Immunolgy Graduate Final

Front 1

1. What are some of the properties of MHC-I?

Back 1

Peptide binding domain is α1/α2. Peptide binding cleft is closed at both ends. Bound peptides are 8-10 aa long.

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2. What are some properties of MHC-II?

Back 2

Peptide binding domain α1/β1. Peptide binding cleft is open at both ends. Bound peptides are 13-18 aa long.

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3. How does MHC exhibit diversity?

Back 3

There are many different allleles of each gene. Presence of duplicate genes with overlapping function-polygenic. HLA class I genes have 46 million class I haplotypes in population.

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4. What is linkage disequilibrium?

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When the observed number of allelic combinations in a population is fewer or greater than the expected calculated number based on allelic frquencies.

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5. How is MHC regulated?

Back 5

By transcription factors that bind to promoter sequences on the gene. Class I TF, ZFX(zinc finger protein). Class II TF, CIITA and RFX. By cytokines, IFN and TNF increase class I. IL-4 increase class II on resting B cells. IFN-γ decrease class II on B cells. Viruses decrease MHC expression and TAP proteins.

Front 6

6. What is MHC restriction?

Back 6

Target cells are nucleated cells that display peptide associated to class I to CD8 cells. APCs are cells that display peptide associated with class II to CD4 cells.

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7. What is the antigen processing pathway for MHC-I?

Back 7

Intracellular antigen is degraded by proteosome→TAP proteins recruit the peptide to the RER→MHC-I α chain and β2 microglobulin binds calnexin→Calnexin dissociates→Calreticulin, Tapasin, Erp57 bind→MHC captures peptide→chaperones dissociate→MHC-I peptide is transported from RER to golgi to plamsa membrane.

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8. What is the antigen processing pathway for MHC-II?

Back 8

MHC-II α and β chain bind invarient chain, blocking binding of endogenous Ag→MHC is routed through golgi to endocytic pathway compartments→invarient chain is degraded, leaving CLIP fragment→exogenous Ag is taken up, degraded and routed to endocytic compartments→HLA-DM mediates exchange of CLIP for antigenic peptide→Class II MHC-peptide is transported to plasma membrane.

Front 9

1. What are the features of the αβ TCR?

Back 9

Possess a CD3 complex, large TCR V gene germline repertoire, 60% CD4, 30% CD8, α chain has 61 joining gene segments.

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2. What are the features of the γδ TCR?

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10% possess a CD3 complex, small TCR V germline repertoire, no MHC restriction, binds phospholipids and intact protein.

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3. Where does the TCR obtain its diversity?

Back 11

Alternative splicing, combinatorial and junctional diversity.

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4. What are the co-receptors involved with TCR and MHC-peptide?
TH – APC:

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(CD2-LFA3), (LFA1-ICAM1), (TCR/CD3/CD4:P56lck-MHC-II), (CD45R-CD22), (CD28-B7).

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5. What are the co-receptors involved with TCR and MHC-peptide?
TC – Target Cell:

Back 13

(CD2-LFA3), (LFA1-ICAM1), (TCR/CD3/CD8-MHC-I), (CD45R-CD22).

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6. What is allogenic?

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Genetically different individuals of the same species.

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1. What are three markers that may be expressed during T cell development?

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C-kit, CD44, CD25(IL-2 receptor).

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2. Describe T cell development?

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Migrate from bone marrow→Thymus. T cell precursor rearranges T cell receptor genes. Immature T cells that recognize self-MHC receive survival signals (positive selection). T cells that interact strongly with self-MHC or are unable to recognize MHC-I or MHC-II fail to receive survival signals and are eliminated by apoptosis (negative selection). Mature naïve CD4 and CD8 migrate to peripheral lymphoid organs. Here they encounter foreign antigen and are activated to aid in eliminating the infection.

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3. What is the T cell activation time course?

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Immediate genes – 30min. Early genes – 1-2 hrs. Late genes – 2 days.

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4. Explain in detail the T cell activation pathway.

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a. Engagement of MHC-peptide initiates processes that lead to the assembly of CD signaling complex
b. CD4/8-associated p56lck phosphorylates ITAMs of zeta chains, this creates docking site for ZAP-70
c. Sustained activation is more effective if a immunological synapse froms through LFA1-ICAM
d. ZAP-70 phosphorylates LAT
e. Phosphorylated LAT activates PLC and GEF
f. PLC cleaves PIP2→IP3(Ca2+ mediated pathways) and DAG(protein kinase C mediated pathways)
g. GEF influences small G protein pathways (Ras,Rac)
h. IP3 mediates NFAT into nucleus
i. DAG influences NF-kβ into nucleus
j. Causes expression of T cell growth cytockines IL-2 , IL-4

Front 19

1. Describe the process of extravastation.

Back 19

Microvascular hemodymic process that necessitates mechanically stable interactions through specialized adhesion molecules. Leukocyte adhesion 3 steps: rolling, chemoattractant/activating signal, firm arrest. Then trans-endothelial migration. Rolling is mediated by selectins. Firm arrest is mediated by activated integrins. Strategy for anti-inflammatory therapy?

Front 20

2. What is lymphocyte homing/trafficking?

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The difference in lymphocyte extravasation (from neutrophils) is diff. subsets (effector and memory T cells) migrate to diff. tissue with the help of vascular addressins(CAM).

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3. What are other mediators(enhance) of inflammation?

Back 21

Plasma contains 4 systems with Hageman factor a common intermediate.
a. Kinin system: increase in Bradykinin, vascular permeability, vasodilation, pain.
b. Clotting system: fibrin
c. Fibrinolytic system: plasmin
d. Complement system: anaphylatoxins (C3a,C5a)
e. Lipid mediators: Mem. Phosph lipids→PL→ArachidonicA→cyclooxygenase pthwy(prostaglandin) → lipoxygenase pthwy(leukotriene A4)

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4. What cell type is critical in the inflammatory process?

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Neutrophils (PMN), a phagocyte that internalizes and kills microbes through reactive O2 and hydrolytic enzymes. Express Fc receptors and CR receptors(opsonize through C3b). 1st cell to arrive at infection through IL-8 chemotaxis. Release MIP-1 to attract macrophages

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1. What is cell mediated immunity?

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Involves specific (CD8 mediate cell-mediated; CD4 mediate delayed type hypersensitivity) and non-specific (NK, Marcophages, PMNs, Eos)cell types to detect and and eliminate intracellular pathogens, virus-infected cells, and cancer cells.

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2. What are some properties of naïve T cells?

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Co-stimulatory signal (CD28-B7) required for activation, CD45RA, Low expression of CAMs CD2 and LFA-1, trafficking patterns to high endothelial venulesin (HEVs) secondary lymphoid tissue. Secondary or peripheral lymphoid organs maintain mature naive lymphocytes and initiate an adaptive immune response. The peripheral lymphoid organs are the sites of lymphocyte activation by antigen.

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3. What are some properties of effector T cells?

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Ag-experience effector cells have less stringent activation requirements. Increased CD2 and LFA-1, trafficking patterns are tertiary lymphoid tissue/inflammation site.

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NK cell

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Innate IR, contain activating and inhibitory receptors, MHC-I restr., express CD16(Fc receptor) and CD2, destroy target cells through ADCC (Fc receptor), express FasL, constitutively toxic, no CD3 expression.

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TH1 cells

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Cell-mediated immunity. Macrophage activating effector molecules: IFN-γ, GM-CSF, TNF-α, CD40L, FasL, LTα.

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TH2 cells

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Humoral immunity. B cell activating effector molecules: IL-4 (↑Activation, growth, IgG1, IgE, ↑MHCII)., IL-5 (↑ IgA syn.), IL-13, CD40L

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TH17 cells

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Induces netrophil recruitment to the sites of inflammation: IL-17A, IL-17F.

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TH22 cells

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Express proteins involved in tissue remodeling and angiogenesis through secretion of IL-22, TNF-α

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Tregs

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Produced suppressive cytokines that inhibit T cell activation and effector functions: TGF-β and IL-10.

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Memory T cells

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Derived from naïve T cells (act. by DC) and effector cells after AG act and diff. Ag generated. Long lived quiecent cells. Same receptors as effector cells Once activated increase ↑ IFN-γ, IL-4,IL-5

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5. What is cross presentation?

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The ability of APCs to load peptides that are derived from exogenous antigens onto MHC-I. Can lead to cross priming or cross-tolerance. Essential for the initiation of the immune response to viruses that do not infect APCs.

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6. What is cross-priming?

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The initiation of an CD8 T cell response to an antigen that is not synthesized by the APC through the traditional MHC-II pathway.

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7. What is DC licensing?

Back 35

A concept that DCs must be converted by an antigen-specific T helper cell into a functional state required for immunogenic activation of CTLs. This dereases the liklihood of autoimmunity.

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8. What is CTL programming?

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A concept that CTLs receive additional information during their activation that effects their: effector functions, life-span, memory, differentiation or migratory properties. These signals determine whether cross-presentation leads to cross-priming or cross- tolerance.

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9. What are the mechanisms for cross-priming DC?

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TFBATF3 (ness. For cross-pres.) Express Fc receptors. Need a “second opinion from TH through CD40L-CD40 and secretes IL-2 this causes: ↑FasL and decrease in TRAIL

Front 38

Type 1: IgE-mediated Hypersensitivity

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Allergen enters the body and is recognized by an APC. APC phagocytoses the allergen and is presented on the plasma membrane by MHC-II molecules. Antigen specific B cells are activated and mature into IgE antibody producing plasma cells. The IgE antibody binds to Fc receptors on mast cells. During the second exposure to the allergen, the allergen crosslinks to the IgE bound Fc receptor activating a inflammation response through the degranulation of mast cells, secreting of vasoreactive amines. This causes smooth muscle contraction, vasodilation and increased vascular permeability.

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RIST (Radioimmunoabsorbent Test)

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agarose bead linked Anti-IgE→add radiolabeled anti-IgE: counts total IgE (Very sens)

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RAST(Radioalergosorbant Test)

Back 40

allergen couples to solid phase, patient IgE binds, add radioIGE probe: detect ng of Ag- specific IgE

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Type 2: IgG or IgM mediated cytotoxicity hypersensitivity

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Ab directed against cel surface antigens mediates cell destruction via complement activation or ADCC. Eg. Blood transfusions, erythroblastosis fetalis (Rh antigen made by fetus), hemolytic anemia.

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Type 3: Immune Complex-mediated hypersensitivity

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Complexes of antibodies and antigens in circulation deposit into the vascular walls of blood vessels, this leads to inflammation. The Ag-Ab complexes can be exdogenous or endogenous within the cell. Formation of the complex→Deposition into tissues, larger complexes clear quicker, longer lived complexes have more time to become lodged within the tissue→Inflammation: Vasculitis, and the activation of complement through IgM and IgG (C3a,C5a)→vascular permeability and recruitment of neutrophils and monocytes.

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Type 4: DTH Cell-mediated hypersensitivity:

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Inappropriate or excessive immune rxns mediated by TH1 and CTLs.
Sensitization Phase(1-2 weeks)-TH1 cells become activated and clonally expanded by Ag-APC.
Effector Phase- TH1 secretes ↑ IFN-γ and TNF-β. This cause huge activation of macrophages:
↑ TNF receptors, O2 radicals, Nitrix oxide, MHC-II molecules, CAMS
Causes a granuloma, extensive tissue damage that possesses: TH1 cells, intracellular bacteria, activated macrophages

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1. What is autoimmunity?

Back 44

An inappropriate immune response against self antigens.

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2. Why is immune regulation important?

Back 45

Avoid excess lymphocyte activation. Prevent innapropriate self reactions against self antigens. Prevents autoimmune disease.

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3. What is immunological tolerance?

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Unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen.

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4. What are 3 central tolerance fates?

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Apoptosis. Receptor editing. Development into Treg cells.

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5. What are 3 peripheral tolerance fates?

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Anergy. Apoptosis. Suppression.

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6. Name inhibitory receptors associated to tolerance.

Back 49

CTLA-4, CD22, FcgammaRII. Polymorphism in these are linked to AID.

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7. How can you identify Tregs?

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FoxP3, CD4, CD25 (IL-2 receptor).

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8. What is central tolerance?

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A primary mechanism to the deletion of B and T cells that possess receptors that recognize self antigens with greater than low-threshhold affinity.

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9. What is peripheral tolerance?

Back 52

A secondary mechanism in lymphoid tissue that renders lymphocytes inactive or anergic.

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10. What is a tolerogen?

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Antigen that induce tolerance.

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11. What is an immunogen?

Back 54

Antigen that induces a IR.

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12. Why does central tolerance not eliminate all self reactive lymphocytes?

Back 55

Not all self proteins are expressd in the central lymph organs where neg. selection occurs. There is a threshold requirement for affinity to self Ag before deletion, therefore weak self-reactive B and T cells survive.

Front 56

13. What is the function of CTLA-4 and where does this occur?

Back 56

It is an inhibitory receptor expressed after T cell activation to regulate activation, imp. in periperal tolerance.

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14. What are the mechanisms for maintaining tolerance?

Back 57

Central tolerance (deletion editing), antigen segregation (physical barrier to self-ag access), peripheral anergy (inactivation-weak signal), Tregs (supp. By cytokines), clonal deletion (apoptosis post-activation).

Front 58

Type II Antibody-mediated Disease

Back 58

AITD (Autoimmune Thyroid Diseases).
Hashimoto’s Disease Thyroiditis produces auto-antibodies and TH¬1 cells specific for thyroid antigens (Tg thyroglobulin) contains SNPs in exon 33, lack Treg cells. Therapy = syn. Thyroid hormone L evothroxin.
Grave’s Disease causes hyperthyroidism, goiter, and presence of stimulating Abs to TSH. Therapy = anti-thyroid meds.

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Type III Immune Complex-mediated Disease.

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SLE, produces auto-antigen (auto-antibodies) to DNA, ribosomes, RBCs, WBCs, histones. The auto-antigens activate complement mediate cell lysis, C3a and C5a. The consequences are vasculitis, arthiritis, glomerulonephritis. Therapy = Molecule that tagets B cell CD22 a reg. molecule prevents overactivation. AND Methotrexate, induces tolerances. Cause anit-proliferative, increases apoptosis of T cells.

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Type IV T cell mediated Disease.

Back 60

Type I Diabetes. A T cell response to antigens expressed in B cells of the islets (Proinsulin/insulin, GAD, I-A2) and to islet antigens. T cell response is TH1 like, makes IFN-γ helps recruit a tissue cell destruction response in insulin producing β cells.

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16. Why do autoimmune diseases occur?

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Failure in T cell tolerance.

Front 62

17. What is the strongest factor for susceptibility to autoimmune disease?

Back 62

HLA (MHC) genetic factor, but no single mutation cause autoimmunity.

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18. Name one gene associated to AI disease.

Back 63

PTPN22 (phosphatase regulates CBL function in T cells), a polymorphism in RA and SLE patients.

Front 64

1. What are the steps needed to establish an infection?

Back 64

Penetrate epithelial barrier. Compete with normal flora for binding sites. Evade innate immunity.

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2. How do pathogens avoid or evade the immune systesm?

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Start living in cells. Continuous antigen variation. Antigen molecular mimicry.

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3. How does the immune system respond to a viral infection?.

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Decrease MHC, continously change antigens through antigenic drift (mutation over time) and shift (2 or more viruses combine).

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4. How do viruses evade the immune system?

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Decrease MHC, continously change antigens through antigenic drift (mutation over time) and shift (2 or more viruses combine).

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5. How are bacterial infections eliminated?

Back 68

By humoral immunity, through antibodies (opsonization, neutralize toxins, complement-mediate lysis, complement anaphylatoxins mediate mast cell activation → inflammation

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6. What are the steps required for bacterial infection?

Back 69

Attachment. Proliferation. Host invasion. Toxin induced damage to host cells.

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1. What is a vaccine?

Back 70

A biological preparation that improves immunity to a particular disease.

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2. What is passive immunity?

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The transfer of active humoral immunity in the form of readymade antibodies, from one individual to another. Acquired through maternal ab, humanized monoclonal ab.

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3. What is active immunity?

Back 72

Acquired through natural infection and vaccines.

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4. What are the advantages and disadvantages of a live attenuated vaccine vs. a inactivated or killed vaccine type?

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Live attenuated: Strong IR, often lifelong immunity few doses. May mutate to virulent form.
Inactive/killed: stable, safer than live atten. vaccines. 4 degree storage not required. Weaker immune response than live vaccines, booster shots required.