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1.3 POM Immunology > Immune Tolerance > Flashcards

Immune Tolerance Flashcards

1
Q

Why must immune response be regulated? (3)

A
  1. Prevent over-activation of lymphocytes —> tissue damage
  2. Prevent reactions against self-antigens
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2
Q

What is immune regulation?

A

Control of the immune response to prevent inappropriate reactions

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3
Q

What can the failure of immune regulation lead to? (4)

A
  1. Autoimmune diseases
  2. Allergies
  3. Hypercytokinemia
  4. Sepsis
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4
Q

What varies within different autoimmune diseases?

A

How organ-specific vs systemic they are

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5
Q

What are 4 examples of autoimmune diseases?

A
  1. Rheumatoid Arthritis
  2. Grave’s
  3. Lupus
  4. Psoriasis
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6
Q

What does rheumatoid arthritis affect?

A

Joints

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7
Q

What does psoriasis affect?

A

Skin

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8
Q

What does Lupus cause?

A

Widespread inflammation

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9
Q

What does Grave’s disease affect?

A

Eyes

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10
Q

What proportion of the UK have an autoimmune disease?

A

10%

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11
Q

What are the underlying causative factors of autoimmune disease?

A

Genes and environment

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12
Q

What do autoimmune responses result from? (2)

A
  1. Self-antigens
  2. Microbial antigens —> overreaction
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13
Q

What causes autoimmunity?

A
  1. T cells
  2. Antibodies
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14
Q

Why can immunological diseases often chronic?

A

Attacking self antigens —> always more antigens in the body (self-perpetuating)

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15
Q

What are allergies?

A

Harmful immune responses to non-infectious agents

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16
Q

What mediates allergic responses?

A
  1. IgE and mast cells —> acute anaphylactic shock
    2 T cells —> delayed type hypersensitivity
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17
Q

When does hypercytokinaemia or sepsis occur?

A

Too much immune response
- Often in positive feedback loop

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18
Q

What are the 2 triggers of sepsis?

A
  1. Pathogens enter wrong area
  2. Failure to regulate response
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19
Q

Which 3 signals are required to activate a T-cell to perform a cell-mediated immune response?

A
  1. Antigen recognition
  2. Co-stimulation (APC and T cell stimulate each other)
  3. Cytokine release
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20
Q

How does the of the adaptive immune response to a pathogen usually end?

A

Apoptosis of lymphocytes —> only memory cells survive

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21
Q

What is the principle of cancer immunotherapy?

A

Use own immune response to target tumour cells (reactivate T cells)

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22
Q

Why does cancer immunotherapy have side effects?

A

May re-activate all T cells —> auto-immune disease symptoms

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23
Q

What are the 3 outcomes of an immune response?

A
  1. Resolution (normal) —> phagocytosis of debris by macrophages
  2. Repair (healing) —> scar tissue and regeneration via fibroblasts and collagen synthesis
  3. Chronic inflammation (doesn’t stop) —> damage repair ongoing
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24
Q

What is immune tolerance?

A

Unresponsiveness to an antigen induced by exposure of lymphocytes to that antigen

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25
Q

Why is immune tolerance important? (2)

A
  1. Self-tolerance
  2. Therapeutic potential (preventing rejection, treat autoimmune/allergy)
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26
Q

What are the 2 types of immune tolerance?

A
  1. Central
  2. Peripheral
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27
Q

When does central immune tolerance occur?

A

Before T and B cells enter circulation

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28
Q

When does peripheral immune tolerance occur?

A

When T and B cells are in circulation

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29
Q

What is central immune tolerance?

A

Destruction/inactivation of self-reactive T and B cells before they enter circulation

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30
Q

Why is central tolerance necessary?

A

Prevent immune responses to own cells
- Because so many (10^15) TCRs and antibodies —> some will inevitably match self-antigens

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31
Q

How does B-cell central tolerance occur?

A

Down-selection
- immature B cell in bone marrow meets antigen that binds to IgM of BCR —> apoptosis

32
Q

How does T-cell central tolerance occur?

A

AIRE (AutoImmune REgulalator)

33
Q

Why is T-cell central tolerance more complicated than for B-cells?

A

Involves MHC
- TCRs should be able to bind to self-MHC

34
Q

Which 3 checks are made to T-cells during T-cell selection for central tolerance?

A
  1. Doesn’t bind to any self-MHC —> death by neglect
  2. Binds too strongly —> negative selection
  3. Binds too weakly —> positive selection
35
Q

Where does positive and negative T cell selection occur?

A

Thymus
- Further selection outside thymus

36
Q

How is T-cell selection done for MHC peptides found outside the thymus?

A

AIRE (transcription factor) —> allows thymus to express genes from other tissue

37
Q

What do mutations in AIRE lead to?

A

Multi-organ autoimmunity

38
Q

How does AIRE promote self tolerance?

A

Allows thymic expression of genes from other tissues

39
Q

What is AIRE?

A

AutoImmune REgulalator

40
Q

What is peripheral tolerance?

A

Destruction/control of self-reactive T or B cells that do enter circulation

41
Q

Why is peripheral tolerance needed? (2)

A
  1. Deals with cells escaping central tolerance
  2. Deals with changes in lymphocytes —> become destructive to self-antigens
42
Q

What changes occur to B cells after antigen exposure?

A

Somatic hypermutation —> affinity maturation

43
Q

What is somatic hypermutation?

A

B cells changing their antigen-specificity after leaving the bone marrow and becoming exposed to antigens

44
Q

What are the 3 mechanisms of peripheral tolerance?

A
  1. Anergy
  2. Ignorance
  3. Deletion (AICD)
45
Q

How does anergy stimulate peripheral tolerance?

A

T cell not appropriately co-stimulated by cognate MHC —> less likely to be stimulated in future even if co-stimulation correct

46
Q

How does ignorance stimulate peripheral tolerance?

A

Antigen concentration too low —> doesn’t reach threshold to trigger TCR
- eye

47
Q

How does AICD stimulate peripheral tolerance?

A

Antigen activates T-cell apoptosis
- Induced expression of death ligand (Fas ligand = CD95 ligand)

48
Q

What is AICD?

A

Antigen Induced Cell Death

49
Q

What type of T cells regulate other T cells?

A

Treg cells (T regulatory cells)
- Th0

50
Q

What are the 3 key phenotypes of Treg cells?

A
  1. CD4 —> Th cells
  2. High IL-2 receptor (CD25)
  3. FoxP3 TF
51
Q

Which 3 cytokines are secreted by Treg cells?

A
  1. TGF-β
  2. IL-10
  3. IL-35
52
Q

What are the 2 mechanisms of Treg cell action?

A
  1. FoxP3 expression
  2. IL-10 secretion
53
Q

Which transcription factor to Treg cells express?

A

FoxP3

54
Q

What do mutations in the FoxP3 TF cause?

A

IPEX syndrome
- Immune dysregulation
- Polyendocrinopathy
- Enteropathy
- X-linked

55
Q

What are the 3 functions of IL-10?

A

Anti-inflammatory:
1. Block pro-inflammatory cytokine synthesis
(TNF, IL-6, IL-8, IFN-γ)
2. Downregulate macrophage functions
3. Viral mimics

56
Q

Why is IL-10 pleiotropic?

A

Single molecule with multiple phenotypic (3) effects

57
Q

Why is IL-10 the master regulator?

A

Regulates other cytokines

58
Q

When are Treg cells essential and why?

A

Pregnancy
- Baby antigens half foreign (from father)

59
Q

What are the 2 types of Treg cells?

A
  1. Natural —> nTreg
  2. Inducible —> iTreg
60
Q

What is the function of nTreg cells?

A

Prevent harmful reactions against self

61
Q

Where do nTreg cells develop and reside?

A
  • Develop —> thymus
  • Reside —> peripheral tissue
62
Q

What is the function of iTreg cells?

A

Limit collateral damage of all immune responses

63
Q

When do iTreg cells develop?

A

Periphery
∵ develop from mature CD4 T-cells exposed to antigen

64
Q

What is the function of cytokines?

A

Tailor immune response to specific type of pathogen

65
Q

What are the 2 categories of cytokines?

A
  1. Inflammatory —> increase response
  2. Anti-inflammatory —> decrease response
66
Q

What is the function of chemokines?

A

Drive immune response to correct place

67
Q

What changes in chemokines when its cell is activated?

A

Chemokine receptor profile

68
Q

What is the difference between antigen-binding in T and B cells?

A
  • T —> MHC on DC/B-cell
  • B —> soluble antigens
69
Q

How do Th and B cells co-stimulate each other?

A
  • Th to B —> Th express CD40L (ligand) and B express CD40
  • B to Th —> B express B7
70
Q

How do Th cells activate themselves?

A

Express CD28

71
Q

What is co-stimulation in lymphocytes?

A

Lymphocytes must be activated by stimulation from…
1. Themselves
2. Other lymphocytes (T vs B)

72
Q

Which cytokine mainly stimulates T-cell activation?

A

IL-28

73
Q

What determines the type of antibody used in an immune response?

A

Th cell cytokines

74
Q

What is Ig class switch

A

Changes in the constant (C) region of an antibody heavy chain
—> Different effector functions
—> Same antigen specificity

75
Q

What drives Ig class switch?

A

Th cytokines

1.3 POM Immunology (13 decks)

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