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HDM Final > Tolerance And Autoimmunity > Flashcards

Tolerance And Autoimmunity Flashcards

1
Q

What is the normal response of an immune cell recognizing a microbe?

A

Proliferation and differentiation –> immune response

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2
Q

What are the 3 mechanisms of self-tolerance when a self-antigen is recognized by an immune cell?

A

Anergy

Apoptosis

Change in specificity/receptor editing (B cells only)

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3
Q

Define anergy

A

Functional unresponsiveness

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4
Q

What is the difference between central and peripheral tolerance?

A

Central refers to developing lymphocytes (in primary lymphoid organs)

Peripheral refers to mature lymphocytes present in peripheral tissues

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5
Q

Where does central tolerance for T cells develop?

A

Thymus

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6
Q

Negative selection for T cells occurs in the presence of _______, which stimulates the expression of peripheral “tissue-restricted” self antigens in the thymus

A

AIRE

[autoimmune regulatory protein]

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7
Q

What does a defect in AIRE lead to?

A

Autoimmune polyendocrinopathy

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8
Q

What is the result of weak recognition of class I or class II HLAs + peptide lead to in the thymus?

A

Positive selection

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9
Q

What two conditions lead to negative selection and apoptosis during T cell development?

A

No recognition of MHC + peptide

Strong recognition of MHC + peptide

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10
Q

How is the formation of regulatory T cells an outcome of central tolerance?

A

Thymocytes with a LOW affinity for self antigen become T cells (CD4 or CD8)

Thymocytes with an INTERMEDIATE affinity for self antigen become T regulatory cells (CD25)

[those with high affinity undergo negative selection]

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11
Q

FOXP3 T cells upregulate what CD marker?

A

CD25

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12
Q

What might the loss of FOXP3 in mice lead to?

A

Widespread autoimmunity

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13
Q

Treg cells account for approx. what percentage of circulating CD4+ T cells?

A

5-10%

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14
Q

What is the general mechanism of peripheral T cell tolerance in preventing autoimmunity?

A

Upregulation and binding of CTLA-4 promotes T cell anergy

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15
Q

Peripheral T cell tolerance relies on the concept of two-signal activation of T cells. What is the first signal?

A

TCR binding to HLA:peptide complex

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16
Q

Peripheral T cell tolerance relies on the concept of two-signal activation of T cells. What is the second signal?

A

Binding of the costimulatory protein B7 (APC) to CD28 (T cell)

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17
Q

Describe the expression of B7 on APCs in the absence of infection or inflammation

A

B7 expression will be low or absent on APCs in the absence of infection/inflammation

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18
Q

Which binds B7 with higher affinity, CD28 or CTLA-4?

A

CTLA-4

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19
Q

Describe the expression of CTLA-4 on APCs in the absence of infection or inflammation

A

Expression will be upregulated and CTLA-4 will preferentially bind B7, leading to anergy

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20
Q

What are the 3 mechanisms of central B cell tolerance?

A

Receptor editing –> non-self reactive B cell

Apoptosis –> deletion

Reduced receptor expression and signaling –> anergy

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21
Q

What are the 3 mechanisms of peripheral B cell tolerance?

A

Functional inactivation –> anergy

Apoptosis –> deletion

Inhibitory receptors –> regulation by inhibitory receptors

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22
Q

Are tolerogenic self antigens present in generative organs?

A

Yes (some self-antigens): high concentrations induce negative selection and regulatory T cells (central tolerance)

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23
Q

Are immunogenic foreign antigens present in generative organs?

A

No: microbial antigens are concentrated in peripheral lymphoid organs

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24
Q

Will tolerogenic self-antigens be presented with second signals like co-stimulation?

A

No: deficiency of second signals may lead to T cell anergy or apoptosis

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25
Q

Will immunogenic foreign antigens be presented with second signals like co-stimulation?

A

Yes; second signals promote lymphocyte survival and activation

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26
Q

Describe the persistence of tolerogenic self-antigens

A

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

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27
Q

Describe the persistence of immunogenic foreign antigens

A

Usually short lived; immune response eliminates antigen

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28
Q

What are the 3 primary factors that contribute to autoimmune disease?

A

Genes (HLA haplotypes)

Infections

Environmental factors (UV radiation, chemicals, etc.)

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29
Q

T/F: the principle factors in the development of autoimmunity are inheritance of susceptibility genes and environmental triggers

A

True

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30
Q

The 3 general effector mechanisms of autoimmunity:

immune __________

Circulating ____________

___________ T lymphocytes

A

Complexes

Autoantibodies

Autoreactive

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31
Q

T/F: Self antigens are often easily identified in cases of autoimmune diseases

A

False; self antigens are often not identified which hinders our understanding of autoimmune disease

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32
Q

Some of the other factors that hinder our understanding of autoimmune disease include that they are heterogenous, ____________, and clinical manifestation is prolonged and ___________ after initiation

A

Multifactorial

Variable

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33
Q

What determines the type of tissue injury in autoimmune disease?

A

Type of tissue injury is determined by the DOMINANT immune response

34
Q

Are autoimmune diseases organ-specific or systemic?

A

Can be both!

35
Q

What makes an autoimmune disease a chronic condition?

A

Chronicity is due to many amplification loops

[normal response to Ag allows a small number of Ag-specific cells to increase their numbers, when response is against same self-Ag, the SAME amplification mechanism exacerbates and prolongs injury]

36
Q

What makes an autoimmune disease persistent and progressive?

A

Epitope spreading

[response against one self-Ag causes damage that leads to the release of other Ags; T cells will react against the epitopes found on newly released Ags]

37
Q

Autoimmune diseases run in families with variations between populations, typically involving HLAs. Which allotypes are primarily involved?

A

HLA class II allotypes

38
Q

Which autoimmune disease is associated with an environmentally acquired infection?

A

Rheumatic fever

39
Q

Which autoimmune disease is related to physical trauma?

A

Sympathetic ophthalmia

40
Q

Which autoimmune disease is considered drug-induced?

A

SLE

41
Q

T/F: pathology of autoimmune diseases is mediated by cell-mediated immunity only

A

False; can be mediated by humoral or cell-mediated immunity

T cell help is often necessary for autoantibody formation

42
Q

What is the sex distribution of common autoimmune conditions like Hashimotos, Sjogrens, Addisons, RA, etc.?

A

Predominantly female

43
Q

What is one theory as to why females tend to develop more autoimmune conditions, especially in middle age?

A

Estrogen may be protective, so when estrogen levels decline during menopause, women develop autoimmune conditions more easily

44
Q

Which autoimmune condition is a 90% female diagnosis?

A

Systemic Lupus Erythematosus

45
Q

HLA-B27 carries a 90% relative risk of developing what autoimmune disease?

A

Ankylosing spondylitis

46
Q

RA is an autoimmune disease associated with which MHC allele?

A

HLA-DR4

47
Q

Type I DM is associated with which MHC allele?

A

HLA-DR3/DR4

48
Q

Pemphigus vulgaris is associated with what MHC allele?

A

HLA-DR4

49
Q

Ankylosing spondylitis is associated with which MHC allele?

A

HLA-B27

50
Q

PTPN22 is a gene that codes for enzyme __________ ___________, this is abnormal in the autoimmune conditions RA, T1D, and autoimmune thyroid conditions

A

Tyrosine phosphatase

51
Q

The _______ gene is implicated in autoimmune disease like T1D and RA due to impaired inhibitory checkpoint and regulatory T cell function

A

CTLA4

52
Q

A single gene defect in _______ leads to autoimmune polyendocrine syndrome (APS-1) due to defective elimination of self-reactive T cells

A

AIRE

53
Q

_________ is a gene necessary for thymic expression of self-proteins and is associate with autoimmune diseases like diabetes, adrenal, and parathyroid diseases

A

AIRE

54
Q

A single-gene defect in _______ leads to immune dysregulation, polyendocrinopathy, enteropathy, and widespread autoimmunity

A

FOXP3

55
Q

A single-gene defect in ______ leads to splenomegaly, lymphadenopathy, and adrenal autoimmune disease due to defective apoptosis of self-reactive T and B cells in the periphery

A

FAS

56
Q

Streptococcus pyogenes is able to form autoantibodies that attack cardiac tissue in people with certain HLAs. By what mechanism is it able to do this?

A

Molecular mimicry

[group A strep –> rheumatic fever (carditis, polyarthritis)]

57
Q

Chlamydia trachomatis associated with HLA-B27 leads to what potential consequence?

A

Reiter’s syndrome (arthritis)

58
Q

Shigella flexneri, Salmonella typhimurium, Salmonella enteritidis, Yersinia enterocolitica, and Campylobacter jejuni in the setting of HLA-B27 may lead to what potential consequence?

A

Reactive arthritis

59
Q

Borrelia burgdorferi in association with HLA-DR2, DR4 may lead to what potential consequence?

A

Chronic arthritis in Lyme disease

60
Q

Coxsackie A virus, Coxsackie B virus, echoviruses, or rubella in association with HLA-DQ2, HLA-DQ8, or DR4 may lead to what potential consequence?

A

IDDM

61
Q

The TSH receptor interacting with and agonist antibody leads to hyperthyroidism in what disease?

A

Grave’s disease

62
Q

The ACh receptor being acted on by an antagonist antibody leading to progressive muscle weakness leads to what syndrome?

A

Myesthenia gravis

63
Q

The insulin receptor being acted on by an antagonist with the consequence of hyperglycemia and ketoacidosis occurs in the setting of what disease?

A

Insulin-resistant diabetes

64
Q

The insulin receptor being acted on by an agonist antibody with the result of hypoglycemia occurs in the setting of what syndrome?

A

Hypoglycemia

65
Q

Name the antigen, antibody classification, and consequence for the following syndrome:

Grave’s disease

A

Ag: TSH receptor

Antibody: Agonist

Consequence: Hyperthyroidism

66
Q

Name the antigen, antibody classification, and consequence for the following syndrome:

Myasthenia gravis

A

Ag: ACh receptor

Antibody: Antagonist

Consequence: Progressive muscle weakness

67
Q

Name the antigen, antibody classification, and consequence for the following syndrome:

Insulin-resistant diabetes

A

Ag: Insulin receptor

Ab: Antagonist

Consequence: Hyperglycemia, ketoacidosis

68
Q

Name the antigen, antibody classification, and consequence for the following syndrome:

Hypoglycemia

A

Ag: Insulin receptor

Ab: Agonist

Consequence: Hypoglycemia

69
Q

What is the prototypic immune complex disease causing defective apoptotic process leading to increased nucleic acid Ags available to stimulate an immune response and auto-antibody production?

A

SLE

70
Q

What disease is characterized by inflammation of the synovium wherein Th17 and Th1 cytokine release sustains the inflammatory response and there is auto-Ab production including Rheumatoid factor?

A

RA

71
Q

What are the auto-antibodies associated with rheumatoid arthritis specifically targeting?

A

The auto-antibodies (IgM) are against the Fc portion of IgG

72
Q

In the setting of RA, you can find all immune mediators in the ________ space, and in advanced cases even including establishment of _________ and ________ _______ (tertiary lymphocyte tissue)

A

Synovial
Follicles
Germinal centers

73
Q

________ is a pleiotropic cytokine with widespread roles in inflammation and host defense.

Agents directed against this cytokine were the first to develop and are currently approved and in use. They are typically _________ antibody-based.

A

TNF-a

Monoclonal

74
Q

The ________ monoclonal Ab decreases T cell autocrine response to IL-2

A

Anti-CD25

75
Q

The ________ monoclonal Ab blocks B7 frfom binding CD28 and promotes anergy

A

Anti-CTLA-4

76
Q

The ________ monoclonal Ab targets mature naive B cells for deletion

A

Anti-CD20

77
Q

What type of monoclonal Ab prevents T cells from infiltrating tissues?

A

Abs for adhesion molecules/chemokine receptors

78
Q

________ is an autoimmune condition involving ________ mutations, leading to loss of function of Treg cells and uninhibited T cell activation.

A

IPEX

FOXP3

79
Q

What are the most common symptoms of IPEX?

A

Intractable diarrhea leading to failure to thrive

Autoimmune diabetes type I, developing in infancy

[diarrhea is due to widespread inflammation of the gut, including colitis, resulting in villous atrophy]

80
Q

What would you expect for serum Abs in a patient with IPEX?

A

Normal serum levels of Abs, except for elevated IgE, but the mechanism for hyper-IgE is unclear

81
Q

Hyper-IgE results in what symptom in IPEX patients?

A

Dermatitis

HDM Final (12 decks)

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