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IMM Exam 2 > Tolerance & Autoimmunity > Flashcards

Tolerance & Autoimmunity Flashcards

1
Q

Self-antigens

A

an individual’s own antigens

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2
Q

Immunologic tolerance

A

unresponsiveness to self-antigens

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3
Q

Tolerogens

A

antigens that induce tolerance

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4
Q

Immunogens

A

antigens that induce an immune response

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5
Q

Autoimmunity

A

failure of self-tolerance and resulting immune reaction to self-antigens

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6
Q

Location: Tolerogenic self antigens

A

presence in generative organs (some self antigens) induces negative selection and other mechanisms of central tolerance

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7
Q

Location: Immunogenic foreign antigens

A

presence in blood and peripheral tissues (most microbial antigens) permits concentration in secondary lymphoid organs

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8
Q

Tolerogenic self antigens and Accompanying costimulation

A

Deficiency of costimulators may lead to T cell anergy or apoptosis, development of Treg, or sensitivity to suppression by Treg

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9
Q

Immunogenic foreign antigens and Accompanying costimulation

A

Expression of costimulators, typically seen with microbes, promotes lymphocyte survival and activation

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10
Q

Tolerogenic self-antigens and Duration of antigen exposure

A

Long-lived persistence (throughout life); prolonged TCR engagement may induce anergy and apoptosis

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11
Q

Immunogenic foreign antigens and Duration of antigen exposure

A

Short exposure to microbial antigen reflects effective immune response

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12
Q

3 Characteristics of Tolerance

A

Induced

Antigen-specific

Induced during central tolerance OR peripheral tolerance

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13
Q

Generative (central) tolerance occurs

A

in central lymphoid organs

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14
Q

Central tolerance for T cells occurs in

A

thymus

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15
Q

Central tolerance for B cells occurs in

A

bone marrow

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16
Q

Mechanisms of Central Tolerance for T cells

A

Deletion (- selection)

Regulatory T cells

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17
Q

Mechanisms of Central Tolerance for B cells

A

Receptor editing

Anergy

Deletion

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18
Q

Peripheral Tolerance occurs in

A

peripheral tissues

-spleen, lymph nodes, etc.

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19
Q

Mechanisms of Peripheral Tolerance for T cells

A

Suppression

Anergy

Deletion

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20
Q

Mechanisms of Peripheral Tolerance for B cells

A

Suppression

Anergy

Deletion

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21
Q

Positive selection occurs in the

A

cortex of thymus with assistance of cTECs (cortical epithelial cells)

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22
Q

Negative selection occurs in the

A

medulla of thymus with assistance of mTECs (medullary epithelial cells)

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23
Q

Type of cells that undergo positive selection in thymus

A

Double positive (CD4+/CD8+) thymocytes

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24
Q

Weak recognition of class II MHC + peptide

A

results in Mature CD4+ T cell

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25
Q

Weak recognition of class I MHC + peptide

A

results in Mature CD8+ T cells

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26
Q

Strong recognition of either class I or class II MHC + peptide

A

results in apoptosis (negative selection)

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27
Q

T cells surviving negative selection

A

exist as Mature, Single Positive CD4+ or CD8+ T cells and leave the thymus

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28
Q

AIRE (Autoimmune Regulator Protein)

A

TF that resides in mTECs

Controls expression of peripheral tissue self-antigens

Critical role in negative selection and self-tolerance

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29
Q

Expression of air leads to

A

protective immunity

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30
Q

Deficiency of air leads to

A

Autoimmunity (APS-1 disease)

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31
Q

AIRE deficiency and regulatory T cells

A

Even in the absence of AIRE, you still get development of Tregs!

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32
Q

Central T lymphocyte Negative Selection

A

Deletion of immature lymphocytes that interact strongly with self antigen

but, Imperfect Process

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33
Q

APECED

A

aka APS1

Autosomal recessive inheritance

Mutations in AIRE gene (chromosome 21q22.3)

Triad: “HAM”

34
Q

APECED triad (symptoms)

A

“HAM”

Mucocutaneous candidiasis

Adrenal insufficiency

Hypoparathyroidism

35
Q

T cell Central Tolerance: Regulatory T cell Development

A

Some self-reactive CD4+ T cells will not be deleted, but instead will differentiate into regulatory T cells

36
Q

Are all self-reactive T cells deleted following failure of Negative selection?

A

No, some self-reactive CD4+ T cells become Tregs

37
Q

Development of Tregs is independent of

A

AIRE

38
Q

Tregs exit thymus and enter the periphery in order to

A

inhibit responses against self-antigens

39
Q

Important for inhibiting responses against self-antigens

A

Tregs

40
Q

CD markers on Tregs

A

CD3+ CD4+ CD25 (high) and FoxP3+

41
Q

Cytokines produced by Tregs

A

IL-10 and TGF-beta

42
Q

Natural Tregs

A

made in thymus

43
Q

APECED Clinical Manifestations

A 
Candidiasis
Hypoparathyroidism 
Adrenal failure
Hypothyroidism 
DM
Alopecia
Vitilligo
Gastritis/Pernicious anemia
Immune hepatitis
44
Q

Anergy defiintion

A

Functional unresponsiveness

45
Q

Suppression definition

A

Block in activation

46
Q

Deletion definition

A

apoptosis

47
Q

Two signal hypothesis

A

-T cell proliferation and differentiation requires antigen-induced signals and costimulators

48
Q

Best characterized pathway in T cell activation

A

B7: CD28 family of costimulators

49
Q

CD28 expressed on

A

T cells

50
Q

B7 expressed on

A

APCs

51
Q

CTLA-4 expressed on

A

activated T cells and Tregs

52
Q

CTLA-4 function

A

negative regulation of immune responses; self-tolerance

53
Q

2 Mechanisms by which T cells become Anergic (unresponsive)

A

(1) block in signaling from TCR complex

(2) engagement of inhibitory receptors

54
Q

2 Drugs involved in therapeutic manipulation of CTLA-4

A

Ipilimumab

Abatacept

55
Q

Ipilimumab

A

Monoclonal antibody against CTLA-4

enhances T cell activation and antitumor immunity

56
Q

Abatacept

A

consists of EC domain of CTLA4 and Fc region of IgG1

binds CD80/86 (B7) on APC

interrupts CD28-mediated costimulation

causes T cell anergy

57
Q

What cells do the drugs Ipilimumab and Abatacept bind?

A

Ipilimumab binds up T cells (binds at CTLA4)

Abatacept binds up APCs (binds at CD80/86)

58
Q

Tregs require ______ for growth

A

IL-2

59
Q

CD25

A

receptor for IL-2

60
Q

Tregs require _______ for function; expression is induced by ________

A

FoxP3

TGF-beta

61
Q

3 Mechanisms by which Induced Peripheral T regs suppress immune responses

A

(1) Production of inhibitory cytokines (IL-10, TGF-beta) to inhibit effector T cell functions
(2) Expression of CTLA-4 (to inhibit naive T cell activation)
(3) Expression of IL-2 receptor and capture of IL-2

62
Q

IPEX

A

mutations in FoxP3 gene

X-linked recessive

Triad: EDE

63
Q

IPEX triad (symptoms)

A

EDE

Enteropathy (diarrhea)

Dermatitis (eczemous rash)

Endocrine disease (diabetes/thyroid)

64
Q

2 Mechanisms of Peripheral T cell Deletion (apoptosis)

A

(1) Deficiency of survival signals (expression of pro-apoptotic proteins induces apoptosis)
(2) Engagement of death receptors (FasL binding Fas induces apoptosis)

65
Q

Fas ligand expressed on

A

T cells

66
Q

ALPS

A

disorder of apoptosis

mutations in Fas, FasL, caspase 8/10

chronic accumulation of lymphoid cells

defective lymphocyte apoptosis in vivo

67
Q

ALPS symptoms

A

(1) Lymphoproliferation
- splenomegaly
- hepatomegaly
- lymphadenopathy

(2) Autoimmunity to RBCs
- autoimmune hemolytic anemia
- autoimmune thrombocytopenia
- autoimmune neutropenia

(3) Increased risk for lymphomas

68
Q

B lymphocyte tolerance important for maintaining unresponsiveness to

A

(1) nonprotein, T-independent antigens (e.g. polysaccharides, lipids, nucleic acids)
(2) protein self-antigens

69
Q

Defective B lymphocyte tolerance may contribute to

A

autoantibody production in autoimmune disorders

70
Q

In response to lipids, polysaccharides, etc. (non-protein antigens), B cells…

A

become (short-lived) IgM secreting plasma cells

71
Q

2 responses to High-Avidity self-antigen recognition by Central B cells

A

(1) Receptor editing: expression of new Ig V region –> non-self reactive B cell
(2) Apoptosis –> deletion

72
Q

Response to Low-Avidity self-antigen recognition by Central B cells

A

(1) Reduced receptor expression, signaling –> anergic B cell

73
Q

3 Mechanisms of Peripheral B Cell Tolerance in response to self-antigen binding

A

(1) Functional inactivation –> anergy
(2) Apoptosis –> deletion
(3) inhibitory receptors –> regulation/suppresion by inhib receptors

74
Q

Failure of Self-tolerance results in

A

Self-reactive lymphocytes

75
Q

Reaction to environmental stimuli in Autoimmunity

A

Environmental stimuli

Tissue injury and inflammation

Activation of tissue APCs

Activation of self-reactive lymphocytes

Self-reactive effector lymphocytes cause tissue injury: autoimmune disease

76
Q

Single Gene Defects that cause autoimmunity

A

AIRE

FOXP3

FAS

77
Q

SLE

A
  • Systemic autoimmune disorder (multi-organ)
  • Loss of immunological tolerance to multiple self antigens (defective B and T cell tolerance)
  • Autoantibodies primarily to nuclear constituents
  • Predominantly affects women of childbearing age
78
Q

Genetic influences of SLE

A

family history

complement deficiency (C1q, C2, C4)

TREX1

HLA-DR2 and DR3

79
Q

Antinuclear antibodies in SLE

A

Anti-dsDNA antibody

Anti-Smith antibody

80
Q

SLE symptoms

A

Malar rash

Phostosensitivity

Oral or nasal mucocutaneous ulcerations

Nonerosive arthritis

Nephritis

Encephalopathy (seizures, psychosis)

81
Q

Immunological self tolerance

A

unresponsiveness to specific antigenes INDUCED by exposure of lymphocytes to that antigen

IMM Exam 2 (15 decks)

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