Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Foundations of Disease > Exam 2: Immune Regulation & Tolerance > Flashcards

Exam 2: Immune Regulation & Tolerance Flashcards

1
Q

Antigen Effects

A

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

  1. Presence of Ag
    • Ag removal by immune system is a control mechanism
  2. Antigen concentration/dose
    • Very large doses of Ag ⇒ tolerance
    • Very, very low doses of Ag ⇒ fail to reach activation threshold
  3. Antigen route
    • Ag given by subcutaneous or intradermal injection tend to induce a more active response
    • Ag given IV, PO, or inhaled has increased chance of an altered or tolerogenic response
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Cytokine Effects

A

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

Forms an extracellular communication network between cells.

Examples:

  • IFN-α/β
    • Produced during viral infection
    • ↑ MHC class I
    • 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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Immune Development

Effects

A

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

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Antibody Effects

A

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

  1. High affinity IgG antibodies compete with naive B cells for Ag
  2. Anti-idiotype network model
    • Ab-1 specific for the Ag
    • Anti-antibodies (Ab-2) can arise in later stages of an immune response to foreign Ag
      • Ab-2 ⇒ anti-idiotypes
    • Ab-2 can recognize variable regions on Ab-1
      • Variable regions on Ab-1 ⇒ idiotypes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

APC

Effects

A

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

  • MHC and B7 expression varies by cell type and activation
  • Stimulation of PRRs by PAMPs and DAMPs ⇒ ↑ expression of MHC & B7 ⇒ more active response
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

B-cell

Down Regulatory Receptors

A

Contain motifs that down-regulate activation:

  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
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

T-cell

Down Regulatory Receptors

A

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

  • CD-28:B7 delivers secondary activating signal to T-cell ⇒ proliferation
  • CTLA-4:B7 delivers inhibitory signal ⇒ anergy
    • Activated T-cells begin expressing CTLA-4 later in the immune response
    • CTLA-4 has a higher affinity for B7 than CD-28
  • Regulation of both CD-28 and CTLA-4 on mature primed T-cells important in control of auto-reactive T-cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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 components
  • TH1, TH2, TH17 cells express different combinations of chemokine receptors
    • Recruited in different circumstances
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
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
      • Induces production of 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
  • Components and cytokines generated by the immune response can ∆ neural and endocrine systems
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Genetic Effects

A

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

Proposed mechanisms:

  • MHC haplotype
    • ∆ 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)
      • Components of Ag processing and presentation (TAP)
      • Heat shock proteins
  • Genes outside of MHC
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Immunologic Tolerance

A

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

  • Ag specific
  • Induced following T or B cell exposure to Ag
  • Tolerogen ⇒ Ag for which tolerance was induced
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Self-tolerance

A

The lack of immune reactivity against self-antigens

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Mechanisms that promote tolerance in immature lymphocytes are known as…

A

central tolerance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Mechanisms that promote tolerance in mature lymphocytes are known as…

A

peripheral tolerance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Ignorance

A

Immune system does not react to an Ag because it cannot “see” the Ag.

Throught to be a mechanism of autommune avoidance.

17
Q

Factors Affecting Tolerance

A
  • Increases tolerance:
    • High doses of Ag
    • Persistent of Ag in the host
    • IV or PO admin
    • Low levels of costimulators
  • Decreases tolerance:
    • subQ or IM admin
    • Adjuvants
      • Substances added to increase the body’s inflammatory response
      • Ex. aluminum gels or salts in vaccines
    • Other stimuli present during engagement
      • Pro-inflammatory signals
  • Maturation state of Ag-specific lymphocyte
18
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
19
Q

Principal mechanisms of lymphocyte tolerance include…

A
  • Deletion
  • Anergy
  • Suppression
20
Q

T-Cell

Central Tolerance

A

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

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 ⇒ 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 are 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
    • Leaves thymus and inhibit responses in the periphery
    • Helps to control immune responses
21
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 autoimmune 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
22
Q

Treg Cell

Characteristics

A
  • From CD4+ lineage
  • Express high affinity IL-2R receptors
    • Including α-chain/CD25
  • Dependent on IL-2 for function
  • Estimated to account for ~10% of CD4+ T cells
23
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.

24
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
25
Q

IPEX

Disease

A

Deficiency of FoxP3 leads to absence of Treg cells.

26
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
27
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
    • Activation results in inhibition of BCR signaling
  3. Undergoes anergy and deletion in the periphery
28
Q

B-cell Tolerance

Complicating Factors

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
29
Q

Clonal 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

Foundations of Disease (46 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions