Lecture 19: Mechanisms of Autoimmunity Flashcards
- Autoimmunity is a ________ type of disease.
- What causes autoimmunity?
- What plays a key role in the pathogenesis of autoimmune diseases?
- 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
What are the 4 mains ways autoimmunity is prevents?
- Immunologic ignorance
- when T cells are physically separated from their specific Ag and cannot become activated
- i.e. BBB
- Deletion
* When T cells expressing Fas (CD95) receive signals from cells expressiong FasL undergo apoptosis - Inhibition
* CTLA4 (CD152) binds CD80 (B7) on APC inhibiting T cell activaiton - Suppression
* Treg cells inhibit via IL-10 and TGF-β
What are the immunopriveled sites?
- eye
- brain
- pregnant uterus
- ovary
- testis
- adrenal cortex
- hair follicles
Explain role of genetic factors in autoimmunity.
- which genes have the strongest associations with MHC?
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
What are the two primary mechanisms of autoimmunity?
- Genetic susceptibility –> influences self-tolerance (i.e. failure of self tolerance)
-
Environmental triggers –> i.e. infections, inflammatory stim.
* promote influx of lymphocytes into tissues & activation of self-reactive T cells –> tissue injury
What are the 4 mechanisms of Infection-Induced Autoimmunity?
- Molecular mimicry
- Bystander (polyclonal) activation
- Epitope spreading
- Release of Hidden/Cryptic Ags
Describe molecular mimicry in autoimmune dz’s
- what type of infection would you most commonly see this in?
- 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
Describe Bystander Activation in autoimmune dz’s
- acute or chronic viral infection?
***microbial infection causes polyclonal activaiton (robost IR) of autreactive lymphocytes (cytokine field); no cross-reactivity just overwhelming response in activaiton of auto-reactivce lymphocytes**
- Non-specific & strong anti-viral response leads to liberation of self-Ags & release of inflammatory cytokines
- Self Ag released from damaged tissue
- Self Ags presented on APC activate autoreactivec T cells –> cause tissue destruction
What is epitope spreading?
- acute or chronic?
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))
- Persistent viral infection
- Continued tissue damage and release of new self-Ags
- Self-Ags presented on APC activating autoreactive T cells
- T cell response spreads to other autoreactive T cells leading
What is the process for releasing hidden/cryptic Ags?
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
Is autoimmunity more common in men or women?
Why?
Women
- testosterone has more anti-inflammatory processes than estrogen
- Estrogens exacerbate SLE by altering B-cell repertoire in absence of inflammation
What two drug classes alter the immune repertoire?
Penicillins and Cephalosporins
- bind RBC memb & generate a neoAg which eleicits an auto-Ag that causes hemolytic anemia
What factor has inhibibitory effect on activated T cells?
If this factor is blocked, it can induce antinuclear Abs and even SLE and ______.
- TNF-α (TNF induced apoptosis via extrinsic pathway)
- MS (if they are susceptible)
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?
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
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?
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
Which autoimmune dz is involved with cryptic carbohydrate strucutes on Ag-bound IgG molecules?
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
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?
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
Type 1 Diabetes is an autoimmune disorder mediated by what cell type?
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
IBD (inflammatory bowel DISEASE) is used to describe what 2 disorders that involve chronic inflammation of the GI tract?
- Ulcerative colitis (UC) –> chronic inflammation & ulcers in the innermost lining of the colon &/or rectum (superficial)
-
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
What are the two leading problems in IBD?
- Increased permeability of the epithelial barrier (caused by impared formation of tight jxns)
-
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
IBD is a result of persistent & inappropriate perturbation b/w IS and commensal bacteria of the normal microbiome resulting in what 2 things?
- Dysbiosis –> microbial imbalance
- mucosal inflammation
* both of which affect permeability
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?
- Ulcerative colitis
- Crohn’s dz
- BOTH
In IBD, innate cells produce which chemokines?
What type of cells is markedly increased?
KEY CONCEPTS
- 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
