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I-2 > Tolerance and Autoimmunity > Flashcards

Tolerance and Autoimmunity Flashcards

1
Q

Define Immunogenic?

A

Elicits an immune response

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2
Q

Define Tolerogenic?

A

Does not elicit a functional lymphocyte response

-As a result lymphocytes are either killer, inactivated, or there is no reaction at all (Immune ignorance)

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3
Q

What two locations are best examples of immune ignorance?

A

The eyes and the testis

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4
Q

Compare Central tolerance to Peripheral tolerance

A

Central: occurs during lymphocyte development in primary lmyphoid organs (thymus and BM)

Peripheral: Occurs in periphery (Secondary lymphoid organs or non-lymphoid tissue

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5
Q

What happens to the thymus as we age?

A

It involvues with age, becomes for adipose tissue

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6
Q

What is positive selection in the thymus?

A

When T cells recognize MHC for self with low affinity

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7
Q

What is negative selection in the thymus?

A

When T cells recognize MHC with strong affinity and undergo apoptosis (this is not 100% efficient and hence you need peripheral tolerance)

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8
Q

What are the three populations of T cells that come from the thymus

A

Regulatory T cells (Tregs), CD4s, or CD8s

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9
Q

What is death by neglect?

A

In the thymus when T cells do not recognize MHC at all and undergo apoptosis

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10
Q

How are Tregs selected for? What must they express?

A

They recognize MHC with strong affinity, and survive, they contribute to peripheral tolerance

-must express FoxP3 genes

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11
Q

What is the fate, and how is it done, of a T cell specific for antigen that is not expressed in the thymus?

A

They are negatively selected by the AIRE gene (autoimmune regulator)

-AIRE induces the expression of peripheral tissue antigens by cells in the thymus. That way if a maturing T cell has afffinity for these antigens, it can be negatively selected against.

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12
Q

What happens if there is a mutation in AIRE?

A

APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrohpy syndrome)

-this is a multi-organ autoimmunity

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13
Q

In peripheral tolerance, what are the 4 options for dealing with autoreactive T cells?

A
  1. Anergy (functional inactivation)
  2. Treg- mediated suppression
  3. Death (apoptosis)
  4. Ignorance (this is most dangerous)
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14
Q

What induces anergy, and how long does it last? (for T cells)

A

Anery is long-lived functional inactivation

  • Induced in two ways.
    1. Lack of costimulation by CD28 to B7 (also known as CD80/84)
    2. Stimulation of an inhibitory signal like CTLA-4 with B7 or PD-1 with PDL
    note: CTLA-4 is expressed in high levels on activated T cells making it a good off switch.
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15
Q

What are the targets of Ipilimumab and Nivolumab?

A

Ipilimumab is a anti-CTLA-4 antibody

Nivolumab is a anti-PD-1 antibody

  • both work to prevent T cell anergy or inactivation
  • this is dangerous and can lead to autoimmunity
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16
Q

What transcription factor is required for Tregs, and what would a mutation in this cause?

A

FoxP3, a mutation in FoxP3 leads to IPEX (multiorgan autoimmunity)

  • FoxP3 is a transcription factor
  • Tregs suppress the function of other T cells specific for self-antigens that did not get negatively selected
17
Q

What interaction is responsible for lymphocyte activation induced cell death (AICD)?

A

Fas-FasL interaction

  • make effector T cells short lived
  • helps to return to homeostasis after infection
18
Q

What is induced upon on effector T cell upon activation?

A

Fas is induced

FasL is always expressed

19
Q

What causes Autoimmune Lymphoproliferative Syndrome?

A

Mutation in genes involved in FAS signaling

-leads to autoimmunity, and lymphocyte accumulation

20
Q

What is receptor editing?

A

Immature B cells (that mature in the BM) that recognize self antigens, they will reexpress RAG genes, resume Ig light chain recombination and rexpress a new Ig light chain to avoid self recognition

-25-50% of B cells undergo receptor editing

21
Q

How is Ig concentration related to Ig Half-life?

A

Inverse. The higher the Ig conc, the shorter the half life

22
Q

What receptor interaction is required for B cell stimulation by T cells and what happends without it?

A

CD40L (on T cell) with CD40 (on B cell) is required for B cell stimulation.

-without you get anergy, this is an example of B cell peripheral tolerance

23
Q

What is the main inhibitory receptor of both B cells and machrophages?

A

Fc receptors

-although there are both stimulatory and inhibitory Fc receptors

24
Q

What is the main inhibitory signal for B cells?

A

Co-cross linking of BCR and Fc-gamma-Receptor II turns off the B cell.

-this co-cross linking is more likely to happen at high Ig concentrations.

25
Q

What is Rhogam and what is it used for?

A

Rhogam is immune gammaglobulin to Rh antigens (IgG ab)

  • given to Rh neg mothers with an Rh+ fetus during pregnancy.
  • elimantes fetal Rh pos RBCs from maternal circulation
  • turns off maternal B cells by cross-linking BCR and FcgammaRII
  • Rh- mom would have Rh antibodies that would attack the Rh antigens of the Rh+ fetus.
26
Q

Which three cytokines are secreted by macrophages to aid in the return to homeostasis after infection? What does each inhibit?

A

IL-10 inhibits Th1 cells

TNF-beta inhibits macrophage and T cell activation

PRGe2 inhibits lymphocyte proliferation

27
Q

What Ab is present in Graves disease, what does it cause? and what type of hypersensitivity is it?

A

Graves disease has agonistic TSH antibodies that over stimulate the Thryoid stimulating hormone receptor.

  • leads to hyperthyroidism, also Goiter (thyroid hyperplasia)
  • leads to B and T cell infiltration

type II hypersen. b/c ab mediated

28
Q

What causes Goodpasture’s disease?

A

Ab against non-collagenous domains of type IV collagen of glomerular basement membrane (GBM)

  • leads to linera IgG in kidney GBM and anti-GBM antibodies
  • neutrophil mediated cytotoxicity
  • Bleeding in the lungs and progressive kidney failure
  • type II hypersen.
29
Q

What causes Systemic Lupus Eryhtematosus?

A
  • Ab against nuclear contents; dsDNA, snRNPs
  • leads to skin, kidney, joint symptoms reflect immune complex deposition
  • type III hypersen, ab-ag-immune complex
  • prevalent immune-complex mediated diease in developed countries among women
  • fever, arthritis, myalgia, skin involvement, photosensitivity, anemia
30
Q

What is a ANA test?

A

Cells fixed on slide, add patient serum, anti-nuclear ab bind, secondary antiody against human ab taged with a fluorescent dye

  • 95% of SLE patients test postivie
  • up to 15% of healthy patients have anti-ANA ab and would also test positive, this would be false positive
31
Q

What causes MS?

A

Immune attack of myelin sheath that cover nerve fibers

-type IV hypersens (cell mediated)

32
Q

What causes DM type I?

A

Descrution of insulin-producing Beta cell in pancreatic islets

  • type IV hypersen (cell mediated)
  • CD4 and CD8 T cells specific for Beta cell antigens responsible for islet cell desrtuction
33
Q

What does infection have to do with risk of autoimmunity?

A

Hypothesis that infection increases risk of autoimmune disease because it increases co-stimulation. So you have a higher risk of co-stimulating cells that recognize self that would normally be anergetic.

  • also molecular mimicry: peptide antigens from a microbe is very similar to a self antigen : like rheumatic fever, where antibodies against streptococci cross-react with myocardial antigen
  • remember though in some cases infection can be protective from autoimmunity
34
Q

What set of genes has a strong association with AI dz?

A

HLA genes

HLA-B27 is 90 relative risk in developing AI

-important is HLA does not cause disease, and vast majority of peopple with HLA allele do not develop disease

-

35
Q

What are 5 polymorphisms that affect a person’s genetic susceptibility to an AI dz? What dz’s are they associated with?

A

PTPN22: involved in B and T cell signaling – RA, SLE, TIDM

NOD-2: involved in NLR (innate) – 25% of Crohn’s dz

high affinity chain of IL-2 receptor (CD25): effector Treg balance – multiple AI dz

IL-23R: involved in Th17 differentiation – multiple AI dz

CTLA-4: multiple AI dz

36
Q

What is Abatcept?

A

CTLA-4-Ig biologic

  • fusion or protein composed of Fc region of IgG fused to CTLA-4
  • trigger off switch, treat autoimmune
37
Q

Name an anti-CD20 antibody?

A

Rituximab

38
Q

What are the 3 anti-TNF abs?

A

Infliximab

Adalimumab

Certolizumab Pergol

39
Q

What is the Anti-IL-6 Ab?

A

Toclizumab

I-2 (36 decks)

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