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IMS: Immunology > Immune Regulation & Tolerance > Flashcards

Immune Regulation & Tolerance Flashcards

1
Q

Antigen Effects

A

Generation of an immune response depends on the dose, timing, and nature of the antigen.

  • Presence of antigen / controlled antigen removal by immune system
  • Antigen concentration / dose
    • Very large doses of Ag = tolerance
    • Very, very low doses of Ag = fail to reach threshold for activation
  • Antigen route
    • Ag given by subcutaneous or intradermal injection tend to induce more active response
    • Ag given IV, PO, or inhaled has increased chance of an altered or tolerogenic response
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2
Q

Cytokine Effects

A

Cytokines have a profound impact on regulation of the immune response.

Forms an extracellular communication network between cells.

  • IFN-α/β
    • Produced during viral infection
    • Increases class I MHC
    • NK cell activation
    • Indirectly promotes TH1 pathway through NK cell and macrophage cytokines.
  • IL-4
    • Promotes TH2 pathway
    • Promotes Ab production by B cells
  • High [TGF-β] with low IL-6 and IL-23
    • Production of TREG cells
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3
Q

Immune Development Effects

A

Immune system more likely to be tolerized during prenatal and neonatal periods than in adults.

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4
Q

Antibody Effects

A

Pre-existing IgG antibodies inhibits production of Ab with similar reactivity.

  • High affinity IgG antibodies compete with B cells for Ag.
  • Anti-idiotype network model
    • Anti-antibodies (Ab-2) can arise in later stages of an immune response to foreign Ag
    • Ab-2 can recognize variable regions on Ab-1 elicited previously
    • Ab-2 = anti-diotypes
    • Variable regions on Ab-1 = idiotypes
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5
Q

FcγRIIB-1

Receptors

A

Cross-linking of FcγRIIB-1 receptors on naïve B-cells by IgG inhibits activation.

Prevents low affinity IgM from being produced if high affinity IgG is already being made by other B-cells with similar reactivities.

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6
Q

APC Effects

A

Characteristics of cell or APC presenting Ag to naïve celsl can impact whether response robust or tolerogenic.

MHC and B7 expression varies by cell type and activation.

Stimulation of PRRs by PAMPs and DAMPs increases expression of MHC & B7 shifting towards a more active response.

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7
Q

B-cell

Down Regulatory Receptors

A
  1. CD22
    • Found on mature B cells and some immature B cells
    • Inhibitory receptor for BCR signaling
    • Prevents overactivation of the immune system and development of autoimmune diseases
  2. FcγRIIB-1 receptors
    • Cross-linking by IgG on naive B-cells inhibits activation.
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8
Q

CTLA-4

A

Both CD-28 and CTLA-4 found on T-cells.

  • CD-28:B7 delivers secondary activating signal to T-cell.
  • CTLA-4:B7 delivers inhibitory signal causing anergy.
  • Regulation of both CD-28 and CTLA-4 on mature primed T-cells important in control of auto-reactive T-cells.
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9
Q

Selective Cell Migration

A

Immune regulation involves the spatial and temporal recruitment of different cell types.

Occurs through differential expression of chemokines and cellular adhesion molecules.

Ex.

  • Innate immunity
  • TH1, TH2, TH17 cells express different combinations of chemokine receptors and are recruited in different circumstances.
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10
Q

Neuroendocrine Regulation

A

There is extensive communication between the immune system and the neuroendocrine system.

  • Innervation of primary and secondary lymphoid organs by ANS.
  • Many hormones exert direct & indirect effects on the immune system.
    • Stress responses
      • Corticosteroids → immunosuppresive
      • Endorphins → either immunosuppresive or immunostimulatory
    • IL-1 and IL-6
      • Induce production ACTH → corticosteroid release
      • Inhibition of TH1 cytokine production
      • Promotes induction of TGF-β
      • Increase body temp
      • Suppresses appetite
      • Enhance duration of slow-wave sleep
    • Growth hormone
    • Prolactin
    • Thyroxine
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11
Q

Genetic Impact

on

Immune Response

A

Possible genetic impact on individual susceptibility to infection, allergy, and autoimmunity.

Proposed mechanisms:

  • MHC haplotype impacts
    • Peptide presentation
    • Thymic education
  • Non-MHC genes in the MHC region
    • HLA locus encodes > 100 genes including
      • complement components (C4, C2, factor B)
      • cytokines (TNF-α)
      • compnents of Ag processing and presentation (TAP)
      • heat shock proteins
  • Genes outside of MHC
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12
Q

Immunogenic Tolerance

A

The ACQUIRED inability of an individual to respond to a particular antigen.

  • Ag specific
  • Induced following T/B cell exposure to Ag
  • Tolerogen = Ag in which tolerance was induced
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13
Q

Ignorance

A

Immune system doesn’t react to the antigen because it doesn’t “see” the antigen.

Throught to be a mechanism of autommune avoidance.

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14
Q

Factors Promoting Tolerance

A
  • High doses of Ag
  • Persistent of Ag in the host
  • IV or PO administration
  • Absence of adjuvants
    • Substances added to increase the body’s response
    • Ex. aluminum gels or salts in vaccines
  • Low levels of costimulators
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15
Q

Characteristics of Tolerance

A
  • Shows Ag specificity
  • Shows memory
  • Is not merely the absence of immunity
  • Can be induced more readily in immnature than in mature lymphocytes
  • Can be broken
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16
Q

T-Cell

Central Tolerance

A

A selection process by which auto-reactive immature T-cells are toleraized.

Occurs primarily through deletion via apoptosis.

  1. Thymic Education
    • Positive Selection
      • Double positive cells expressing TCR capable of binding self-MHC receive “to live signal”
      • Remainder undergo passive neglect and die by apoptosis
      • Ensures that mature T cell pool can interact with self-MHC molecules leading to MHC restriction
    • Negative Selection
      • Cells tested for the avidity to self-peptide presented by self-MHC
      • Some Ag from blood
      • Ectopic gene expression of peripheral organ-specific genes by medullary thymocytes induced by autoimmune regulatory (AIRE) transcription factor
      • T-cells that recognize self-peptide:MHC with high affinity deleted
        • Inhibits development of auto-immunity
        • Promotes self-tolerance
      • Cells that bind with low avidity mature into naive T-cells
  2. Cells with intermediate affinity for self-Ag upregulate FoxP3 → TREG cells
    • Leave thymus and inhibit responses in periphery
    • Help to control immune responses
17
Q

T-Cell

Peripheral Tolerance

A

~ 1/3 of auto-reactive T-cells with low affinity for self escape into the periphery.

Peripheral tolerance prevents cells from causing damage and auto-immune disease.

  1. Anergy
    • New, naive autoreactive T-cells most likely stimulated by self-Ag without co-stimulation from resting APCs → anergy
    • During infection, PAMPs and DAMPs → “danger signal” → expression of costimulatory molecules on APCs → activation of functional lymphocytes with foreign Ag specificity
    • Relies on constant expression of self-Ag and transient expression of foreign Ag
  2. Down-regulation by CTLA-4
    • CTLA-4 upregulated on effector T-cells after many rounds of stimulation and replication
    • CTLA-4:B7 delivers inhibitory signal
  3. PD-1 Receptor
    • PD-1 on T-cells binds PD-L1 or PD-L2 on APCs
    • Delivers inhibitory signal
  4. Constant self
    • Extended presence of self-Ag (or persistent foregin-Ag) leads to waning of immune response and tolerance
  5. Activation-induced cell death (AICD)
    • Mature TH cells receiving repetitive stimulation by Ag past a threshold express Fas
    • Fas:FasL → caspase cascade → T-cell death
    • Because self-Ag persist, function as “exhaustion” model of tolerance
  6. Suppression by Treg cells
    • Suppress immune responses
    • Promotes self-tolerance
    • Generated in thymus or periphery
18
Q

Treg Cell

Generation

A

Central

  • Immature CD4 T-cells which bind self-Ag with intermediate affinity
  • Upregulate FoxP3
  • Become Treg then travels from thymus to periphery

Peripheral

  • Naive CD4+ T-cells stimulated by dendritic cells producing high TGF-β without other cytokines for TH development
  • Expression of FoxP3
  • Development of Treg phenotype

Express high affinity IL-2R including α-subunit.

Dependent on IL-2 for function.

19
Q

Treg Cell

Function

A

Functions to suppress immune responses and promote self-tolerance.

  • IL-10
    • Inhibits proinflammatory effects of macrophage
    • Down-regulates costimulatory molecules
    • Down-regulates class II MHC
    • Inhibits IL-12 production
  • TGF-β
    • Inhibits development of TH1 and TH2 cells
    • Inhibits proinflammatory effects of macrophage
    • Promotes tissue repair through collagen synthesis
  • High levels of CTLA-4 expression
    • Competes with CD28 on naive and effector T-cells for binding to B7
20
Q

IPEX

A

Deficiency of FoxP3 leads to absence of Treg cells.

21
Q

B-Cell

Central Tolerance

A
  1. Receptor Editing
    • High levels of multivalent self-Ag can prompt immature (IgM+ IgD-) high affinity auto-reactive B-cells to reactivate RAG1/RAG2
    • Initiate new round of VJ (light chain) rearragement
    • Results in new light chain with different reactivity
  2. If editing fails, autoreactive cells are:
    • clonally deleted
    • anergized
22
Q

B-cell

Peripheral Tolerance

A
  1. Control by tolerant T-cells
    • B-cell function partially dependent on T-cell help
    • Efficient self-tolerance of T-cells attenuates or blocks pathology of auto-reactive B-cells
  2. CD22 inhibitory receptor
    1. Activation results in inhibition of BCR signaling
  3. Undergoes anergy and deletion in the periphery
23
Q

Features Complicating

B-cell Tolerance

A
  1. Naive B-cells shorter-lived so tolerance also shorter.
  2. Ig genes capable of somatic mutation, can mutate away from tolerance.
  3. T-cell help can be given by neighboring T-cells reacting to another Ag.
24
Q

Colonal Ignorance

A

Auto-reactive T or B cells can sometimes co-exist with Ag and remain in an un-activated state.

  • Lymphocyte has low-affinity for self-Ag
  • Reacts against auto-Ag which is present at very low concentrations
  • Upregulation of Ag following tissue damage can promote breaking of tolerance

Auto-reactive T or B cells sometimes unable to see self-Ag due to an immune privileged site.

  • Protected by tight junctions and immunosuppressive cytokines
  • Ex. brain, spermatozoa/testes, ovary, placenta, eye

IMS: Immunology (19 decks)

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