Theories of Autoimmunity D. I. Stott

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

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.

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.

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

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

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

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

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

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

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

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

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

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

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

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.

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