Expansion
Central and peripheral tolerance, and the ways each fails
Expansion
Tolerance operates at two levels
- Central tolerance: negative selection of self reactive lymphocytes in the thymus and bone marrow. Depends on AIRE, which expresses peripheral self antigens in the thymus; its mutation causes the APECED polyendocrine syndrome
- Peripheral tolerance: anergy, regulatory T cells, and deletion. Failure of Tregs through FOXP3 mutation causes IPEX syndrome
Mechanisms of failure
- Molecular mimicry: a microbial antigen resembles a self antigen. Rheumatic fever (streptococcal M protein and cardiac myosin), Guillain-Barre after Campylobacter, reactive arthritis
- Release of sequestered antigen: sympathetic ophthalmia after eye trauma, anti-sperm antibodies after vasectomy
- Polyclonal activation by superantigens
- Epitope spreading: the response broadens to further self antigens over time
- Altered self: drugs binding to self proteins, as in drug induced lupus and immune haemolysis
Predisposing factors: genetic (HLA associations, and female sex in most conditions), environmental (infection, smoking in rheumatoid arthritis, ultraviolet light in lupus), and hormonal.
“Autoimmune disease clusters”: a patient with one organ specific autoimmune disease is at much higher risk of another, which is why thyroid function and coeliac serology are checked in type 1 diabetes.