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Immunology test III > Lecture 19 > Flashcards

Lecture 19 Flashcards

1
Q

What is Immunological Tolerance?

A

specific unresponsiveness to an Ag

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2
Q

All individuals are tolerant to what type of Ags?

A

Self-Ags (self-tolerance)

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3
Q

The breakdown of self-tolerance results in what?

A

autoimmunity

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4
Q

What type of selection of self-reactive T lymphocytes in the thymus is not perfect?

A

negative selection

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5
Q

What level of physiological auto-reactivity is crucial to normal immune function?

A

low level

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6
Q

Central tolerance is induced in what?

A

in immature self-reactive lymphocytes in the generative lymphoid organs

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7
Q

Peripheral tolerance is induced in what?

A

in mature self-reactive lymphocytes in peripheral sites

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8
Q

What does central tolerance ensure?

A

ensures that mature lymphocytes are NOT reactive to self Ags

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9
Q

What is peripheral tolerance needed for?

A

to prevent activation of potentially dangerous lymphocytes

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10
Q

T cells responding to ubiquitous Ags presented by thymic epithelial cells and hematopoietic cells are efficiently deleted when?

A

During intra-thymic development

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11
Q

In the thymus, medullary epithelial cells (mTecs) ectopically express a broad range of organ-specific genes and present or, via thymic DCs, cross-present gene products for what?

A

negative selection

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12
Q

Tolerizing the T cell repertoire to (peripheral tissue Ag) PTA depends on negative selection in the thymus, but autoreactive T cells can also be eliminated where?

A

in the peripehry

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13
Q

Induction of both central and peripheral tolerance to PTA involves DCs that carry Ags acquired in nonlymphoid tissues and nonhematopoietic cells that do what?

A

‘promiscuously’ express PTA

PTA peripheral tissue Ag

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14
Q

In the periphery, lymph node stromal cells show ‘promiscuous’ expression and directly provide ligands that facilitate the deletion of what?

A

mature autoreactive T cells

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15
Q

TCR signaling in immature T cells triggers _______ pathway of apoptosis - negative selection

A

mitochondrial

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16
Q

The thymus also has a special mechanism for expressing many protein Ags that are present only in what certain tissues?

A

peripheral

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17
Q

Recognition of self Ags by immature T cells in the thymus leads to what 2 things?

A
  1. the death of the cells by negative selection or

2. the development of Treg cells that enter peripheral tissues

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18
Q

Immature T cells in the thymus encounter what Ags?

A

Self Ag presented by thymic epithelial cells

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19
Q

Cells with T-cell receptors with no affinity for the complex of self peptide and a self MHC molecule do not receive what signal?

A

They DO NOT receive a surviving signal and undergo spontaneous apoptosis dying int he thymus

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20
Q

Cells whose T-cell receptors have a high affinity for such complexes receive what signals?

A

The death signal and are eliminated by means of apoptosis

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21
Q

The remaining T cells that have intermediate affinity for self peptide and self MHC molecule go on to do what?

A

mature in the thymus and migrate to the periphery, where they can become activated

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22
Q

Immature lymphocytes specific for self Ags may encoutner these Ags in the generative (central) lymphoid organs and are either:

A

deleted
change their specificity (b cells only)
develop into Treg cells

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23
Q

Mature self-reactive lymphocytes in peripheral tissues may be:

A

inactivated or deleted

suppressed by the T reg cells

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24
Q

Mutations in what causes Incomplete induction of tolerance in the thymus, failure of central tolerance

A

AIRE deficiency: autoimmune polyendocrine syndrome

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25
Q

Impaired production of reg T cells

A

FoxP3 deficiency causes IPEX syndrome

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26
Q

Decreased clearance and impaired tolerance induction by apoptotic cells

A

Complement deficiency of C1q and C4

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27
Q

Altered immune signaling thresholds

A

CTLA-4 polymorphisms

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28
Q

AIRE stands for:

A

AutoImmune REgulator

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29
Q

What process in the thymus is necessary for the maintenance of self tolerance?

A

Negative selection of T cells

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30
Q

Medullary thymic epithelial cells have a key function as what?

A

APCs

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31
Q

What do medullay thymic epithelial express a large number of?

A

Self-Ags that are presented to developing T cells

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32
Q

Mutation in AIRE is associated with decreased expression of what Ags in the thymus?

A

self-Ags

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33
Q

The AIRE regulates the expression of what type of Ags?

A

tissue-restricted Ags (TRAs)

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34
Q

Peptides derived from TRAs are displayed on what APCs?

A

Medullary Thymic Epithelial Cells

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35
Q

Ags displayed on medullary thymic epithelial cells are recognized by immature Ag-specific T cells and cause what to occur

A

Deletion of self-reactive T cells

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36
Q

In the absence of functional AIRE in medullary thymic epithelial cells, self-reactive T cells are not eliminated and causes what to occur?

A

The T cells enter tissues where the Ags continue to be produced and cause injury

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37
Q

T cell responses are induced by what 2 signals?

A
  1. TCR recognizes and Ag presented by APC

2. CD28 recognize B7 costimulators on the APCs

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38
Q

If the T cell recognizes a self Ag without costimulation, what happens to the T cell?

A

Becomes unresponsive to the Ag because of a block in signaling from the TCR complex

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39
Q

Blocking in T cell anergy may be the result of what?

A
  1. recruitment of phosphatases to the TCR complex
  2. Activation of upiquitin ligases
  3. engagement of inhibitory receptors CTLA-4
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40
Q

The anergic T cell remains viable but is unable to respond to what?

A

Self Ag

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41
Q

When T cells recognize self Ags, they may engage inhibitory receptors of the CD28 family, whose function is to do what?

A

Terminate T cell responses

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42
Q

What are the best established inhibitory receptors?

A

CTLA-4

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43
Q

Individual populations of T cells undergo ______ and ______ upon Ag encounter.

A

Expansion and contraction

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44
Q

T cell activation is regulated by members of the __-___ family of costimulatory molecules

A

B7-CD28

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45
Q

What type of receptor is CTLA4?

A

A CD28-family receptor

Inhibitory

46
Q

What signals do CTLA4 provide?

A

Signals that terminate immune responses and maintain self-tolerance

47
Q

What do CTLA-4 KO mice develop?

A

Uncontrolled lymphocyte activation with massively enlarged lymp nodes and spleen and fatal multi organ lymphocyte infiltrates suggestive of systemic autoimmunity

48
Q

Blocking of CTLA-4 with Abs also enhances what?

A

autoimmune diseases in animal models

49
Q

Polymorphisms in the CTLA4 are associated with several autoimmune diseases in humans, name two

A

Type 1 diabetes

Graves’ disease

50
Q

CTLA-4 has what two important actions?

A
  1. CTLA-4 expression is low on resting T cells until the cells are activated by Ag
  2. Once expressed CTLA-4, terminates continuing activation of these responding T cells
51
Q

CTLA-4 is expressed on what type of cells? It mediates the suppressive function of these cells by inhibiting the activation of naive T cells.

A

T reg cells

52
Q

CTLA-4 mediated inhibition by Treg cells is what type of mechanism?

A

cell-extrinsic action

53
Q

The cytokines for common gamma chain, also known as IL-2 receptor subunit gamma are what?

A

IL-2, 4, 7, 9, 15

54
Q

Where do Treg cells develop?

A

In the thymus

55
Q

Treg cells are positively selected in the thymus via what strong interactions?

A

TCR interactions with self-Ags

56
Q

After recognition of self-Ags, Treg cells are (eliminated/not eliminated) by apoptosis

A

Not eliminated

57
Q

Treg cells are able to produce anti-apoptotic molecules which protect them from what?

A

negative selection in the thymus

58
Q

The generation of some Treg cells requires what cytokine?

A

TGF-β

59
Q

Treg cells express ____ transcriptional factor and are CD4+CD25+ positive

A

FOXP3

60
Q

Treg cells typically express high levels of what receptor?

A

CTLA-4

61
Q

The survival and functional competence of Treg cells are dependent in what cytokine?

A

IL-2

62
Q

Treg cells are what type of populations?

A

Endogenous long-lived populations of self-Ag-specific T cells

63
Q

Treg cells serve to prevent what types of reactions?

A

potentially autoimmune reactions

64
Q

Inducible Treg cells are produced by Ag recognition where?

A

In LNs

65
Q

Natural Treg cells are generated by self Ag recognition where?

A

in the thymus

66
Q

TGF-β inhibits the proliferation and effector functions of what cells?

A

T cells

67
Q

TGF-β inhibits the development of what T cell subsets?

What T cell subset does it promote the development of?

A

Inhibit development of Th1 and Th2

Promotes Th17 in cooperation with IL-1 and IL-6

68
Q

TGF-β inhibits the activation of what APCs?

A

macrophages

69
Q

TGF-β regulates the differentiation of peripheral ______ T reg cells

A

FOXP3+

70
Q

TGF-β stimulates production of what Ab by inducing B cells to switch to this isotype?

A

IgA

71
Q

TGF-β promotes tissue repair after local immune and inflammatory reactions subside stimulating what actions?

A

collagen synthesis and matrix-modifying enzyme production by macrophages and fibroblasts

72
Q

How many people in the US suffer from autoimmune diseases?

A

5% or 12-15 million

73
Q

How many diverse autoimmune diseases affect various tissues of the human body?

A

60-70

74
Q

Most autoimmune diseases are treated how?

A

symptomatically

75
Q

The autoimmune diseases bring the paradox proposition that “__________________-“

A

The body both is and is not itself

76
Q

There is no fundamental difference between the structure of self auto-Ags and non-self Ags because of what reason?

A

Ags are all proteins

77
Q

Pathologic immune response against self Ags often clinically manifested as what?

A

immune-mediated inflammatory diseases

78
Q

What causes chronic autoimmunity ?

A

Activation of T cells or B cells, or both, in the absence of an ongoing infection or other discernible cause

79
Q

What is a result of a hypersensitive immune system?

A

That one’s own immune system attacks the self

80
Q

What is immunologic ignorance?

A

Process in which T cells that are physically separated from their specific Ag (the BBB) cannot become activated

81
Q

T cells that express the Fas (CD95) can receive their signals from cells that express FasL. What does this interaction cause?

A

apoptosis/deletion

82
Q

What binds to CD80 on APC that inhibits T cells activation?

A

CTLA4 (CD152)

83
Q

Regulatory T cells can inhibit through the production of inhibitory cytokines such as IL-___ and ____.

A

10

TGF-B

84
Q

Weak recognition of self Ags in the bone marrow may lead to what process in B cells?

A

Anergy (functional inactivation)

85
Q

Mature B cells that recognize self Ag in the peripheral tissues in the absence of specific Th cells may be rendered what?

A

functionally unresponsive or die by apoptosis

86
Q

CD22 inhibitory receptor is phosphorylated by what?

A

Lyn

87
Q

What does the active CD22 recruit?

A

SHP-1tyrosine phosphatase and then attenuates B cell receptor signaling

88
Q

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

A

autoimmunity

89
Q

How may various genetic loci confer susceptibility to autoimmunity?

A

In part by influencing the maintenance of self-tolerance

90
Q

Environmental triggers, such as infections and other inflammatory stimuli, promote the influx of lymphocytes into tissues and the activation of self-reactive T cells resulting in what?

A

Tissue injury

91
Q

Autoimmune diseases may be either systemic or organ specific depending on what?

A

the distribution of the auto-Ag that are recognized

92
Q

Various ______ mechanisms are responsible for tissue injury in different autoimmune diseases

A

effector

93
Q

Autoimmune diseases tend to be chronic, progressive and _______.

A

self-perpetuating

94
Q

Failure of the mechanisms of self-tolerance in T or B cells underlies cause of all _________.

A

autoimmune disease

95
Q

What is the initial innate immune response?

A

inflammation

96
Q

Most autoimmune diseases are complex _____ traits

A

polygenic

97
Q

Affected individual inherit multiple genetic _______ that contribute to disease susceptibility

A

Polymorphisms

98
Q

Susceptibility genes act with _________ to cause the diseases

A

environmental factors

99
Q

Among the genes that are associated with autoimmunity, the strongest associations are with _____ genes

A

MHC

100
Q

Polymorphisms in non-____ genes are also associated with autoimmunity

A

HLA

101
Q

Microbial Ags can initiate autoimmune disorder through:

A

Molecular mimicry
Polyclonal (bystander) activation
Release of previously sequestered Ags

102
Q

Rheumatic fever is triggered by streptococcal infection and mediated by cross-reactivity between streptococcal Ags and _________.

A

Cardiac myosin

Molecular mimicry

103
Q

Multiple-sclerosis - T cells react with ________ and peptides from epstein-barr virus, infleunze virus type A,and human papillomavirus.

A

Myelin basic protein

Molecular mimicry

104
Q

Microbial infection can also cause polyclonal activation of autoreactive _______.

A

lymphocytes (cytokine field).

Polyclonal activation

105
Q

Microbes that kill cells can cause inflammation, the release of sequestered Ags, and _______.

A

autoimmunity

Release of perviously sequestered Ags

106
Q

Autoimmune diseases are much more common in what sex?

A

women

107
Q

Estrogens exacerbate ___________ in mouse models of the disease by altering the B-cell repertoire in the absence of inflammation.

A

Systemic lupus erythematosus (SLE)

108
Q

Drugs can also alter the immune repertoire: penicillins and cephalosporins can bind to _____ membrane and generate a neoantigen that elicits an auto-Ag that causes hemolytic anemia

A

RBC

109
Q

The blockade of TNF-a (ENBREL or other inhibitors) can induce antinuclear Abs and even SLE and ________ in certain persons.

A

multiple sclerosis

110
Q

TFN-a has inhibitory effects on activated ___ cells, but it remains unknown how TFN-a induces autoimmunity

A

T

Immunology test III (7 decks)

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