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 = FOXP3 mutation) causes multi-organ autoimmunity. (5) Immune checkpoint failure — CTLA-4 and PD-1 are inhibitory receptors that prevent excessive immune activation; polymorphisms increase autoimmune risk; therapeutic checkpoint inhibitors (pembrolizumab, nivolumab) can trigger autoimmune adverse effects (thyroiditis, colitis, hepatitis). HLA associations: HLA-B27 → ankylosing spondylitis, reactive arthritis; HLA-DR4 → rheumatoid arthritis; HLA-DQ2/DQ8 → celiac disease; HLA-DR3/DR4 → type 1 DM. Pathogenic autoantibodies: anti-dsDNA (SLE nephritis), anti-Smith (SLE — highly specific), anti-CCP (RA — more specific than RF), anti-SSA/SSB (Sjögren), anti-centromere (limited scleroderma/CREST), anti-Scl-70 (diffuse scleroderma), anti-Jo-1 (polymyositis/dermatomyositis with ILD).