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Immunology - Unit 3 - Zach H. > Immunologic Tolerance and Autoimmunity > Flashcards

Immunologic Tolerance and Autoimmunity Flashcards

1
Q

What is ummunological tolerance?

A

Specific unresponsiveness to an Ag.

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2
Q

What is self-tolerance?

A

All individuals are tolerant to self-Ags.

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3
Q

What dos central tolerance ensure?

A

That mature lymphocytes are NOT REACTIVE to self Ags.

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4
Q

What results in autoimmunity?

A

From Breakdown of self-tolerance.

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5
Q

You know negative selection of self-reactive T lymphocytes in the thymus is not perfect. What is this important?

A

Low level of physiological auto-reactivity that is crucial to normal immune function.

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6
Q

Is tolerance Ag specific?

A

Yes

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7
Q

What is central tolerance induced by?

A

Immature self-reactive lymphocytes in the primary lymphoid organs.

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8
Q

What is peripheral tolerance induced by?

A

Mature self-reactive lymphocytes in peripheral sites.

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9
Q

In central T cell tolerance, what does TCR signaling in immature T cells trigger?

A

Mitochondrial pathway of apoptosis - negative selection.

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10
Q

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

A

1) Death of the cells by negative selection.

2) Development of Treg cells that enter peripheral tissues.

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11
Q

In which primary lymphoid organ does central tolerance occur?

A

thymus

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12
Q

What type of T lymphocytes does a small percentage of T cell that emigrate from the thymus and express FOXP3?

A

Develop into natural CD4+CD25+CTLA4+ Treg cells.

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13
Q

Which type of T cells are key mediators of peripheral tolerance?

A

Treg cells

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14
Q

What do Treg cells prevent T cells from providing?

A

Help to B cells in the production of Abs.

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15
Q

True or False:

In peripheral tolerance, Treg cells may inhibit T cell activation by APCs and inhibit T cell differentiation into CTLs.

A

True

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16
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 functoin.

A

True

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17
Q

What are induced Treg cells (iTreg cells)?

A

Mature T cells OUTSIDE THE THYMUS that acquire Treg phenotype and function.

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18
Q

What signal induces FoxP3 expression in naive CD4+ cells in vitro?

A

By Ag recognition in the presence of TGF-beta.

if IL-6 is NOT present

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19
Q

Between which two T cells types is there a close developmental relationship?

A
  • iTregs

- Th17

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20
Q

Ag recognition in the presence of TGF-beta induces FoxP3 expression if what?

A

IL-6 is NOT present.

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21
Q

What happens in Ag recognition in the presence of TGF-beta + IL-6?

A

Prevents FoxP3 expression, induces expression of the retinoic acid receptor (RAR) related orphan nuclear receptor RORgammat expression and therefore, Th17 cell differentiation.

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22
Q

During Ag recognition in the presence of TGF-beta and not IL-6, will iTregs or Th17 cells result?

A

iTregs

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23
Q

Central B Cell Tolerance

A

> 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 BCRs.

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24
Q

What is BCR editing?

A

Further rearrangement and replacement of the IgL-chain genes that occurs until non-self-recognizing receptors are produced or the cell dies.

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25
Q

What does weak recognition of self Ags in the bone marrow lead to?

A

Anergy (functional inactivation) of the B cells.

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26
Q

What does BCR signaling promote?

A

Developmental arrest and continued recombination.

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27
Q

True or False:

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

A

True

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28
Q

What does both RAG1 and RAG2 being turned on?

A

cell death

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29
Q

In peripheral B cell tolerance, what happens to mature B cells that recognize self Ag in peripheral tissues in the absence of specific Th cells?

A

Rendered functionally unresponsive or die by apoptosis.

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30
Q

What signaling cascade attenuates BCR signaling?

A

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

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31
Q

What can defects in Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and the CD22 inhibitory receptor lead to?

A

autoimmunity

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32
Q

What are the three possibilities in central tolerance?

A
  • deleted
  • change BCR specificity (B cells only)
  • develop into Treg cells
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33
Q

What are the three possibilities in peripheral tolerance?

A
  • inactivated (anergy)
  • deleted (apoptosis)
  • suppressed by the Treg cells
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34
Q

What does an AIRE deficiency cause?

A

autoimmune polyendocrine syndrome

incomplete induction of tolerance in the thymus

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35
Q

What does impaired production of regulatory T cells (FoxP3 deficiency) cause?

A

IPEX syndrome

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36
Q

What does a complement deficiency of C1q and C4 lead to?

A

Decreased clearance and impaired tolerance induction by apoptotic cells .

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37
Q

What is CTLA-4 polymorphisms?

A

Altered immune signaling thresholds.

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38
Q

What gene has a mutation leading to the failure of central tolerance?

A

AIRE

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39
Q

What gene has a mutation leading to the defective clearance of immune complexes; failure of B cell tolerance?

A

C4

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40
Q

What gene has a mutation leading to the failure of anergy in CD4) T cells?

A

CTLA-4

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41
Q

What gene has a mutation leading to the defective deletion of anergic self-reactive B cells; reduced deletion of mature CD4 T cells?

A

Fas/FasL

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42
Q

What gene has a mutation leading to the deficiency of regulatory T cells?

A

FoxP3

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43
Q

What gene has a mutation leading to the defective development, survival or function of regulatory T cells?

A

IL-2; IL2R alpha/beta

44
Q

What gene has a mutation leading to the failure of negative regulation of B cells?

A

SHP-1

45
Q

What is the key function of medullary thymic epithelial cells?

A

Have a key function as APCs.

46
Q

What do medullary thymic epithelial cells express?

A

A large number of self-Ags that are presented to developing T cells.

47
Q

What does mutations in AIRE (autoimmune regulator) cause?

A

Breakdown of central tolerance.

48
Q

What is mutation in AIRE associated with, leading to the breakdown of central tolerance?

A

Decreased expression of self-Ags in the thymus.

49
Q

When AIRE is functioning normally, Ags are recognized by immature Ag-specific T cells, leading to the deletion of self-reactive T cells. What happens in the absence of functional AIRE?

A

Self-reactive T cells are not eliminated and they can enter tissues where the Ags continue to be produced and causes injury.

50
Q

T cell responses are induced when?

A

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

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

51
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?

A
  • Recruitment of phosphatases to the TCR complex.
  • Activation of ubiquitin ligases that degrade signaling proteins.
  • Engagement of inhibitory receptors CTLA-4.
52
Q

True or False:

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

A

True

53
Q

What is the best established inhibitory receptor?

A

CTLA-4

54
Q

True or False:

When T cells recognize self Ags, they may engage inhibitory receptors of the CD28 family, whose function is the terminate T cell responses.

A

True

55
Q

What family of receptors is CTLA-4 a member of?

A

CD28-family receptor

56
Q

What kind of receptor is CTLA-4?

A

An inhibitory receptor - provides signals that terminate immune responses and maintain self-tolerance.

57
Q

What is seen in CTLA-4 KO mice?

A

uncontrolled lymphocyte activation with massively enlarged LNs and spleen and fatal multi-organ lymphocytic infiltrates is seen in CTLA-4 KO mice.

58
Q

What are the two important properties of CTLA-4?

A

> CTLA-4 expression is low on resting T cells until the cells are activated by Ag.

> Once expressed CTLA-4, terminates continuing activation of these responding T cells.

59
Q

What type of cell is CTLA-4 expressed on?

A

regulatory T cells and mediates the suppressive function of these cells by inhibiting the activation of naive T cells

60
Q

Name two diseases that are enhanced by blocking CTLA-4 with Abs in mice.

A

type 1 diabetes and Graves’ disease

61
Q

What is the cell-extrinsic action of CTLA-4?

A

CTLA-4 on Treg cells or responding T cells binds to B7 molecules on APCs or makes unavailable to CD28.

62
Q

What is the cell-intrinsic function of CTLA-4?

A

Engagement of CTLA-4 on a T cell may deliver inhibitory signals that terminate further activation of that cell.

63
Q

True or False:

Treg cells are positively selected in the thymus via strong TCR interactions with self-Ags.

A

True

after recognition of self-Ags they are NOT ELIMINATED by apoptosis

64
Q

How do Treg cells protect themselves from negative selection in the thymus?

A

Produce anti-apoptotic molecules.

65
Q

True or False:

Treg cells express FoxP3 transcriptional factor and are CD4+CD25+ positive.

A

True

66
Q

What does IL-2 do for Treg cells?

A

Critical for survival and functional competence of Treg cells.

67
Q

What are Treg cells?

A

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

serve to PREVENT potentially AUTOIMMUNE REACTIONS

68
Q

What do Treg cells do in peripheral tissues?

A

Suppress the activation of self-reactive lymphocytes.

69
Q

Natural Treg cells -> are generated by self Ag recogition in the thymus.

Inducible Treg cells -> are produced by Ag recognition in LNs and GI tract.

A

True

70
Q

What is the function of TGF-beta?

A

> INHIBITS the proliferation and effector functions of T cells.

> INHIBITS development of Th1 and Th2 subsets but PROMOTES Th17 in cooperation with IL-1 and IL-6.

> INHIBITS activation of M1 macrophages

> REGULATES the differentiation of induced FoxP3 Treg cells.

> STIMULATES production of IgA by inducing B cells to switch to the isotype.

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

71
Q

What percentage of people in the world have an autoimmune disease?

A

5%

72
Q

True of False:

There are 60-70 diverse autoimmune diseases which affect various tissues of the human body.

A

True

73
Q

True of False:

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

A

True

74
Q

What results in a autoimmue chronic disease?

A

hypersensitive immune system that causes one’s own immune system to attack the self

75
Q

What is immunologic ignorance?

A

T cell that are physically separated from their specific Ag (the BBB) cannot become activated, a process termed immunologic ignorance.
(immunologic ignorance)

76
Q

What is the process known as deletion?

A

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

77
Q

What signaling inhibits T cells activation?

A

CTLA-4 (CD152) that binds CD80 on APC.

(inhibition)

78
Q

Regulatory T cells can inhibit through the production of which inhibitory cytokines?

A

> IL-10
TGF-beta
(suppresion)

79
Q

List the four ways in which autoimmunity is prevented.

A

> immunologic ignorance
deletion
inhibition
suppression

80
Q

What features favor immune responses in APCs?

A

high levels of costimulators

81
Q

What features favor tolerance in APCs?

A

low levels of costimulators and cytokines

82
Q

What features favor immune responses in presence of adjuvants?

A

Ags with adjuvants: stimulate helper T cells.

83
Q

What features favor tolerance in presence of adjuvants?

A

Ags without adjuvants: non-immunogenic or tolerogenic.

84
Q

What features favor immune responses in portal of entry; location?

A

subcutaneous, intradermal; absence from generative organs.

85
Q

What features favor tolerance in portal of entry; location?

A

intravenous, mucosal; presence in generative organs.

86
Q

What features favor immune respones in persistence?

A

short-lived (eliminated by immune response).

87
Q

What features favor tolerance in persistence?

A

prolonged

88
Q

What are the two postulated mechanisms of autoimmunity?

A

> Various genetic loci may confer susceptibility to autoimmunity, in part by influencing the maintenance of self-tolerance.

> 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 injury.

89
Q

True or False:

Autoimmune diseases may be either SYSTEMIC or ORGAN SPECIFIC, depending on the distribution of the auto-Ag that are recognized.

A

True

90
Q

What is responsible for tissue injury in different autoimmune diseases?

A

various effector mechanisms

91
Q

Autoimmune diseases tend to be?

A

> chronic
progressive
self-perpetuating

92
Q

The failure of what underlies causes of all autoimmune diseases?

A

Failure of the mechanisms of self-tolerance in T or B cells.

93
Q

In the genetics of autoimmunity, most autoimmune diseases are?

A

complex polygenic traits

94
Q

In genetics of autoimmunity, what do most affected individuals inherit?

A

Multiple genetic polymorphisms that contribute to disease susceptibility.

95
Q

Amoung the genes that are associated with autoimmunity, the strongest associations are with what?

A

MHC genes

96
Q

True or False:

Polymorphisms in NON-HLA genes is also associated with autoimmunity.

A

True

97
Q

What do susceptibility genes act with to cause autoimmune diseases?

A

environmental factors

98
Q

List the three ways in which microbial Ags can initiate autoimmune disorders?

A

> Molecular mimicry

> Polyclonal (bystander) activation

> Release of previously sequestered Ags.

99
Q

What is molecular mimicry?

A

An environment trigger in which microbial Ags can initiate autoimmune disorders.

> Rheumatic fever is triggered by streptococcal infection and mediated by cross-reactivity between streptococcal Ags and cardiac myosin.
Multiple sclerosis - T cells react with myelin basic protein and peptides from Epstein-Barr virus, influenza virus type A, and human papillomavirus.

100
Q

What is polyclonal (bystander activation?

A

An environment trigger in which microbial Ags can initiate autoimmune disorders.

> Microbial infection can also cause polyclonal activation of autoreactive lymphocytes (cytokine field).

101
Q

What is release of preveiously sequestered Ags?

A

An environment trigger in which microbial Ags can initiate autoimmune disorders.

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

102
Q

True or False:

Autoimmune diseases are much more common in women than in men.

A

True

103
Q

What are autoimmune diseases much more common in women?

A

Estrogens exacerbate systemic lupus erythematosus (SLE) in mouse models of the disease by altering the B-cell repertoire in the absence of inflammation.

104
Q

Drugs can also alter the immune repertoire. Give examples.

A

Penicillins and cephalosporins can bind to RBC membrane and generate a neoantigen that elicits an auto-Ag that causes hemolytic anemia.

105
Q

True or False:

The blockade of TNA-alpha (ENBREL or other inhibitors) can induce antinuclear Abs and even SLE and Multiple Sclerosis (MS) in certain persons.

A

True

*TNF-alpha has inhibitory effects on activated T cells, but it remains unknown how TNF-alpha induces autoimmunity.

Immunology - Unit 3 - Zach H. (4 decks)

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