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Immuno Exam 3 > Immunologic Tolerance & Autoimmunity > Flashcards

Immunologic Tolerance & Autoimmunity Flashcards

1
Q

Immunological tolerance (IT) is specific unresponsiveness to an ________.

A

Antigen (Ag)

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2
Q

This is the term for when all individuals are tolerant to self-Ags.

A

Self-tolerance

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3
Q

The negative selection of self-reactive T lymphocytes in the thymus is NOT perfect. There is a low level of physiological _______-_______ that is crucial to normal immune function. The challenge is to understand how it becomes a pathologic process and how T cells and B cells recognize self and contribute to tissue injury.

A

Auto-Reactivity

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4
Q

Unlike “nonspecific” immunosuppression, _______ is Ag specific.

A

Tolerance

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5
Q

Central tolerance is induced in immature self-reactive lymphocytes in the _________ lymphoid organs.

A

Primary

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6
Q

Central tolerance ensures that mature lymphocytes are NOT REACTIVE to self _____.

A

Ags

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7
Q

________ tolerance is induced in mature self-reactive lymphocytes in peripheral sites. It is needed to prevent activation of these potentially dangerous lymphocytes in the tissues.

A

Peripheral

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8
Q

With this type of tolerance, immature lymphocytes specific for self Ags may encounter these Ags in the generative lymphoid organs and are either:

    • deleted
    • change BCR specificity (B cells only)
    • develop into Treg cells
A

Central tolerance

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9
Q

With this type of tolerance, mature self-reactive lymphocytes in peripheral tissues may be either:

    • inactivated (anergy)
    • deleted (apoptosis)
    • suppressed by the Treg cells
A

Peripheral tolerance

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10
Q

The _______ also has a special mechanism for expressing many protein Ags that are present only in certain peripheral tissues.

A

Thymus

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11
Q

TCR signaling in immature T cells triggers mitochondrial pathway of apoptosis – _______ _______.

A

Negative selection

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12
Q

Recognition of self Ags by immature T cells in the thymus leads to:

1) The _______ of the cells by negative selection
(OR)
2) The development of ______ cells that enter peripheral tissues

A

Death

Treg

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13
Q

Central tolerance takes place in the thymus. Thymocytes undergo a maturation and selection process. Nonfunctional thymocytes showing no affinity at all undergo _________.

A

Apoptosis

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14
Q

Strongly self-reactive thymocytes – as determined by interactions with _____-self peptide complexes – are also deleted.

A

MHC

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15
Q

Only thymocytes that are activated by MHC-self peptide complexes below a certain threshold are ________ selected and migrate into the periphery as mature T cells.

A

Positively

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16
Q

T/F. Most of these thymic emigrants develop into effector CD4+ and CD8+ T cells, and mediate both cell-mediated and humoral (Ab-mediated) immune responses.

A

True

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17
Q

A small percentage of T cells that emigrate from the thymus express ______ and develop into natural CD4+ CD25+ CTLA4+ Treg cells.

A

FOXP3

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18
Q

Immature B cells that recognize self Ags in the bone marrow with high avidity die by apoptosis or undergo receptor editing and change the specificity of their ______.

A

BCRs

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19
Q

This is the term for further rearrangement and replacement of the IgL-chain genes that occurs until non-self-recognizing receptors are produced or the cell dies.

A

Receptor editing

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20
Q

Weak recognition of self Ags in the bone marrow may lead to _______ (functional inactivation) of the B cells.

A

Anergy

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21
Q

_______ _______ and anergy were major mechanisms mediating central tolerance of developing autoreactive B cells, resulting in the elimination of autoreactive clones, and preventing immune responses against self.

A

Clonal deletion

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22
Q

______ regulates expression and helps to eliminate T cells that are reactive to normal, healthy proteins.

A

AIRE

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23
Q

When an immature B cell reacts with a self-antigen with high _______, such as a highly expressed membrane-bound protein, it undergoes apoptosis within 2-3 days.

A

Avidity

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24
Q

Low _______ interactions of B cells with self-antigens induce unresponsiveness to subsequent stimulation or anergy but allowed for migration into peripheral compartment. The anergic B cells fail to enter follicle and have reduced life-span.

A

Avidity

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25
Q

Clonal deletion and anergy are not the only modes of selection against autoreactive immature B cells, but there operates another system, namely, ______ ______.

A

Receptor editing

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26
Q

Autoreactive immature B cells reactivated their Ig gene rearrangement program at the Ig light chain loci resulting in the expression of a new light chain that paired with the existing H chain to form a non-autoreactive _____, and event that promoted the selection of these edited B cells into the periphery.

A

BCR

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27
Q

The kappa/lambda ratio in the peripheral B cells is estimated to be ______.

A

3:2

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28
Q

T/F. Precursor (pre)-B cells, which already express rearranged IgH chains recombine the locus that encodes IgL chain, yielding a lymphocyte with an autoreactive antigen receptor. BCR signaling promotes developmental arrest and continued recombination.

A

True

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29
Q

Receptor editing of the IgL chain leads to expression of a distinct IgL chain, generating cell-surface _________ that lacks self-reactivity.

A

Immunoglobulin

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30
Q

______ cells are key mediators of peripheral tolerance.

A

Treg

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31
Q

Treg cells may inhibit T cell activation by ______ and inhibit T cell differentiation into ______.

A

APCs

CTLs

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32
Q

Treg cells may prevent T cells from providing help to _______ in the production of Abs.

A

B cells

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33
Q

_______ Treg cells can also be generated from peripheral T cells and they are called induced Treg cells (iTreg cells).

A

FOXP3+

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34
Q

In addition to the natural Treg cells which differentiate in the thymus, mature T cells outside the thymus can also acquire Treg phenotype and function. These are called…

A

Induced Treg cells (iTreg cells)

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35
Q

FoxP3 can be induced in naive CD4+ cells in vitro by antigen recognition in the presence of ______.

A

TGF-B

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36
Q

There is a close developmental relationship between iTregs and ______ cells.

A

Th17

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37
Q

Ag recognition in the presence of TGF-B induces FoxP3 expression if ____ is not present. In contrast, Ag recognition in the presence of TGF-B + ______ prevents FoxP3 expression, induces expression of the retinoic acid receptor (RAR) related orphan nuclear receptor RORyt expression and therefore, Th17 cell differentiation.

A

IL-6

IL-6

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38
Q

The development and survival of these regulatory T cells (Treg) require ______ and ______.

A

IL-2

FoxP3

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39
Q

In peripheral tissues, Treg cells suppress the activation of ________ lymphocytes.

A

Self-reactive

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40
Q

(NATURAL/INDUCED) Treg cells are generated by self Ag recognition in the thymus.

A

Natural

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41
Q

(NATURAL/INDUCED) Treg cells are produced by Ag recognition in LNs and GI tract.

A

Induced

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42
Q

Mature _____ cells that recognize self Ag in peripheral tissues in the absence of specific Th cells may be rendered functionally unresponsive or die by apoptosis.

A

B cells

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43
Q

The CD22 inhibitory receptor is phosphorylated by Lyn and then recruits SHP-1 tyrosine phosphatase attenuating BCR signaling. Therefore, defects in Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and the CD22 inhibitory receptor lead to _________.

A

Autoimmunity

44
Q

Peripheral tolerance is primarily found in splenic transitional B cells, which depends on tonic BCR signaling thresholds and survival signals from ______.

A

BAFF

45
Q

The balance of ______ vs. ______ signaling controls the outcome of peripheral tolerance.

A

BCR

BAFF

46
Q

Incomplete induction of central tolerance in the thymus (______ deficiency causes Autoimmune Polyendocrine Syndrome).

A

AIRE

47
Q

Impaired production of regulatory T cells (_______ deficiency causes IPEX syndrome).

A

FoxP3

48
Q

Decreased clearance and impaired tolerance induction by apoptotic cells (complement deficiency of _____ and _____).

A

C1q

C4

49
Q

Altered immune signaling thresholds (_____ polymorphisms).

A

CTLA-4

50
Q

The (POSITIVE/NEGATIVE) selection of T cells in the thymus is necessary for the maintenance of self tolerance.

A

Negative

51
Q

Medullary thymic epithelial cells have a key function as ______. They express a large number of self-Ags that are presented to developing T cells.

A

APCs

52
Q

Mutations in ______ protein cause a breakdown of central tolerance. This protein has been proposed to function as a transcription factor.

A

AIRE

53
Q

Mutation in ______ is associated with decreased expression of self-Ags in the thymus.

A

AIRE

54
Q

The AIRE regulates the expression of tissue-restricted Ags (TRAs). Peptides derived from these Ags are displayed on the Medullary Thymic Epithelial cells. Ags are then recognized by immature Ag-specific T cells, leading to the deletion of ______-______ T cells.

A

Self-reactive

55
Q

In the absence of functional ______, these self-reactive T cells are not eliminated and they can enter tissues where the Ags continue to be produced and cause injury and autoimmunity.

A

AIRE

56
Q

T cell responses are induced when (1) TCR recognizes an Ag presented by APC (signal 1) and (2) ______ recognize B7 costimulators on the APCs (signal 2).

A

CD28

57
Q

If the T cell recognizes a self Ag without costimulation, the T cell becomes unresponsive to the Ag because of a block in signaling from the TCR complex. Blocking may be the result of:

– recruitment of ________ to the TCR complex

– activation of ________ ligases that degrade signaling proteins

– engagement of inhibitor receptors CTLA-4

***The anergic T cell remains viable but is unable to respond to the self Ag.

A

Phosphatases

Ubiquitin

58
Q

When T cells recognize self Ags, they may engage inhibitory receptors of the ______ family, whose function is to terminate T cell responses. The best established inhibitory receptors are ______.

A

CD28

CTLA-4

59
Q

Upon Ag encounter, individual populations of T cells undergo expansion and later contraction after the elimination of Ag. T cell activation is regulated by members of the _____-_____ family of costimulatory molecules.

A

B7-CD28

60
Q

CTLA4 is homolog of ______ and is an inhibitory receptor.

A

CD28

61
Q

_______ provides signals that terminate immune responses and maintain self-tolerance.

A

CTLA4

62
Q

Uncontrolled lymphocyte activation with massively enlarged LNs and spleen and fatal multi-organ lymphocytic infiltrates is seen in CTLA4 KO mice. Blocking of CTLA4 with Abs also enhances ________ diseases in animal models.

A

Autoimmune

63
Q

Polymorphisms in the ______ are associated with several autoimmune diseases in humans, including type 1 diabetes and Graves’ disease.

A

CTLA4

64
Q

CTLA4 has two important properties:

– CTLA4 expression is low on resting T cells until the cells are activated by ______.

– Once expressed CTLA4, terminates continuing activation of these responding T cells.

A

Ag

65
Q

CTLA4 is expressed on ________ T cells (Treg) and mediates the suppressive function of these cells by inhibiting the activation of naive T cells.

A

Regulatory

66
Q

Engagement of _______ on a T cell may deliver inhibitory signals that terminate further activation of that cell.

A

CTLA4

67
Q

CTLA4 on _____ cells or responding T cells binds to B7 molecules on APCs or makes unavailable to CD28 and blocking T cell activation.

A

Treg

68
Q

________ Treg cells develop in the thymus and are positively selected in the thymus via strong TCR interactions with self-Ags. After recognition of self-Ags they are not eliminated by apoptosis.

A

Natural

69
Q

________ Treg cells are able to produce anti-apoptotic molecules which protect them from negative selection in the thymus.

A

Natural

70
Q

The generation of ________ Treg cells requires the TGF-B.

A

Inducible

71
Q

All Treg cells express _______ transcriptional factor and are ______ ______ positive.

A

FOXP3
CD4+
CD25+

72
Q

All Treg cells typically express high levels of CTLA4, and cytokine _____ is critical for survival and functional competence of all Treg cells.

A

IL-2

73
Q

Treg cells are endogenous long-lived populations of ________ specific T cells.

A

Self-Ag

74
Q

Treg cells serve to prevent potentially ________ reactions.

A

Autoimmune

75
Q

IL-2 receptor alpha chain (IL-2Ra) is also called ______.

A

CD25

76
Q

The immunoregulatory enzyme _______ suppresses T cell responses and promotes immune tolerance by mechanisms of tryptophan starvation.

A

IDO (indoleamine 2,3-dioxygenase)

77
Q

______ inhibits the proliferation and effector functions of T cells.

A

TGF-B

78
Q

TGF-B inhibits development of Th1 and Th2 subsets but promotes _____ in cooperation with IL-1 and IL-6.

A

Th17

79
Q

TGF-B inhibits activation of M1 macrophages, and regulates the differentiation of induced _______ Treg cells.

A

FoxP3

80
Q

TGF-B stimulates the production of _____ by inducing B cells to switch to this isotype.

A

IgA

81
Q

_______ promotes tissue repair after local immune and inflammatory reactions subside, stimulating collagen synthesis and matrix-modifying enzyme production by macrophages and fibroblasts.

A

TGF-B

82
Q

There is no fundamental difference between the structure of self auto-Ags and non-self Ags because Ags are all proteins composed by the same ______ ______.

A

Amino acids

83
Q

Pathologic immune response against self Ags often clinically manifested as “immune-mediated inflammatory diseases”. Caused by the activation of T cells and/or B cells in the absence of an ongoing infection or other discernible cause. This is a result of a _________ immune system that causes one’s own immune system to attack the self.

A

Hypersensitive

84
Q

T cells that are physically separated from their specific Ag cannot become activated, a process termed…

A

Immunologic ignorance

85
Q

T cells that express the _____ (CD95) can receive their signals from cells that express ______ and undergo apoptosis, a process known as deletion.

A

Fas

FasL

86
Q

_______ (CD152) that binds CD80 on APC and inhibits T cells activation.

A

CTLA4

87
Q

Regulatory T cells can inhibit through the production of inhibitory cytokines such as ______ and ______.

A

IL-10

TGF-B

88
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 tissue ______.

A

Injury

89
Q

Autoimmune diseases may be either ______ or ______ specific, depending on the distribution of the auto-Ag that are recognized.

A

Systemic

Organ

90
Q

________ disease tend to be chronic, progressive, and self-perpetuating.

A

Autoimmune

91
Q

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

A

Autoimmune

92
Q

_________ or an initial innate immune response is the first step in autoimmunity development.

A

Inflammation

93
Q

Most autoimmune diseases are complex ______ traits.

A

Polygenic

94
Q

Affected individuals inherit multiple genetic _________ that contribute to disease susceptibility.

A

Polymorphisms

95
Q

Among the genes that are associated with autoimmunity, the strongest associations are with ______ genes.

A

MHC

96
Q

Polymorphisms in _______ genes is also associated with autoimmunity.

A

Non-HLA

97
Q

Susceptibility genes act with _________ factors to cause the diseases.

A

Environmental

98
Q

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

A

Cardiac myosin

99
Q

Multiple sclerosis – T cells react with _______ ______ ______ and peptides from Epstein-Barr virus, influenza virus type A, and human papilloma virus.

A

Myelin basic protein

100
Q

_________ (bystander) activation: Microbial infection can also cause polyclonal activation of autoreactive lymphocytes due to massive activation of naive cells and release of cytokines (cytokine field).

A

Polyclonal

101
Q

Microbes that kill cells can cause inflammation, the release of sequestered Ags (Ags that ARE NOT well presented in the _______ _______ organs) leading to autoimmunity.

A

Primary lymphoid

102
Q

T/F. Autoimmune disease are much more common in men.

A

False. More common in women.

103
Q

________ exacerbate Systemic Lupus Erythematosus (SLE) in mouse models of the disease by altering the B-cell repertoire in the absence of inflammation.

A

Estrogens

104
Q

Drugs can also alter the immune repertoire: Penicillins and cephalosporins can bind to RBC membrane and generate a neoantigen that elicits an auto-Ag that causes ______ ______.

A

Hemolytic anemia

105
Q

The blockade of TNF-a (ENBREL or other inhibitors) can induce antinuclear Abs and even SLE and Multiple Sclerosis (MS) in certain persons. TNF-a has inhibitory effects on activated T cells, but it remains unknown how TNF-a induces ________.

A

Autoimmunity

Immuno Exam 3 (6 decks)

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