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Autoimmunity/Tolerance Flashcards

(27 cards)

1
Q

Describe AIRE

A

AIRE is a transcription factor in mTEC that controls the expression of self-antigens in thymic medullary epithelial cells. Essential for negative selection/self-tolerance.

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2
Q

What happens if AIRE gets deleted or inhibited?

A

Negative selection/self-tolerance does not occur possibly leading to autoimmunity.

Ex. APECED

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3
Q

Describe APECED

A

An AR autoimmune disorder caused by mutations in AIRE gene. Its clinical presentation varies greatly.

Classic Triad:

  1. mucocutaneous candidiasis
  2. adrenal failure
  3. hypoparathyroidism.
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4
Q

What is the fate of CD4 T cells that are self-reactive during negative selection?

A
  1. Apotosis

2. Differentiate into regulatory T cells (“natural Treg”)

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5
Q

What are the lymphocyte markers of Treg T cells?

A
  1. CD3+CD4+CD25high

2. FoxP3+

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6
Q

What cytokines are secreted by Treg?

A

IL-10 & TGF-B

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7
Q

What are the three outcomes of peripheral T lymphocyte (Induced) tolerance?

A
  1. Anergy
  2. Suppression
  3. Deletion/Apotosis
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8
Q

What costimulator molecules are expressed on T cells and APCs, respectively to assist in activation?

A

CD28:B7

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9
Q

What inhibitory molecules are expressed on Treg cells and APCs, respectively, to assist in suppression?

A

CTLA4:B7

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10
Q

What is a monoclonal antibody against CTLA4 to enhance T cell activation and antitumor immunity?

A

Ipilimumab

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11
Q

What drug is CTLA4 agonist that interrupts CD-28 mediated costimulation, causing T cell energy?

A

Abatacept (bind to B7)

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12
Q

What are the components of Abatacept?

A
  1. human CTLA4

2. Fc region of IgG1

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13
Q

What is another name for B7 protein on APCs?

A

CD80/CD86

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14
Q

What cytokines are required to induce peripheral T reg?

A
  1. IL-2

2. TGF-B (allows Fox P3 gene expression of Treg)

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15
Q

What are 3 mechanisms of peripheral T reg in suppression?

A
  1. Production of inhibitory cytokines (IL-10, TGF-B)
  2. Expression of CTLA4
  3. Consumption of IL-2
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16
Q

Describe IPEX

A

An XR disorder caused by mutations in FoxP3 gene.

Classic Triad:

  1. Enteropathy (diarrhea)
  2. Dermatitis (Eczematous rash)
  3. Endocrine disease (diabetes or thyroid-related)
17
Q

What are 2 mechanisms of apoptosis in peripheral T lymphocytes

A
  1. Intrinsic Cell Death: Apoptotic inducing proteins are released from mitochondria (within T cell).
  2. Extrinsic Cell Death: Apoptosis induced by the interaction of FasL (death receptor ligand) and Fas (death receptor) on T cells.
18
Q

Describe ALPS

A

A disorder caused by mutations in Fas/FasL gene leading to defective apoptosis causing chronic accumulation of lymphoid cells.

Clinical presentations:

  1. Enlarged tissues (splenomegaly, hepatomegaly, lymphadenopathy)
  2. Blood cell autoimmunity (hemolytic anemia, thrombocytopenia, neutropenia)
  3. Increased risk for lymphomas
19
Q

What are the three outcomes of Central B Lymphocyte Tolerance?

A
  1. Apoptosis/Deletion
  2. Anergy (reduced receptor expression/signaling)
  3. Receptor Editing
20
Q

What immunoglobulin is produced by Marginal Zone B Cells when they become plasma cells?

21
Q

What is receptor editing?

A

The process in which B cells can go through to become Non-Celf Reactive B cells.

22
Q

What are the three outcomes of Peripheral B Lymphocyte Tolerance?

A
  1. Apoptosis/Deletion
  2. Anergy
  3. Suppression (has inhibitory receptors)
  • Same outcomes as Peripheral T Lymphocyte Tolerance
23
Q

What are three single-gene defects that cause autoimmunity that we have to know?

A
  1. AIRE (APECED)
  2. FOXP3 (IPEX)
  3. FAS (ALPS)
24
Q

What are 2 mechanisms of microbial/environmental-induced autoimmunity?

A
  1. Induction of costimulators on APCs
    - Microbes activate APCs to express costimulator, and APCs present self-antigens instead. This can cause self-reactive T cells to get activated leading to autoimmunity.
  2. Molecular Mimicry
    - Microbial antigens may cross-react with self antigens (mimicry) and initiate self-reactive T cells that attack self tissues.
25
Describe SLE
Multi-organ autoimmune disorder caused by defective B and T lymphocyte tolerance due to mutations in many genes. Anti-NUCLEAR antibodies are produced. * Predominant in women in childbearing age. due to estrogen.
26
What three factors can lead to loss of self tolerance in SLE?
1. Genetic Mutations (complement deficiency, and others) 2. Environmental Factors (UV, infection, chemicals) 3. Hormonal
27
What are examples of anti-NUCLEAR antibodies produced by SLE patients?
1. Ab to dsDNA 2. Ab to smith nuclear antigen 3. Ab to phospholipid