Immunology 4: Autoimmunity

Question 1

What are AID a dysregulation of?

Answer 1

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)

Question 2

What are the criterias for a disease to be AID?

Answer 2

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

Question 3

What genetic and environemental factors most important for AID?

Answer 3

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

Question 4

What are the mechanism leading to AID?

Answer 4

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

Question 5

What is the epiedemology of AID?

Answer 5

100 chronic disorders exist-80% in women
8% of people are AID
increasing incidence–maybe because higher hygene-immune system reacting to other things

Question 6

What AID are most common in men? And women?

Answer 6

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)

Question 7

List 5 important AID?

Answer 7

RA, T1DM, MS, SLE, Autoimmune thyroid disease (ATD-hashmotos, graves, etc)

Question 8

Do AID diseases target specific organs?

Answer 8

Spectrum-some go from organs-graves

SOme are a lot more general-RA, SLE

Question 9

Are AB involved in AID?

Answer 9

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

Question 10

What are the mechanisms of Type II, III and IV hypersensitivity? relation to AID?

Answer 10

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

Question 11

How do normal T cells recognise pathogens? Does that differ in AID?

Answer 11

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

Question 12

Why arent AID super common? What are the mechanisms present to stop it?

Answer 12

Tolerance-if cattle share Ag in Utero-then can get graft with no reaction–

Question 13

How important is timing of Ag presentation in tolerance?

Answer 13

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

Question 14

What are the 3 As of tolerance? define tolerance

Answer 14

Acquired
Antigen specific
Active process, specially active in neonates

Aqcuired inability to respons to Ag stimulus

Question 15

What are the 2 forms of tolerance? And subgroups if present?

Answer 15

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

Question 16

How is central tolerance achieved?

Answer 16

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

Question 17

Does Central tolerance fail in AID?

Answer 17

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

Question 18

Why are most AID linked to multiple genes?

Answer 18

Lot of the genes involved in lymphocyte activation and Ag clearance–important
mess with peripheral tolerance too

Question 19

How is peripheral tolerance achieved?

Answer 19

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)

Question 20

What are Tregs and their role in AID?

Answer 20

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

Question 21

What is the evidence that infection are linked to AID? Why?

Answer 21

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