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FPP: pre-midterm > Tolerance and Autoimmunity > Flashcards

Tolerance and Autoimmunity Flashcards

1
Q

What are the central and peripheral fates of lymphocytes that recognize self antigen?

A

Central Tolerance:

  1. Apoptosis (deletion)
  2. Change in receptors (receptor editing: B cells only)
  3. Development of regulatory T lymphocytes (CD4+ T cells only, express Foxp3 and suppress immune response)

Peripheral Tolerance:

  1. Anergy (inactivation)
  2. Apoptosis (3 mechanisms; Fas/Fas ligand, cytokine withdrawal, AICD)
  3. Suppression (e.g. by T regulatory cells)
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2
Q

What is AIRE?

What results when there is a defect in AIRE?

A

“AutoImmune REgulatory gene” is a transcription factor that induces expression of self-antigens by the thymic medullary epithelial cells. **key to negative selection

**When AIRE is lost:

  1. Self reactive T cells are not deleted
  2. Self reactive T regulatory cells are not generated
  3. Autoimmunity occurs (APECED; example of failure of central tolerance)
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3
Q

What two signals are needed for lymphocyte activation?

A
  1. T cell receptor sees an antigen on MHC
  2. Co-stimulation; CD28 ligation by B7-1 (CD80) and B7-2 (CD86) on antigen presenting cells
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4
Q

What is the result of antigen presenting cells that lack co-stimulatory molecules?

A

APCs lacking B7 promote anergy (the functional inactivation of lymphocytes)

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5
Q

Contrast CD28 and CTLA-4

A

Both are on the T cell and bind B7-1 (CD80) and B7-2 (CD86)

CD28 is the activating receptor

CTLA-4 is the inhibitory receptor and binds B7 with higher affinity (Abatacept= recombinant CTLA-4 for autoimmunity)

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6
Q

What is PD-1?

A

A checkpoint inhibitor induced in T cells

*Targeted in cancer

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7
Q

What induces B7 molecules? What is the result if an APC lacks B7?

A

Microbes induce B7 molecules on APCs by recognition of PAMPs by TLRs/NOD receptors

Without B7 (or with B7 engagement of CTLA-4), anergy/unresponsive T cells result

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8
Q

What are the mechanisms of T/B cell death after an immune response?

A
  1. AICD (activation-induced cell death) from repeated activation of mature T cells by self antigens
  2. Fas/FasL (potent actiator of apoptosis); CD4+ T cell activation upregulates expression of Fas “death receptor”
  3. Cytokine withdrawal; properly activated T cells express IL-2 (growth/survival factor). Lack of IL-2 when immune stimulus is gone results in apoptosis
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9
Q

What is the result of mutation in Fas/FasL?

A

ALPS (autoimmune lymphoproliferatice syndrome); example of failure of peripheral tolerance

*High levels of IgG, IgA, IgM, and double negative (CD4-/CD8-) T cells common

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10
Q

What is Foxp3?

A

Transcription factor expressed by T regulatory cells

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11
Q

Where are T regulatory cells generated? How/where are they activated?

A

Generated by self antigens in the thymus (remember AIRE), activated in the periphery by self antigen and IL-2

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12
Q

How to T regulatory cells suppres the immune response?

A
  1. Contact Dependent; Treg binds directly to mature T cells, inducing inhibitory signaling
    (e. g. CTLA-4, surface bound TGF-beta, killing of targets through perforin and granzyme)
  2. Contact Independent; Tregs secrete TGFbeta/IL-10 that inhibit T cell activation
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13
Q

What is the result of lacking T regulatory cells?

A

IPEX (immune dysregulation polyendocrinopathy enteropathy, X-linked)

*Foxp3 mutation, affects boys in infancy

*Autoimmune, very high IgE levels

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14
Q

What characteristics of an antigen may contribut to tolerance or the breakdown of tolerance?

A

Location, abundance, and persistence of antigen

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15
Q

How does genetics affect our ability to respond to foreign and self tissue?

A

HLA affects what peptides are presented to lymphocytes
*Having certain HLA alleles increases relative risk of developing certain autoimmune disorders

Also many other genetic susceptilibility loci (AIRE, complement proteins, Fas/FasL, Foxp3, IL-2, etc)

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16
Q

What role do environmental factors play in autoimmunity?

A

In some cases infection can trigger autoimmunity in a susceptible person

**The infectious organism could have antigens that look like self resulting in autoimmunity (molecular mimicry)

17
Q

Summarize type 1 hypersensitivity

A
  • Immediate hypersensitivity
  • Requires TH2 development
  • IgE mediated
  • E.g. allergic rhinitis, asthma, eczema, food allergies
18
Q

Summarize type 2 hypersensitivity

A

**Antibody mediated hypersensitivity

  • Crosslinking Fc receptors on macrophages/neutrophils
  • > inflammation
  • Complement activation -> inflammation
  • Phagocytosis promoted by IgM and IgG
  • Function blocking/activating Abs (e.g. myathenia gravis)
19
Q

What are the JONES criteria?

A

For acute rheumatic fever (a type II hypersensitivity reaction and an example of molecular mimicry):

Joints

Heart

Nodules

Erythema marginatum

Sydenham’s chorea

20
Q

What are the treatments of antibody mediated disease?

A

Non-life threatening disease:

  • High dose IV immunoglobulin (IVIG); competes for Fc receptors and activates inhibitory Fc receptor
  • Corticosteroids (prednisone); anti-inflammatory
  • Rituximab (anti-B cell therapy)

Life threatening disease:

  • Plasmapheresis (rare)
21
Q

Summarize type 3 hypersensitivity

A

Immune complex deposit in vasculature leads to disease (antigen + antibody= IC, normally activate complement and are cleared)

e.g. systemic lupus erythematosus from complement defects

*injury mainly from leukocyte recruitment and inflammation

22
Q

Summarize type 4 hypersensitivity

A

Cell mediated disease (CD4/CD8);

  1. TH1 mediated hypersensitivity reaction
  2. TH17 mediated inglammatory reaction
  3. Kiling of host cells by CD8+ CTLs

*Delayed response

23
Q

What is the pathology of arthritis?

A
  1. T cells in synovial spaces are self reactive
  2. Monocytes, macrophages, fibroblasts are activated by T cells -> release IL1, IL6, TNF -> inflammation
  3. Panus formation; aggregates of mononuclear cells (T/B cells, macrophages)

**both cell-mediated and humoral immune response contributing to inflammation

24
Q

What are the common treatments for arthritis?

A
  1. NSAIDs
  2. Anti-metabolites (inhibit DNA synthesis; e.g. methotrexate and azathioprine)
  3. Glucocorticoids
  4. Monoclonal Ab to immune molecules (e.g. anti-TNF, anti-IL1/6, etc)
25
Q

Define hypersensitivity reaction

A

Immune response that causes tissue injury (may arise from uncontrolled/abnormal response to foreign antigen or an autoimmune respons against self antigen)

FPP: pre-midterm (19 decks)

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