03/15b Immune Tolerance and Autoimmunity

Question 1

What is immune tolerance? What is its goal?

Answer 1

A state of unresponsiveness of adaptive antigen-responsive cells to a specific antigen
Goal - to prevent you from mounting immune responses against yourself

Question 2

What are the mechanisms of tolerance induction?

Answer 2

1) Deletion - cells are killed
2) Anergy - cells are rendered unresponsive
3) Change in antigen receptors (B cells only)
4) Cellular regulation - inhibition of immune responses by regulatory cells

Question 3

By what mechanisms do T cells generate tolerance?

Answer 3

Central - deletion and regulation

Peripheral - regulation, deletion, and anergy

Question 4

What are regulatory T cells?

Answer 4

A subset of CD4 T cells that are induced to differentiate from autoreactive T cells
Function - to suppress immune responses and maintain self-tolerance
Express high levels of IL-2 receptor
Inhibit T cell activation and T cell effector functions

Question 5

What are the two sources of regulatory T cells?

Answer 5

Thymus - gives rise to “central/natural” Treg cells

Secondary lymphoid organs - gives rise to “induced” Treg cells

Question 6

What are the mechanisms of action of T regulatory cells?

Answer 6

Production of IL-10 and TGF-beta (immune-inhibitory cytokines)
Expression of CTLA4 - blocks the interaction of B7-CD28

Question 7

What are the functions of TGF-beta? What does it inhibit and stimulate?

Answer 7

Inhibits the proliferation of and effector functions of T cells and activation of macrophages
Stimulates production of regulatory T cells and IgA antibodies
Promotes tissue repair

Question 8

What are the functions of IL-10?

Answer 8

Inhibits the production of IL-12 by and expression of costimulators and MHC II on dendritic cells and macrophages
Makes these cells less able to activate T cells

Question 9

What is anergy?

Answer 9

Response of mature CD4 T cells when they are exposed to an antigen in the absence of costimulation - cells become incapable of responding to that antigen
Can also be induced by inhibitory costimulation (CTLA4)
Often associated with prolonged or repeated antigen exposure

Question 10

What factors determine the immunogenicity of protein antigens? List four

Answer 10

Persistence
Portal of entry and location
Presence of adjuvants
Properties of APCs

Question 11

How is central tolerance in B cells developed?

Answer 11

Immature B cells that recognize self with high affinity in the bone marrow either change their receptor specificity or are deleted
If receptor editing fails, cells are deleted

Question 12

How is peripheral B cell tolerance developed?

Answer 12

Mature B cells that recognize self in the absence of T cell help may be rendered anergic or die by apoptosis

Question 13

What is autoimmunity?

Answer 13

The failure of the mechanisms of self-tolerance in T or B cells
Results in an imbalance between lymphocyte activation and control mechanisms

Question 14

What are the mechanisms of tolerance failure? List five

Answer 14

1) Defects in deletion during T or B cell maturation
2) Defective or insufficient Treg cells
3) Defective apoptosis of mature self-reactive cells
4) Inadequate function of inhibitory receptors
5) Activation of APCs, which can overcome regulatory mechanisms

Question 15

What genes are most strongly associated with autoimmune disorders?

Answer 15

MHC genes

Question 16

How might MHC alleles lead to autoimmunity?

Answer 16

A particular MHC molecule may present a particular self peptide and activate pathogenic T cells

Question 17

How can infection lead to autoimmunity?

Answer 17

Bystander activation - activation of T cells that are not specific to the infectious pathogen, leading to high levels of costimulators and activating cytokines, which break tolerance
Molecular mimicry - microbes can contain antigen that looks like self, which results in cross-reactivity against self proteins

Question 18

How do anatomic alterations lead to autoimmunity?

Answer 18

Alterations (caused by inflammation, ischemic injury, or trauma) can lead to the exposure of new self antigens that are normally concealed from the immune system
Example - post-traumatic uveitis and orchitis

Question 19

What entry routes by protein antigens favor stimulation of an immune response?

Answer 19

Subcutaneous
Intradermal
Absence from generative organs

Question 20

What entry routes by protein antigens favor tolerance?

Answer 20

Intravenous
Mucosal
Presence in generative organs

Question 21

Does prolonged antigen exposure favor immune activation, or tolerance?

Answer 21

Tolerance