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immunology > L: 19 Immunological Tolerance and Autoimmunity > Flashcards

L: 19 Immunological Tolerance and Autoimmunity Flashcards

1
Q

Where is Central Tolerance induced?

A

In immature self-reactive lymphocytes in the primary lymphoid organs (thymus, bone marrow)

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2
Q

Where is peripheral tolerance induced?

A

Mature self reactive lymphocytes in peripheral sites

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3
Q

Why is peripheral tolerance needed?

A

To prevent activation of these potentially dangerous lymphocytes in the tissue

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4
Q

What does central tolerance ensure?

A

That mature lymphocytes are not reactive to self Ags.

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5
Q

Unlike “nonspecific” immunosuppression tolerance is ?

A

Ag specific

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6
Q

Immunological Tolerance is specific ___________ to an Ag

A

Unresponsiveness

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7
Q

What is the result of autoimmunity?

A

Breakdown of self-tolerance

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8
Q

Immature lymphocytes specific for self Ags may encounter these Ags in the generative lymphoid organs and are either?
What type of tolerance?

A
  • Deleted
  • Change BCR specificity(B cells only)
  • Developed into Treg cells

Central Tolerance

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9
Q

Mature self-reactive lymphocytes in peripheral tissues may be either?

What type of tolerance?

A
  • Inactivated (anergy)
  • Deleted (apoptosis)
  • Suppressed by the Treg cells

Peripheral tolerance

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10
Q

The thymus has a special mechanism for expressing many protein Ags that are?

A

Present only in certain peripheral tissues

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11
Q

TCR signaling in T cells triggers what?

A

Mitochondrial pathway of apoptosis- negative selection

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12
Q

What 2 things does recognition of self Ags by immature T cells in the thymus lead to?

A
  1. Death of the cell by negative selection

2. Development of Treg cells that enter peripheral tissue

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13
Q

Where does Central Tolerance take place?

A

Thymus

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14
Q

What happens to nonfunctioning thymocytes showing no affinity?

A

Apoptosis

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15
Q

What happens to strongly self-reactive thymocytes, and where is this determined?

A

Determined my interaction with MHC self peptide complexes

They are deleted

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16
Q

Thymocytes that are activated by MHC-self peptide complexes below a certain threshold are what?

A

positively selected and migrate into the periphery as mature T-cells

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17
Q

Most of the thymocytes that migrate into the periphery develop into what?

A

Effector CD4+ and CD8+ T cells and mediate both cell- mediated and humoral immune response

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18
Q

What happens to only a small percentage of T cells that emigrate from the thymus?

A

Express FOXP3 and develop into natural CD4+ CD25+ CTLA4+ Treg cells

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19
Q

What happens to immature B cells that recognize self Ags in the bone marrow with high avidity?

A

Die by apoptosis or undergo receptor editing and change specificity of BCRs

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20
Q

Define receptor editing

A

Rearrangement and replacement of the IgL-chain genes that occur until non-self recognizing receptors are produced or the cell dies

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21
Q

What may lead to anergy of the B cells?

A

Weak recognition of self Ags in bone marrow

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22
Q

What are two major mechanisms mediating central tolerance?

A

Clonal deletion

Anergy

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23
Q

What happens when an immature B-cell reacts with high avidity?

A

Apoptosis within 2-3 days

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24
Q

What happens when an immature B-cell reacts with low avidity?

A

induced unresponsiveness or anergy but allowed for migration into peripheral compartment

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25
Q

There is one other mode of selection against autoreactive immature B cells called receptor editing. Describe receptor editing

A

rearrangement program at the Ig light chain resulting i expression of a new light chain with the existing H chain to form a non-autoreactive BCR

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26
Q

What is the ration of kappa/lambda in peripheral B cells?

A

3:2

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27
Q

Receptor editing of the IgL chain generates cell-surface immunoglobulin that lack?

A

Self-reactivity

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28
Q

Deletion of self-reactive lymphocytes occur via what two pathways?

A 
Mitochondrial (intrinsic) pathway
Death receptor (extrinsic) pathway
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29
Q

Key mediator of peripheral tolerance?

A

Treg cells

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30
Q

Treg cells may inhibit T cell activation by _____ and inhibit T-cell differentiation into ____.

A

APCs

CTLs

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31
Q

Treg cells may prevent T-cells from providing what?

A

Help to B cells in the production of Abs

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32
Q

What are induced Treg cells?

A

FOXP3+ Treg cells generated from peripheral mature T cells OUTSIDE the thymus

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33
Q

What cells can also acquire Treg phenotype and function?

A

iTreg cells (induced) OUTSIDE THE THYMUS

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34
Q

Theree is a close relationship between iTreg and what cells?

A

Th17

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35
Q

What needs to be present for FoxP3 expression in naive CD4+ cells in vitro?

A

TGF-Beta

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36
Q

What prevents FoxP3 expression

A

IL-6

37
Q

What sparks Th17 cell differentiation?

A

TGF-B + IL-6 prevents FoxP3 expression and induces retinoic acid receptors (RAR) and related orphan nuclear receptors therefore activating Th17 differentiation

38
Q

What do Treg cell suppress in peripheral tissues

A

Activation of self-reactive lymphocytes

39
Q

Development and survival of regulatory Tcell requires?

A

IL-2 and FoxP3

40
Q

Natural Treg cells are generated by?

A

self Ag recognition in the thymus

41
Q

Inducible Treg cells are produced by Ag recognition where?

A

Lymph nodes and GI tract

42
Q

What attenuates BCR signaling?

A

CD22 inhibitory receptor is phosphorylated by Lyn and then recruits SHP-1 tyrosine phosphatase

43
Q

Defects in what Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and CD22 inhibitory receptor leads to what?

A

Autoimmunity

44
Q

The balance of what controls the outcome of peripheral tolerance

A

BCR vs BAFF signaling controls

45
Q

AIRE deficiency causes?

A

Failure of central tolerance causing Autoimmune polyendocrine syndrome (APS)

46
Q

FoxP3 deficiency causes?

A

Impaired production of regulatory T calls causing IPEX syndrome

47
Q

C1q and C4 deficiency causes?

A

Decreased clearance and impaired tolerance induction by apoptotic cells

48
Q

CTLA-4 polymorphisms causes?

A

Failure of anergy in CD4+ T cells causing Altered Immune Signaling thresholds

49
Q

Loss of self tolerance leads to what?

A

Autoimmunity

50
Q

What does AIRE stand for?

A

AutoImmune REgulator

51
Q

What has a key function as APCs and express large numbers of self-Ags that are presented to developing T-cells

A

Medullary Thymic Epithelial Cells

52
Q

Mutations in AIRE proteins cause?

A

breakdown of central tolerance by decreased expression of Self-Ags in the thymus

53
Q

AIRE regulates the expression of?

A

Tissue-restricted Ags (TRAs)

54
Q

Peptide from what are displayed on the Medullary Thymic Epithelial cells

A

Tissue restricted Ags (TRAs)

55
Q

The recognition of TRAs by T-cells leads to?

A

Deletion of self-reactive T cells

56
Q

What happens in the absence of AIRE

A

Self-reactive T-cells are not eliminated and can enter tissue and cause injury

57
Q

What is outcome of normal T-cell response?

A

An Effector and Memory T cell

58
Q

T cell responses are induced when?

A
  1. TCR recognizes an Ag presented by APC (signal 1)

2. CD28 recognizes B7 costimulators on the APCs (signal 2)

59
Q

If the T cell recognizes a self Ag without costimulation, the T cell becomes unresponsive to the Ag because of a block in signal from the TCR complex. What are three possible causes of the block?

A
  1. Recruitment of phosphatase to TCR complex
  2. Activation of Ubiquitin Ligase that degrades signaling protein
  3. Engagement of inhibitory receptors CTLA-4
60
Q

What happens with an Anergic T-cell?

A

Remains viable but unable to respond to the self Ag

61
Q

T cell activation is regulated by members what family of costimulatory molecules

A

B7-CD28

62
Q

Homolog of CD28?

A

CTLA4

63
Q

what does CTLA-4 do?

A

Inhibitory receptor that terminates immune responses and maintains self tolerance

64
Q

What two autoimmune diseases is caused by polymorphisms in CTLA-4?

A

Type 1 diabetes and Graves disease

65
Q

Two important properties of CTLA-4

A
  1. Expression is low on resting T-cell until cell is activated by Ag
  2. CTLA-4 terminates continuing activation of responding Regulatory T cells
66
Q

Explain CTLA-4 cell intrinsic inhibitory signal?

A

Engagement of CTLA-4 on T cell delivers inhibitory signal that terminates further activation

67
Q

Explain Cell-extrinsic Action of CTLA-4

A

CTLA-4 on Treg cell or responding T-cell binds to B7 on APC or makes unavailable to CD28 blocking T cell activation

68
Q

Where is CTLA-4 expressed?

A

Regulatory T-cell and mediates the suppressive function of these cells by inhibiting the activation of naive T cells

69
Q

Natural Treg cells are ______ selected in the Thymus

A

Positively

70
Q

Are Natural Treg cells eliminated by Apoptosis?

A

No they produce an Anti-apoptotic molecule which protects them from negative selection in the thymus

71
Q

All Treg cells express______ transcriptional factor and are _____ _____ positive

A

FoxP3

CD4+ CD25+

72
Q

All Treg cell express high levels of _______

A

CTLA-4

73
Q

What cytokine is critical for the survival and competence of all Treg cells

A

IL-2

74
Q

Treg cells are endogenous ________ population of ________ T-cells

A

Long Lived

Self-Ag-specific

75
Q

What does growth factor-B inhibit?

A

Inhibits development of Th1 and Th2 subsets
Inhibits M1 macrophages
Inhibits proliferation of effector function of T-cell

76
Q

What does growth factor-B Promote?

A
  • Th17 in cooperation with IL-1 and IL-6
  • Tissue repair/collogen synthesis
  • Stimulates production of IgA by inducing B cells to switch to this isotype
77
Q

What does Growth Factor-B regulate?

A

Differentiation of induced FoxP3+Treg cells

78
Q

What is Autoimmunity essentially caused by?

A
  • Activation of T cells and/or B-cells in the absence of an ongoing infection or discernible cause
  • Hypersensetive Immune System that causes one’s own immune system to attack itself
79
Q

What is immunologic ignorance?

A

T cells are physically separated from their specific Ag and cannot become activated

80
Q

Describe the process known as deletion

A

T-cells that express Fas (CD95) can recieve signal from cells that express FasL and undergo apoptosis

81
Q

Describe T-cell inhibition

A

CTLA4 binds CD80 on APC inhibiting T cell activation

82
Q

Describe T-cell Suppression

A

Regulatory T cells can inhibit through the production of inhibitory cytokines such as IL-10 and TGFbeta

83
Q

What is the underlying cause of all autoimmune disease?

A

Failure of self-tolerance mechanism

84
Q

What is the first step in autoimmune development?

A

Inflammation

85
Q

Genetically most autoimmune diseases are?

A

Complex polygenic traits. The individual typically inherits multiple genetic polymorphisms that contribute to disease susceptibility

86
Q

What genes have strongest association to autoimmunity?

A

MCH genes*

Polymorphism in NON_HLA genes is also associated

87
Q

Microbial Ags can initiate autoimmune disorders through?

A
  • molecular mimicry
  • polyclonal activation
  • release of previous sequestered Ag
88
Q

Who is more common to autoimmune disorders men or woman?

A

Women. Estrogen exacerbates systemic lupus erythematous by altering B-cell repertoire

immunology (6 decks)

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