Pathophysiology
Clinical meaning
Autoimmunity results from the failure of self-tolerance — the immune system's ability to distinguish self from non-self. Central tolerance eliminates autoreactive T and B cells during development (negative selection in the thymus for T cells, bone marrow for B cells), but some autoreactive cells escape. Peripheral tolerance mechanisms (regulatory T cells [Tregs], anergy, deletion, immune checkpoint molecules) normally suppress these escapees. Autoimmune disease occurs when genetic susceptibility + environmental triggers overwhelm tolerance mechanisms. Molecular mechanisms: (1) Molecular mimicry — pathogen antigens share structural similarity with self-antigens, causing cross-reactive immune responses (Group A Strep M protein mimics cardiac myosin → rheumatic heart disease; Campylobacter lipooligosaccharides mimic gangliosides → Guillain-Barré syndrome). (2) Epitope spreading — initial immune response against one antigen damages tissue, exposing previously sequestered self-antigens to the immune system, broadening the autoimmune attack (occurs in MS, SLE). (3) Bystander activation — non-specific inflammation at a tissue site activates autoreactive T cells that happen to be present (viral infections causing type 1 diabetes). (4) Defective Tregs — FOXP3+ regulatory T cells normally suppress autoreactive effectors; loss of Treg function (IPEX syndrome...