Immunology 4: Autoimmunity Flashcards
What are AID a dysregulation of?
Breakdown of self tolerance of the normal autoimmunity action-symptoms often adaptive (all have it)
Mix of environemental factor and genetic componets (diet/infection/genes, etc)
What are the criterias for a disease to be AID?
Evidence of ADAPTIVE response
Can transfer disease by transfering autoreactive cells/AB
If can control Autoimmune response, eliminate the disease
History of AID-personal or family and/or MHC associations
What genetic and environemental factors most important for AID?
Genes-many twin studies/family + GWAS (eg SLE: 40 loci)–run in families, and if have one more likely to have another
Gender-depends on condition but women are much higher chance
Infections-inflammatory environement
Diet-Obesity, high fat (effects on microbiome +direct on Autoimmune cells)-may relieve AID symptoms
Stress-phsyical and psychological
Microbiome-gut microbiome crucial for regulation and development of microbiome
What are the mechanism leading to AID?
Adaptive response is same than for pathogens
AID involve T cell tolerance loss and IgG production
Because self tissue always present-AID are chronic and can become latent
Mechanisms ressemble type II, III, IV
What is the epiedemology of AID?
100 chronic disorders exist-80% in women
8% of people are AID
increasing incidence–maybe because higher hygene-immune system reacting to other things
What AID are most common in men? And women?
women-Sjorgens, SLE, thyroid
Men-T1DM, UC (equal)
some get better during pregancy, some get worse
AB mediated usually get worse, while cell mediated get better (because switch to Th2 cells a lot)
List 5 important AID?
RA, T1DM, MS, SLE, Autoimmune thyroid disease (ATD-hashmotos, graves, etc)
Do AID diseases target specific organs?
Spectrum-some go from organs-graves
SOme are a lot more general-RA, SLE
Are AB involved in AID?
Yes-very
AUtoantibodies have been seen in many diseases-
Anti erythrocytes-heamolytic aneamia
Graves in pregnant mother-IgG can cross placenta and cause graves in young child after birth
What are the mechanisms of Type II, III and IV hypersensitivity? relation to AID?
AID ressemble these 3 types–
Type II-AB response -eg: AI heamolytic aneamia, Goodpastures (angaisnt collagen IV in BM), graves (stimulate), myasthenia gravis (AChR)
Type III-immune complexes (SLE-vs Nuclear components-desposit activate complement)
Type IV-tcells-delayed-T1DM, RA, MS
NO TYPE I AID
How do normal T cells recognise pathogens? Does that differ in AID?
Recognise AG presented on MHC II
TCL-MHC I
in AID-gene modifications can change a lot
most common genes-MHC II alleles-certain alleles increase that-DR3/4
Very polymorphic-so suceptibility differe a lot
Why arent AID super common? What are the mechanisms present to stop it?
Tolerance-if cattle share Ag in Utero-then can get graft with no reaction–
How important is timing of Ag presentation in tolerance?
Timing-how early in life–if cattle share Ag in Utero-then can get graft with no reaction–
In neonates, if give Ag from adult-then transfer graft-tolerated
BUT its Ag specific-only with those
And wont accept anything else from another donor
What are the 3 As of tolerance? define tolerance
Acquired
Antigen specific
Active process, specially active in neonates
Aqcuired inability to respons to Ag stimulus
What are the 2 forms of tolerance? And subgroups if present?
Central-during lymphocyte development (T-thymus, B bone marrow-rearage of Segments–deletion of self reaction
Peripheral-after development
–Anergy, active supression (also not tolerance but similar-immune privilege (sites in body where immune doest go) and Ag ingoring
How is central tolerance achieved?
Thymic epithelial cells and DC cells in THYMUS present SELF-Ag on CD4 cells on MHCii
Useless cells-cant see MHC-death
Dangerous-react to self Ag-negative selection
USeful-bind weakly to MHC-positive selection
only 5% survive
Similar for B cells, but in BM
if no react, then can go
If they bind to cell surface-deletion/or degenerate receptor
If bind to soluble self molecule-migrate to periphery but dont do anything in periphery-anergic
Low affinity-non cross linking binding to self molecule–go to periphery but have potential to becaume AI-just hasnt seen the Ag yet
Does Central tolerance fail in AID?
YES-but very rarely
APECED (disease)-mutations in AIRE (helps expression of self Ag, normally in other tissues, in thymus)-
Large amount of autoreactive cells-complex conditions
Why are most AID linked to multiple genes?
Lot of the genes involved in lymphocyte activation and Ag clearance–important
mess with peripheral tolerance too
How is peripheral tolerance achieved?
Central tolerance can fail
Need mechanism to regulate outside
Anergy, supression by Tcells, not seing Ag
Anergy-need co stimulation with MHC for activation of b cell-if no stimulation-cell become anergic-cant proliferate-very hard to reverse
Ignorance/not seing Ag-if conc too low for Lympho to see it-fine. Most cells in body dont have MHC II-cant activate T cells. Inflammation can cause MHCII to be expressed on epitheial-can stimulate. Also places where lympho dont go-eye, PNS-cant be exposed to that self Ag (can fail, like trauma to one eye-Ag leak to lympho-and then activate T cells, which can suddently attack BOTH eyes)
Tregs (see other slide)
What are Tregs and their role in AID?
CD4 T cells (also have CD25, CTLA)-need FOXP3 (TF) to develop
IPEX (disease)-mutation in FOXP3-no Tregs–large amounts of AID, accumulation of self reactive T cells–so know its important
What is the evidence that infection are linked to AID? Why?
Over years, incidental evidence that infections linked to certain AID
MS-Epstein barr, etc
Why-
Infections, like streptococci-molecular mimicry-produce nearly self Ag
Induce changes in exression and recontion or self protein
Co stimulatory molecules upregulate MHC, and produce co-stimulatory molecules
Failure in regulation-activate APC that have some Self Ag on their MHC-more co-stimulatory molecules-activate other cells
Immune deviations-shift in type-Th1->2–has a potential to alter
Tissue damage at immunological previledged sites
