Immunological tolerance

Because receptor generation is random, many developing lymphocytes recognise self. Central tolerance removes most of them. In the thymus, thymocytes that bind self-peptide–MHC strongly are deleted (negative selection) or diverted into regulatory T cells; medullary epithelial cells, driven by the transcription factor AIRE, express thousands of tissue-restricted antigens (e.g. insulin, thyroglobulin) so that T cells reactive to peripheral organs can be purged. In the bone marrow, immature B cells that bind self-antigen strongly undergo receptor editing (rearranging a new light chain), deletion by apoptosis, or anergy.

Central tolerance is incomplete, so peripheral tolerance mechanisms act on mature lymphocytes: anergy — functional inactivation when a T cell sees antigen without co-stimulation (signal 1 without signal 2) or engages inhibitory receptors (CTLA-4, PD-1); suppression by FOXP3⁺ regulatory T cells (IL-10, TGF-β, CTLA-4); deletion by activation-induced cell death (Fas–FasL) or Bim-mediated apoptosis; and ignorance of antigens that are sequestered or presented without danger signals. Self-reactive B cells usually cannot respond without T-cell help. Some sites — the eye, testis, brain and the fetus/placenta — have immune privilege maintained by barriers, local immunosuppressive factors (TGF-β, FasL) and, in the placenta, non-classical HLA-G. Tolerance to food and commensal microbes (oral tolerance) depends on gut dendritic cells and peripherally induced Tregs.

Autoimmunity results when tolerance fails, usually through a combination of susceptibility genes (HLA alleles, PTPN22, CTLA4 and others) and environmental triggers: infections that cause molecular mimicry (streptococcal M protein and cardiac myosin in rheumatic fever; Campylobacter lipo-oligosaccharide and nerve gangliosides in Guillain–Barré syndrome) or bystander activation, tissue injury releasing sequestered antigens (sympathetic ophthalmia after penetrating eye injury), drugs and hormonal factors (most autoimmune diseases are commoner in women). Once begun, responses may broaden to new self-epitopes (epitope spreading).