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POM 4 Immunology > 4.6 Immune Tolerance > Flashcards

4.6 Immune Tolerance Flashcards

1
Q

What are the reasons for having immune regulation (2)?

A

Avoid excessive inflammation and tissue damage during normal protective responses

Prevent inappropriate reactions against self-antigens

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2
Q

What is autoimmunity?

A

Systemic or organ specific immune response against self-antigens

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3
Q

What are allergies?

A

Harmful immune responses to non-infectious antigens that cause tissue damage and disease

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4
Q

What 2 things can mediate allergic responses?

A

IgE and mast cells – acute anaphylactic shock

T cells – delayed type hypersensitivity

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5
Q

What do hypercytokinemia and sepsis lead to?

A

Positive feedback loop

Too much immune response leads to cytokine production and damage

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6
Q

What are the 3 phases of cell mediated immunity, and explain each phase?

A

Induction phase – DCs load antigens onto MHC, migrate to lymph nodes and present antigens to lymphocytes

Effector phase – effector T cells migrate to sites of infection and elicit response

Memory phase – once all infected cells cleared, T cells move into contraction phase and immune response is shut down

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7
Q

What is meant by self-limitation?

A

The immune response declines once it has cleared the initial antigen

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8
Q

How do responses against pathogens decline as infection is cleared?

A

Apoptosis of lymphocytes as they lose their survival signals (the antigen)

Memory cells survive

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9
Q

What are the three mechanisms which license a cell to respond?

A

Antigen recognition
Co-stimulation
Cytokine release

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10
Q

What are the three possible outcomes of an immune response?

A

Resolution – no damage
Chronic Inflammation – active inflammation and attempts to repair damage
Repair – healing with scar tissue and regeneration

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11
Q

Inducing tolerance may be exploited to prevent…

A

Graft rejection, treat autoimmune conditions and allergic diseases

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12
Q

What is central tolerance?

A

The destruction of self- reactive T and B cells in the sites of their production / maturation, before they enter circulation

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13
Q

What is the central tolerance mechanism for B cells?

A

If immature B cells encounter antigens which cross link their IgM, apoptosis is triggered

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14
Q

What is the mechanism for central tolerance for T cells?

A

If the T cell binds self-MHC strongly, apoptosis
Doesn’t bind self-MHC, apoptosis
Binds self-MHC weakly, survives

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15
Q

How can a T cell developing in the thymus encounter MHC bearing peptides that might be expressed in other parts of the body?

A

AIRE is a transcription factor allowing for the thymic expression of genes normally expressed in peripheral tissues

Thus these MHC bearing peptides can be made and presented to T cells

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16
Q

What does an AIRE deficiency lead to?

A

Multi-organ autoimmunity

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17
Q

What is peripheral tolerance?

A

Ensures that self reactive T and B cells which escaped central tolerance do not cause autoimmunity

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18
Q

How does the high level of IL-2 receptors on Tregs affect peripheral tolerance?

A

The Tregs reduce the availability of IL-2 for other B cells and T cells

Thus they are not stimulated to proliferate

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19
Q

What are some of the immunosuppresive cytokines that Tregs release?

A

TGF, IL-10

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20
Q

What do Tregs do?

A

Inhibit other immune cells

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21
Q

What affect does IL-10 have?

A

Causes cells to express more death receptors and ligands

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22
Q

What affect do Tregs have on DC’s?

A

They inhibit dendritic cells

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23
Q

What are the two types of Tregs?

A

Natural Tregs (nTreg) and Inducible Treg (iTreg)

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24
Q

What happens when DCs present any antigen to naive T cells?

A

Partial activation

25
Q

What happens when DCs present specifically a foreign antigen to T cells?

A

Stimulates B7 expression on APC which binds CD28 on T cell, leading to full activation

26
Q

What happens when a self-antigen binds a naive T cell?

A

Upregulation of FOXP3 transcription factor

Causes differentiation into T-reg

27
Q

How do T-reg cells cause anergy?

A

Fully developed T-regs express cytotoxic T lymphocyte associated antigen 4 (CTLA-4)

CTLA-4 binds B7 protein on APCs, preventing co-stimulation of other T cells, leading to incomplete activation

28
Q

How do T-reg cells inhibit the proliferation of other T cells?

A

Express adenosine and IL-2 receptors to decrease availability for other T cells

29
Q

What three things can happen to a B cell after it is exposed to an antigen?

A
  1. Antibody production
  2. Becomes a memory cell
  3. Affinity maturation
30
Q

What is affinity maturation?

A

A further round of differentiation for B cells so they can bind to antigens better

Change occurs due to somatic hypermutation

31
Q

What can affinity maturation sometimes lead to?

A

The production of self reactive B cells

32
Q

Where does somatic hypermutation occur?

A

In the germinal centers of lymph nodes and spleen

33
Q

What is Ig class switching?

A

When a B cell goes from producing one type of immunoglobulin to another

34
Q

During class switching, what is happening to the genome of the antibody?

A

Somatic hypermutation

35
Q

During class switching which part of the BCR changes?

A

The constant region of the heavy chain, not the variable region

This is so the antigen specificity is not affected

36
Q

Which enzyme is upregulated by cytokines to allow for class switching?

A

Activation induced cytidine deaminase

Allows cuts to be made in the DNA, thus producing VDJ rearrangement

37
Q

What three signals do immune cells need to be activated?

A
  1. Antigen
  2. Co-stimulation
  3. Cytokines
38
Q

What do mutations in FoxP3 lead to?

A

T-reg cells not produced properly

Severe autoimmune diseases, like immune polyendocrinopathy enteropathy X-linked syndrome (IPEX)

39
Q

What does IL-10 do?

A

Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8, IFN-gamma and downregulates macrophage functions

40
Q

What is an immune privileged area?

A

A site which can tolerance the introduction of new antigens without eliciting an immune response eg eyes and brain

41
Q

Where does immunological ignorance occur?

A

In the eyes or brain as they are immunologically privileged

42
Q

Why are T-regs only found in mammals?

A

They are critical in pregnancy, as you get half MHC from mum and half MHC from dad, which may be seen as foreign antigens so tolerance is critical

43
Q

Which Treg type develops in the thymus?

A

Natural Treg

44
Q

Where do inducible Treg’s come from?

A

Develop from mature CD4 T cells that are exposed to antigen in the periphery

45
Q

How do T cells shape the immune response for different pathogens?

A

Through the use of cytokines

46
Q

Which T helper cell is involved in controlling bacterial and fungal infections?

A

Th17

47
Q

What cytokines do TfH release?

A

IL-21

48
Q

Where are T follicular helper cells located?

A

Secondary lymphoid organs (tonsils, spleen, lymph nodes)

49
Q

What structures do TfH play a particular role in?

A

The development of germinal centers

50
Q

What co-stimulation and cytokines do TfH use to help B cells proliferate?

A

Co-stimulation – have CD40 which interacts with CD40L on B cell

Cytokine – produces IL-21

51
Q

Which T cell cytokines drives Ig class switching?

A

IL-4, IL-5, TGF-Beta, IFN-gamma

52
Q

What is the definition of tolerance?

A

Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen

53
Q

Why is it necessary to delete cells before they enter into circulation?

A

Approximately 10^15 possible TCRs and antibodies generated at random

Some of these will be self-reactive

Therefore need to be removed

54
Q

What is meant by anergy as a mechanism for peripheral toleance?

A

When an APC presents a self-antigen to a T cell, there is no B7 expression on the APC and thus no co-stimulation

Thus TCRs cannot send activating signals and T cells express CTLA-4 which further reduces B7 availability, causing inactivation

55
Q

What is meant by ignorance as a mechanism of peripheral tolerance?

A

When the antigen is not in high enough concentration for the naive T cell to become activated, thus the T cell becomes anergic

56
Q

How does ignorance as a mechanism of peripheral tolerance occur?

A

Compartmentalisation and anti-inflammatory cytokines prevent migration of T cells out of immunologically privileged sites

57
Q

What is AICD as a mechanism for peripheral tolerance

A

When the APC presents an antigen with Fas (death ligand) as its co-stimulatory molecules, drives the cell to apoptosis

58
Q

What is antigen-induced cell death as a mechanism of peripheral tolerance?

A

When T cells repeatedly recognise self antigens and lack co-stimulation, this causes:

Decreased IL2 and anti-apoptotic protein expression
Increased pro-apoptotic protein expression, causing apoptosis
Increased Fas and Fas ligands, causing apoptosis

59
Q

How does the Fas ligand result in antigen induced cell death?

A

When Fas is ligated by FasL on CD8 T killer cells, it triggers apoptosis of the cell

POM 4 Immunology (14 decks)

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