live vaccine - Live cavvines can mimic a natural infection resulting in polyvalent immunity: Neutralizing antibody, CD$ helper T cells, CD8 cytotoxic t cells
Controls
-saline, vehicle, diluent - recurrent infection - additional controls?
Immunity in dogs and cats study
-study that examines the durration of immunity for core viral vaccines -the animals had serum antibody to distemper, parvo type 2, and adenovirus type 1: at protective levels dogs resisted infection/disease -Even a single dose of modified live virus when administered at 16 weeks or older, could provide long-term immunity in a very high percentage of animals, while also increasing herd immunity
Transcytosis of dimeric IgA
-transcytosis across epithelia is mediated by poly-Ig-receptor -Process: Binding of IgA to receptor on basolateral face of epithelial cell; receptor-mediated endocytosis of IgA; IgA is transported to apical face of epithelial cell; Finally receptor is celaved, IgA is bound to mucus through the secretory piece
herd immunity
-vaccination provides herd immunity -reduce the transmission of infectious diseases
Protective immunity
-vaccine-induced effectors (e. g. antibodies) prevent re-infection. -Long-lived plasma cells in the bone marrow: maintain antibody levels in the bloodstream to neutralize the pathogen at the site of pathogen invasion.
How tumors evade immune elimination
1) Avoid immune recognition: Genetic instability can result in; a). Loss of tumor-specific antigens. b). Reduced expression of MHC. c). Reduced expression of MIC. 2) Suppress the immune response: Treg: Cell-surface expression of CTLA-4, produce IL-10 and TGF-Beta1
* Successful primary Immune response
1) Clears the infection 2) Temporarily strengthens defenses to prevent re-infection 3) Establishes a state of long-term immunological memotry to ensure that subsequent infections with the same pathogen will provoke a faster, stronger, secondary immune response (memory)
Original antigenic sin
A phenomenon when the first flu strain to infect the animal constrains the immune response to other strains -Highly mutable viruses such as flu gradually escape from immunological memory without stimulating a compensatory immune response
Mucosal Immune System features
Anatomical features: -Intimate interactions btw mucosal epithela and lymph tissues -Discrete compartments of diffuse lymphoid tissue and more organized structures such as Peyer's patches, isolated lymphoid follicles, and tonsils -Specialized antigen-uptake mechanisms provided by M cells in Peyer's patches, adenoids, and tonsils Effector mechanisms: -Activated effector T cells predominate even in the absence of infection -Plasma cells are in the tissues where antibodies are needed Immunoregulatory environment -Dominant and active downregulation of inflammatory immune responses to food and other innocuour environmental antigens -Inhibitory MP and tolerance-inducing dendritic cells
Three phases of tumor growth
Elimination phase - tumor cells removed; combination of innate and adaptive immunity Equilibrium phase - tumor cells persist. The immune system prevents the spread of tumor cells Escape phase - tumor cells spread into the tissue. Development of new variants, immunosuppressive environment around the tumor. -variant tumor cells may be resistant to immune cells trying to remove, over time variety will continue to develop immune cells
Pathogen replicants in animal compartments
Extracellular: -site: Interstitial spaces, blood, lymph; orgnaisms: viruses, bacteria, protozoa, fungi, worms; protective immmunity: antibodies, complement, phagocytosis, neutralization - site: epithelial surfaces; organisms: worms, mycoplasma, strep, ecoli, c. albicans; protective immunity: antibodies (IgA), antimicrobial peptides Intracellular: -site: cytoplasmic; organisms: viruses, chlamydia, rickettsia, listeria, protozoa; protective immunity: cytotoxic T cells, NK cells -site: vesicular; organisms: mycobacteria, salmonella, yersinia; protective immunity: T cell and NK cell dependend macrophage activation
Acute infection
Fig 13.4 Stages: Establishment of infection, induction of adaptive response, adaptive immune response, immunological memory -There is a threshold level of the antigen to activate adaptive immune response that exists throughout the establishment of infection -Pathogen cleared at the end of the adaptive immune response
Immune responses can contribute to disease
For some infectious diseases *all pathology* is due to the immune response: respiratory syncytial virus, wheezy bronchiolitis caused by Th2 cells responding to infection, schistosoma mansoni excessive activation of Th2 cells
How intracellular proteins cause inflammation
Funciton as DAMPs HMHB1 binds TLR4 Hsp70 binds TLR2 and TLR4
-Innate-like T cell that exresses gamma delta TCR instead of alphabeta TCR -*** gamma delta cells express TCR and CD3 -may or may not express CD4/8 -***exit thymus without positive or negative selection -derived during fetal development -2 classes: natural- mediates innate-like immediate response; induced -takes time, but precedes adaptive responses (no clonal expansion) -In blood -4% of CD3 cells - In tissues - thymus, tonsils, lymphnodes, spleen, gI, gut and skin associated lymph tissues -Freq increases dramatically in blood during infections => ***IL-17 -> NP -Limited diversity compared to alphabeta -Increased in other species (cow,chick,sheep) and more TCR than humans -recognize antigen directly rather than presented by MHC =>rapid response -ligands - proteins up regulated in response to infection - or unusual nucleotides
Gamma delta T cells
Placenta
Hemochorial (humans, primates) - IgG levels in infant are comparable to those of its mother Endotheliochorial (dogs, cats) - 5-10% of IgG may be transfered Syndesmochorial (ruminants) and Epitheliochorial (horses, pigs) - Passage of Ig is totally prevented; Newborns are entirely dependent on antibodies recieved through the colostrum**
Persistence by hiding from the immune response
Herpesviruses persist in a latent state in the trigeminal ganglion Ncp BVDV
Innate vs Adaptive Immunity
Innate: Rapid, can fully control infections, initiate adaptive responses, occur so rapidly that clinical signs of infection may not appear before the pathogen is gone, deficiencies in the mechanisms are rarer Adaptive: specificity, memory, affinity maturation, make possible vaccination
Mammalian placentation
Mammalian placentas classified on the basis of maternal layers retained in the placenta: the more layers there are, the more restricted the movement of blood between mother and fetus
How Type2-Inducing stimuli sensed
Many pathogens and allergens can be sensed by PRRs. Proteolytic cleavage of host proteins by the protease activity of allergens as well as tissue damage and metabolic changes may be sensed by DCs
Maternal antibodies inhibit vaccination
Maternal abs may either bind to injected antigens or pathogens and accelerate their clearance or they may bind the critical epitopes and prevent activation of B cells abs production
Tumor specific antigens (TSA)
Mutated self antigens expressed in tumor cells, not found in healthy cells. The mutations could alter the function of the gene product
Pathogen evolve in reducing effectiveness of human and animal immune responses
Passive: antigenic variation in the pathogen prevents the maturation of adaptive immune responses and immunological memory; latency, means of avoiding immune response while viruses lie low within cells Active: interference with key elements of immune response by inhibiting normal immune ftn or recruiting response to the pathogen's advantage
Tumor associated antigens (TAA)
Self antiens that are over-expressed in tumor cells; also includes reactivation of embryonic genes not normally expressed in the differentiated cell Ex. Prostate cancer: prostatic acid phophatase nad Melanoma:tyrosinase -TSA and TAA can be expressed by the same cell; both surface expressed and internal proteins
Ig classes in serum colostrum and milk
Serum and colostrum: majority IgG, colostrum - half of remaining IgA and other half IgM and with serum the remaining quarter majority is IgM and a little bit IgA Milk:Ruminants - a lot of IgG, osme IgA, little IgM; Non ruminants - a lot of IgA, some IgG and little IgM
Cell-Cell interactions in 2nd immune response
Similar to those activating primary response however: -effector memory T cells can be activated directly at the site of infection by DC macrophages
Sag mediated diseases
Toxic shock food poisoning mastitis
Immune Response to a Pathogen
Ubiquitous innate (0-4hrs): Infection -> Recognition by preformed non specific effectors -> Removal of infectious agent Induced innate (4-96hrs): Infection -> Recruitment of effector cells -> Recognition, activation of effector cells -> Removal of infectious agent Adaptive (>96hrs): Infection -> Transport of antigen to lymphoid organs -> Recognition by naive B and T cells -> Clonal expansion and differentiation to effector cells -> Removal of infectious agent Protective immunity: Re-infection -> Recognition by preformed antibody and effector T cells -> Removal of infectious agent Immunological memory: Re-infection -> Recognition by memory B cells and T cells -> Rapid expansion and differentiation to effector cells -> Removal of infectious agent
Exposure to the flu
With Flu vaccine- the body makes neutralizing anti-flu IgA antibodies. To replicate itself, flu must get inside human cells, which it does by using its hemagglutinin protein to bind to the sialic acid attached to human cell-surface proteins. Internalization of the virus with subsequent fusion of the viral and endosomal membranes, releases the viral RNA into the cytoplasm. This is where replicaiton occurs. This can be prevented by the presence of neutralizing antibodies agains the viral hemagglutinin that cover up its binding for sialic acid. Because flu infects epithelial cells of resp. tract - the effective antibodies are IgA dimers
iLC group 1
cells that produce IFN-g and TNF-a -includes NK cells -anti-viral, anti-tumor
iLC group 3
cells that produce IL-17 and IL-22 (TH17like) • lymphoid organogenesis (lymphoid tissue inducing cell = LTi) anti-bacterial
iLC group 2
cells that produce IL-4, 5, 9 and 13 (TH2-like) anti-helminthic pro-allergy
iLCs vs Lymphocytes
iLCS: lymphoid progenitor - limited receptor rearrangement - do not clonally expand - rapid response Lymphocytes: lymphoid progenitor - receptor gene rearrangements allow for specific pathogen recognition - undergo clonal expansion - takes several days to respond to infection
Protective and pathological responses to intestinal helminths
naive CD4 T cells are activated from helminth and differentiate to TH1 (MP and IgG2a) or TH2 (IL13 - cell repair and mucus; IL5 - eosinophils; IgE - mast and eosinophils; IL3,9,IgE - histamine effector cells
Source of B cells
primary: freq- 1x10^4 or 5; isotype: IgM> IgG; Affinity of antibody- low; somatic hypermutation: low secondary: freq- 1x10^3 (much more than primary); isotype: IgG, IgA; Affinity of antibody- high; somatic hypermutation: high
Toxoplasma gondii
successful obigate intracellular parasite that can invade and replicate in almost all nucleated cells of warm-blodded animals -regulates immune activation and host cell mechanisms by parasite effector proteins -Toxoplasma effectors are master regulators of proinflamm response -Combos of effetos maintain parasite burden in different hosts to ensure parasite transmission
