1. Theories of Autoimmunity
D. I. Stott

2. Self/Non-self Discrimination
Autoimmunity is a problem of self/non-self discrimination.

3. Systemic autoimmune diseases affect skin, joints, kidney & muscle
Systemic autoimmune diseases affect skin, joints, kidney & muscle. Individual organs are more affected in some diseases than others.

4. Autoimmune diseases (AIDs) may be classified as organ-specific or systemic (non-organ-specific). There is a spectrum of AIDs including some that exhibit intermediate features.

5. The Problem:- B &T-cell receptor specificities generated randomly
Anti-self lymphocytes are deleted or  anergic
Some escape: anti-self B (& T) L.s in healthy individuals

6. Evidence for anti-self lymphocytes in healthy individuals:-
L.s bind autoags., e.g. thyroglobulin, DNA
Autoabs. in serum, e.g. RF  with age.
L.s + mitogen or EBV  autoabs. in vitro
Self-ags./FCA  autoimmune response, e.g.
rats + thyroglobulin/FCA  autoimmune thyroiditis
MBP/FCA  EAE
Collagen/FCA  RA

7. Theories: 1. Cryptic Antigen
Ag sequestered from immune system
Damage & release of ag. (injury or surgery)  AIR
e.g. Eye  sympathetic ophthalmia
Testes  anti-sperm & orchitis

8. 2. Somatic Mutation Hypothesis
Mutation in V of -non-self  -self, e.g.
-Phosph. choline myeloma  -DNA
Mice/Ph-AsO3--pr.  B-Ls. with BCRs -AsO3- + -DNA, latter normally  anergic or die

9. 3. Th By-pass Theory (a): B-cell response

10. Th By-pass Theory (b) Foreign Th epitope/self B-cell epitope:-
Ag modification, e.g. by Drugs:
-Me-Dopa  altered synth. of Rh ag  AIHA
Procainamide  nucleosomes  -histone, - DNA  SLE

11. Th By-pass Theory (c) Ag Mimicry: bact. & viruses X self ags.
Strep. pyogenes  -M pr., X heart valves  inflammn. of endocardium & damage to valves rheumatic fever
BK Polyoma virus/Rabs.  -DNA, histones  SLE
Rabies vaccine (brain tissue)  encephalitis

12. 4. Polyclonal Activation Hypothesis
B-cell mitogens, e.g. LPS, EBV
Bact. Superag.  TCR (V)  -self or Th
BUT
Limited specificity, e.g. thyroiditis
Clonally restricted e.g. -DNA in SLE

13. 5. Genetic Defects
(a) Apoptosis: MRL-lpr/lpr & gld/gld mice - Fas or FasL defect  SLE
(b) Association with MHC Class II
e.g. R.A. & DR4, SLE & DR3,
IDDM & DQ - single  at posn. 56, Asp protects, other s  IDDM

14. 6. Regulatory T-cells (a)
-self Ls. suppressed by Tr-cells
Is AIR result of defect in Tr?
Evidence: (a) Tx rats  -Tg & AIT
(b) Tx mice  AIR v. many organs & tissues
+ adult T-L.s, suppress AIR

15. Regulatory T-cells (b): SJL mice
SJL mice have a Tr defect, immunisn. with rat RBC  AIHA

16. 7. Danger Theory Anti-self B & T-cells always present.
AIR is due to release of “danger signals.”
Response to tissue damage, necrosis or cell distress, e.g. infection or injury.
Inflammn. = response to danger signals mediated by effector mols. inc. cytokines.
BUT AIR can occur without tissue damage, e.g. immunisn. with self-ag; Tx; genetic defects.

17. Summary
Self reactive B-cells & T-cells are normally present but anergic.
Several factors can induce an AIR:-
Genetic
Tissue damage & release of cryptic ag.
Somatic mutation in Ig V-genes
Ag mimicry
Tr defects
Danger signals