Exam 2: Immune Regulation & Tolerance

Question 1

Antigen Effects

Answer 1

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

Question 2

Cytokine Effects

Answer 2

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 T_H1 pathway through NK cell and macrophage cytokines
• IL-4
  
  • Promotes T_H2 pathway
  • Promotes Ab production by B cells
• High [TGF-β] with low IL-6 and IL-23
  
  • Production of T_REG cells

Question 3

Immune Development

Effects

Answer 3

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

Question 4

Antibody Effects

Answer 4

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

Question 5

F_cγRIIB-1

Receptors

Answer 5

Cross-linking of F_cγRIIB-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.

Question 6

APC

Effects

Answer 6

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

Question 7

B-cell

Down Regulatory Receptors

Answer 7

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

Question 8

T-cell

Down Regulatory Receptors

Answer 8

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

Question 9

Selective Cell Migration

Answer 9

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
• T_H1, T_H2, T_H17 cells express different combinations of chemokine receptors
  
  • Recruited in different circumstances

Question 10

Neuroendocrine Regulation

Answer 10

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 T_H1 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

Question 11

Genetic Effects

Answer 11

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

Question 12

Immunologic Tolerance

Answer 12

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

Question 13

Self-tolerance

Answer 13

The lack of immune reactivity against self-antigens

Question 14

Mechanisms that promote tolerance in immature lymphocytes are known as…

Answer 14

central tolerance

Question 15

Mechanisms that promote tolerance in mature lymphocytes are known as…

Answer 15

peripheral tolerance

Question 16

Ignorance

Answer 16

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

Throught to be a mechanism of autommune avoidance.

Question 17

Factors Affecting Tolerance

Answer 17

• 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

Question 18

Characteristics of Tolerance

Answer 18

• 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

Question 19

Principal mechanisms of lymphocyte tolerance include…

Answer 19

• Deletion
• Anergy
• Suppression

Question 20

T-Cell

Central Tolerance

Answer 20

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 → T_REG cells
   
   • Leaves thymus and inhibit responses in the periphery
   • Helps to control immune responses

Question 21

T-Cell

Peripheral Tolerance

Answer 21

~ 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 T_H 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 T_reg cells
   
   • Suppress immune responses
   • Promotes self-tolerance
   • Generated in thymus or periphery

Question 22

T_reg Cell

Characteristics

Answer 22

• 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

Question 23

T_reg Cell

Generation

Answer 23

Central

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

Peripheral

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

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

Dependent on IL-2 for function.

Question 24

T_reg Cell

Function

Answer 24

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 T_H1 and T_H2 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

Question 25

IPEX

Disease

Answer 25

Deficiency of FoxP3 leads to absence of T_reg cells.

Question 26

B-Cell

Central Tolerance

Answer 26

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

Question 27

B-cell

Peripheral Tolerance

Answer 27

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

Question 28

B-cell Tolerance

Complicating Factors

Answer 28

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

Question 29

Clonal Ignorance

Answer 29

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