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Immunology Exam 3 > Lecture 19: Mechanisms of Autoimmunity > Flashcards

Lecture 19: Mechanisms of Autoimmunity Flashcards

1
Q
  • Autoimmunity is a ________ type of disease.
  • What causes autoimmunity?
  • What plays a key role in the pathogenesis of autoimmune diseases?
A
  • Chronic (also progressive & self-perpetuating)
  • activation of T and/or B cells in absence of ongoing infection
    • pathologic IRs against self Ags are clinically manifested as “immune-mediated inflammatory dz’s”
  • Dysbiosis of Gi microbiome
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2
Q

What are the 4 mains ways autoimmunity is prevents?

A
  1. Immunologic ignorance
  • when T cells are physically separated from their specific Ag and cannot become activated
  • i.e. BBB
  1. Deletion
    * When T cells expressing Fas (CD95) receive signals from cells expressiong FasL undergo apoptosis
  2. Inhibition
    * CTLA4 (CD152) binds CD80 (B7) on APC inhibiting T cell activaiton
  3. Suppression
    * Treg cells inhibit via IL-10 and TGF-β
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3
Q

What are the immunopriveled sites?

A
  • eye
  • brain
  • pregnant uterus
  • ovary
  • testis
  • adrenal cortex
  • hair follicles
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4
Q

Explain role of genetic factors in autoimmunity.

  • which genes have the strongest associations with MHC?
A

SUSCEPTIBILITY GENES interact w/ ENVIRONMENTAL FACTORS to cause dz’s

  • MHC genes (HLA genes)
    • most autoimmune dz’s are associated with Class II HLA alleles, bc they cntrl action of CD4+ T cells
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5
Q

What are the two primary mechanisms of autoimmunity?

A
  1. Genetic susceptibility –> influences self-tolerance (i.e. failure of self tolerance)
  2. Environmental triggers –> i.e. infections, inflammatory stim.
    * promote influx of lymphocytes into tissues & activation of self-reactive T cells –> tissue injury
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6
Q

What are the 4 mechanisms of Infection-Induced Autoimmunity?

A
  1. Molecular mimicry
  2. Bystander (polyclonal) activation
  3. Epitope spreading
  4. Release of Hidden/Cryptic Ags
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7
Q

Describe molecular mimicry in autoimmune dz’s

  • what type of infection would you most commonly see this in?
A
  • Acute viral infections
    1. Viral Ags carry epitopes strugturally similar to self-Ag epitoptes
    2. Cross reactive response against self and non-self Ags

(APCs present viral epitopes –> activates autoreactive T cells that bind both self and non-self Ags –> tissue damage)

ex) Rheumatic fever: triggered by streptococcal infection; mediated by cross-reactivity b/w streptococcal Ags & cardiac myosin
ex) MS: T cells react w/ myelin basic prtn & peptides from Epstein-Barr, influenza A, and HPV

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8
Q

Describe Bystander Activation in autoimmune dz’s

  • acute or chronic viral infection?
A

***microbial infection causes polyclonal activaiton (robost IR) of autreactive lymphocytes (cytokine field); no cross-reactivity just overwhelming response in activaiton of auto-reactivce lymphocytes**

  1. Non-specific & strong anti-viral response leads to liberation of self-Ags & release of inflammatory cytokines
  2. Self Ag released from damaged tissue
  3. Self Ags presented on APC activate autoreactivec T cells –> cause tissue destruction
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9
Q

What is epitope spreading?

  • acute or chronic?
A

IR to secondary epitopes is distinct from primary dz-causing epitope (1st Ag causing primary response is different from secondary wave of response (auto Ags))

  1. Persistent viral infection
  2. Continued tissue damage and release of new self-Ags
  3. Self-Ags presented on APC activating autoreactive T cells
  4. T cell response spreads to other autoreactive T cells leading
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10
Q

What is the process for releasing hidden/cryptic Ags?

A

INTRACELLULAR SELF Ags are not seen during negative selection and thus are hidden/cryptic

  • so AUTOREACTIVE T and B cell CLONES against auto-Ags are not deleted
  • Tissue damage –> release of hidden Ags–> activates preexisting autroreactive immune clones –> autoimmune dz

So infection & lytic viruses cause the release of these hidden self Ags

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11
Q

Is autoimmunity more common in men or women?

Why?

A

Women

  • testosterone has more anti-inflammatory processes than estrogen
  • Estrogens exacerbate SLE by altering B-cell repertoire in absence of inflammation
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12
Q

What two drug classes alter the immune repertoire?

A

Penicillins and Cephalosporins

  • bind RBC memb & generate a neoAg which eleicits an auto-Ag that causes hemolytic anemia
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13
Q

What factor has inhibibitory effect on activated T cells?

If this factor is blocked, it can induce antinuclear Abs and even SLE and ______.

A
  • TNF-α (TNF induced apoptosis via extrinsic pathway)
  • MS (if they are susceptible)
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14
Q

Systemic Lupus Erythematosus (SLE) is what type of hypersensitivity?

  • what are the principal clinical manifestations?
  • what are the most frequent auto-Abs found?
  • what does the prinicpal diagnostic test for?
A

Type III = immune complex mediated dz

  • rashes, arthritis, glomeulonephritis
  • anti-DNA Abs
  • anti-nuclear Abs

immune complexes formed from auto-Abs + Ag –> responsible for glomerulonephritis, arthritis and vasculitis, via complement activation –> which results in tissue damge

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15
Q

Rheumatoid Arthritis (RA) is an inflammatory dz involving small & large joints. What type of hypersensitivity is it?

  • What type of cells are involved? & which one plays the primary role?
  • what is the auto-Ab involved & used for diagnostic test?
A

Type IV hypersensitivity (mediated by T cells)

  • Th1, **Th17, B cells, plasma cells, and macrophages
  • Rhematoid factor (RF) –> reacts w/ Fc portion of ciruculating IgG

*** susceptibility + environmental factors –> failure of tolerance & unreg lymphocyte actiavation + hidden Ags are released –> T/B cell responses to self Ags (including Ags in joint tissues) –> cytokine production + inflammation –> destrcution of cartilage & bone

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16
Q

Which autoimmune dz is involved with cryptic carbohydrate strucutes on Ag-bound IgG molecules?

A

RA

  • presenece of RF is associated w/ inflammatory RA
  • Ag binding of IgG –> conformationally changes the Fc region –> exposes cryptic carb stx
  • Ab directed at these crytic carb stx on Ag-bound IgG/M mlcls = RF (anticarbohydrate IgM)
  • RF binding to Ag-IgG compexes forms bigger immune complexes and activaiton of complement –> recruitment of macrophages, neutrophils, & lymphoctes to tisses
17
Q

What disease is susceptible to pt’s upon damage of BBB? What type mechansism would this be considered?

What are the primary cytokines involved that trigger the inflammatory response in brain?

A

Multiple Sclerosis & molecular mimicry

  • Immune system gets access to Ag in brain –> Primary basic myelin protein Ag which B & T cells interact with
  • MS = neurdegenerativce autoimmune dz of white matter in CNS

TNF-α, IL-6, IL-17, IFN-γ –> inflammatory response causes plaque development in white matter by stripping myelin from neurons

Commonly tx with IFN-β (antiviral) which thought to attenuate proinflammatory cytokines

18
Q

Type 1 Diabetes is an autoimmune disorder mediated by what cell type?

A

T cell mediated destruction of pancreatic β cells

  • characterized by autoAb markers of β-cell destruction and STRONG HLA associations –> MHC Class II
  • Onset associatied w/ infiltration of the Islets by monocuclear cells & CD8+ T cells
    • Insulitis = infiltrate
19
Q

IBD (inflammatory bowel DISEASE) is used to describe what 2 disorders that involve chronic inflammation of the GI tract?

A
  1. Ulcerative colitis (UC) –> chronic inflammation & ulcers in the innermost lining of the colon &/or rectum (superficial)
  2. Cron’s dz (CD) –> inflammation that spreads deep into affected tissues & can occur in any part of the GI
    * 40% of pt’s with CD –> rectum is spared
20
Q

What are the two leading problems in IBD?

A
  1. Increased permeability of the epithelial barrier (caused by impared formation of tight jxns)
  2. Commensal bacteria of the normal intestinal microbiota cause inflammatory rxns leading to self-sustained mucosal inflammation
    - bacterial components cross the mucosal barrier –> contact immune cells –> inducing both innate & adaptive immunity
21
Q

IBD is a result of persistent & inappropriate perturbation b/w IS and commensal bacteria of the normal microbiome resulting in what 2 things?

A
  1. Dysbiosis –> microbial imbalance
  2. mucosal inflammation
    * both of which affect permeability
22
Q

Aberrent repsonses associated with IBD are large degree genetically determined.

  • disruption of the barrier fxn is mainly associated which disorder?
  • dysfunction of microbe sensing is mainly associated which disorder?
  • changes in immunoregulation of both innate and apative IR’s mainly associated which disorder?
A
  • Ulcerative colitis
  • Crohn’s dz
  • BOTH
23
Q

In IBD, innate cells produce which chemokines?

What type of cells is markedly increased?

KEY CONCEPTS

A
  • TNF-α, IL-1β, IL-6, IL-12 (also ROS & NO)
  • CD4+ T cells

IBD = chronic relapsing idiopathic INFLAMMATION of GI tract

  • IBD pt’s will have inc. intestinal permability
  • IBD often results in irreversible impairment of GI stx & fxn
  • hygeine hypothesis of allergic & autoimmune dz used to exlain inc. incidence of IBD

Immunology Exam 3 (6 decks)

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