Regulation of the Immune System Flashcards by Erin Mustonen

What interaction is responsible for the upregulation of IL-2?

T-cell CD28 and APC B7 (CD80/86)

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What interaction is responsible for the downregulation of IL-2?

T-cell CTLA4 and APC B7 (CD80/86)

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Intracellular organisms elicit what type of a response?

Cell-Mediated Response from NK Cells and CD8+ T-Cells

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Extracellular organisms elicit what type of a response?

Humoral Response from Complement and Antibody-Mediated interactions

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What is CCR7 important for?

Trafficking the Dendritic Cell to the Lymph Nodes

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What are the symptoms of IPEX?

Rashes on the skin and hair falling out, collitis, diarrhea

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What is the cause of IPEX?

An X-Linked inborn lack of Treg cells that cause a severe autoimmune inflammation through immunodysregulation, polyendocrinopathy, and enteropathy.

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What is the function of IL-35?

Autoregulatory positive-feedback loop to produce more Treg cells

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What are the 3 ways that can lead to autoimmunity?

1) Absence of Tregs
2) Insufficient Treg effector functions
3) Resistance of effector T-Cells to Treg effector functions

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What happens at the end of the immune response to T-Cells?

Apoptosis of Antigen-Specific T-Cells

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What does anergy occur in mature dendritic cells?

Lack of co-stimulatory signals in the presence of strong MHC expression

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What co-stimulatory molecules are necessary for tolerogeneic DC:T-Cell interactions?

Surface Molecules: E-Cadherin, PD-1, CD103, CD152 (CTLA-4), ICOS-L (CD275)

Cytokines: IL-10, TGF-B

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What is the function of Regulatory T-cells (Treg)?

Preventing and suppressing immune responses (prevents autoimmune diseases)

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What percentage of T-cells do Tregs make up?

10%

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What surface molecules are present in immunogenic Dendritic Cells?

High CD86
High MCHII
High CD40
High CCR7

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What surface molecules are present in tolerogenic Dendritic Cells express?

Low CD86
Low MHCII
Low CD40
Low CCR7

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What are the pro-inflammatory cytokines that immunogenic Dendritic Cells secrete with presented with antigen?

IL-12

TNF-alpha

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What is the function of immunogenic Dendritic Cells?

T-cell proliferation and activation of effector functions

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What is the function of tolerogenic Dendritic Cells?

Clonal deletion or anergy of antigen-specific T-cells

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What are the 4 mechanisms of Treg effectors?

1) Immunosuppressive cytokines (IL-10, TGF-B, IL-35) –> Cell Cycle Arrest
2) IL-2 Consumption –> Bim-Mediated Apoptosis
3) Cytolysis (Granzyme-Mediated) –> Apoptosis
4) Modulation of DC Maturation and Function (CD152/CTLA4 CD80/86) –> Cell Cycle Arrest

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How does IL-35 work with Treg?

IL-35 is an autoregulator for a positive feedback loop to produce more Treg Cells.

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What are the 3 ways that loss of Treg Effector Functions can cause autoimmunity?

1) Absence of Tregs (IPEX)
2) Insufficient Treg Effector Functions (RA)
3) Resistance of Effector Tcells to Treg Effector Functions (TNF)

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What is Grave’s Disease?

Over-production of thyroid hormones caused by autoantibodies from B-cells and plasma cells that act as agonists for the thyroid stimulating hormone receptor

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What are the 3 mechanisms of B-Cell Tolerance?

1) Clonal Deletion
2) Receptor Editing
3) B-Cell Intrinsic Mechanisms

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Define Clonal Deletion in B-Cell Tolerance.

Induction of apoptosis via inhibition of survival signals or activation of death receptors

Define Receptor Editing in B-Cell Tolerance.

Continued V(D)J recombination to avoid self-reactivity

Define the 2 B-Cell Intrinsic Mechanisms in B-Cell Tolerance.

Anergy, downregulation of the BCR, upregulation of CD5 OR Lack of T-Cell help or survival factors

What type of response is evoked with administration of antigens subcutaneously or intradermally?

Active Th1 CD4+ T-Cell Immune Response

What type of response is evoked with administration of antigens orally, IV or aerosol?

Tolerance or a Th2 CD4+ T-Cell Immune Response

How is IFN-Gamma production induced in T-Cells and NK Cells and what is the consequence of this?

IL-12 stimulates IFN-Gamma production, which leads to the differentiation of Th1 T-Cells

How is IL-12 induced and what is the consequence of this?

Production of IFN-alpha early in viral infection to switch T-cells from Th2 to Th1.

What Th1 cytokines promote what cell actions?

``` IFN-y TNF-B IL-2 Macrophage Activation Antibody-dependent cell-mediated cytotoxicity Delayed Hypersensitivity ```

What Th2 cytokines promote what humoral immune responses?

``` IL-4, IL-5, IL-9, IL-10, IL-13 IgG1 and IgE isotype switching Mucosal Immunity IgA Synthesis Mast Cell/Eosinophil Differentiation ```

What Th17 cytokine promotes what cell action?

IL-17 Neutrophil Recruitment and Inflammation

How does IgG inhibit B-Cell differentiation?

By cross-linking the antigen receptor with the Fc receptor on the same cell

What 2 ways can antibody-dependent B-Cell suppression occur?

Antibody blocking by soluble Ig binding to membrane Ig when there is too much antibody in the system OR Receptor cross-linking by membrane protein FcyRIIb binding soluble IgG in a plasma cell signaling apoptosis

What are the 2 regulatory effect of immune complexes?

Inhibition through FcyRIIb OR Augmentation through complement CR2 binding to antigen and signaling the B-cell to undergo Class-Switching Recombination or Somatic Hypermutation

What chemokine receptors do Th1 T-Cells express to attract what cells?

CXCR3 and CCR5 Monocytes

What chemokine receptors do Th2 T-Cells express to attract what cells?

CCR3, CCR4, and CCR8 Mast Cells and Eosinophils

What chemokine receptors do Th17 T-Cells express to attract what cells?

CCR6 | Neutrophils

Where are the two areas of the body that immune responses do not occur and what cytokines prevent an immune response?

Anterior chamber of the eye and the testes TGF-B and IL-10

What diseases are people with C1q, C1r, and C1s defects prone to?

Systemic Lupus Erythematosus (SLE) | Lupus Nephritis

What susceptibility is increased with a deficiency in C3 (C2 or C4)?

Bacterial Infections

What is TLR4 important for and what does polymorphism Asp299Gly result in?

TLR4 is an important sensor of gram negative bacterial infections, which results in higher increase in TNFa when stimulated with LPS.

In Africans with the TLR4 polymorphism, what are they protected against?

Cerebral Malaria

In Europeans with the TLR4 polymorphism, what are they susceptible to?

Septic Shock from the plague

What mutation gives rise to a reduced number of T-Cells?

IL-7R alpha chain mutation

What mutations gives rise to reduced numbers of T-Cells and NK-Cells, as well as impaired B-cell function?

Mutation in the common cytokine receptor y chain (yc) | --component in IL-2, IL-4, IL-7, IL_9, and IL-15 receptors

What mutations increase susceptibility to mycobacterial infections?

IFNy receptor | IL-12 receptor

What mutations in cytokine receptor genes are associated with SCID?

Defect in yc or Jak 3 | Defect in IL-7R alpha

What have mutations in the cytokine promotes been linked to?

Susceptibility to infections and autoimmune conditions

What diseases has a mutation in the TNFalpha gene promoter region been associated with?

Cerebral Malaria Lepromatous Leprosy Mucocutaneous Leishmaniasis Meningococcal Disease

What mutation in cytokine promoters is associated with progression from HIV to AIDS?

Chemokine Receptor Gene-5 (CCR5)

What genotype is resistant to HIV-1 infections?

Homozygous for the CCR5 mutation

What is the root mutation causing IPEX?

FOXP3 mutation --> defective Treg Cells --> Failure of peripheral tolerance

Define Central Tolerance.

Result of the removal of self-reactive lymphocytes in the central organs

Define Peripheral Tolerance.

Inactivates T and B cells that escape central tolerance and exit to the periphery

Due to the risk of disease flare-up in IPEX patients, what is contraindicated?

Vaccination

How would you treat a flare-up of IPEX on exposure to pathogens?

IVIG

What is APECED?

Autoimmune Polyglandular Syndrome Type 1

How is APECED inherited?

Autosomal Recessive

What is the root cause of APECED?

Defect in T-cell tolerance and production of autoantibodies to IL-17 and IL-22 (produced by Th17

What abnormality might be found in the lymph nodes of individuals that lack the AIRE gene?

T-Cell zone expanded because negative selection is not present

What would you expect to find if you transferred lymphocytes from AIRE deficient mice to RAG knock-out mice?

No recombination taking place, no B-Cells or T-Cells --> APECED

What would you expect to find if you transferred lymphocytes from wildtype mice to RAG knock-out mice?

Normal transient phenotype that can fight a pathogen initially, but nothing major will happen.

How might IVIG be an effective therapy for IPEX?

Blocking the immune system to never be stimulated so you get less risk for inflammation