# Autoimmunity Mechanisms > Autoimmunity mechanisms in MBBS Pathology: tolerance breakdown, molecular mimicry, HLA associations, Witebsky criteria and autoantibody interpretation. - Canonical URL: https://prepelephant.com/topics/mbbs/pathology/autoimmunity-mechanisms - Exam / course: MBBS · Subject: Pathology - Publisher: PrepElephant (https://prepelephant.com) — Prepared and reviewed by the PrepElephant Academic Review Team - First published: 2026-10-02 - Last updated: 2026-10-02 - How to cite: "Autoimmunity Mechanisms", PrepElephant, https://prepelephant.com/topics/mbbs/pathology/autoimmunity-mechanisms ## Direct answer Self-tolerance normally holds because developing lymphocytes that recognise self are deleted in the marrow and thymus (central tolerance), while mature cells are held in check by anergy, suppression by regulatory T cells and activation-induced death (peripheral tolerance). Autoimmunity is the breakdown of these checkpoints — helped by genetic susceptibility concentrated in the HLA locus, female preponderance, and triggers such as molecular mimicry, release of sequestered antigens, drugs and epitope spreading. The resulting disease uses every hypersensitivity mechanism: antibody against fixed tissue (type II, as in autoimmune haemolytic anaemia and Goodpasture disease), immune complexes (type III, lupus nephritis), and T-cell-mediated injury (type IV, type 1 diabetes, multiple sclerosis, Hashimoto thyroiditis). Diagnosis rests on autoantibodies whose sensitivity and specificity the student must know separately. ## What you must remember - **Checkpoint genes as experiments of nature:** AIRE mutations (autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, APECED) cripple thymic expression of tissue antigens; FOXP3 mutations (IPEX) abolish functional regulatory T cells — both prove that tolerance is actively maintained. - **Molecular mimicry with its exemplars:** group A streptococcal M protein versus cardiac myosin in rheumatic fever; Campylobacter jejuni lipo-oligosaccharide versus peripheral-nerve gangliosides in Guillain-Barré syndrome. - **Mechanisms to list in vivas:** molecular mimicry, release of sequestered antigens (lens, sperm, brain — sympathetic ophthalmia after eye trauma), bystander activation, epitope spreading, polyclonal activation (EBV), and drug-induced neoantigens (hydralazine, procainamide-induced lupus). - **HLA associations to quote:** HLA-B27 and ankylosing spondylitis — the strongest human association; HLA-DR3/DR4 with type 1 diabetes; HLA-DR4 with rheumatoid arthritis. - **Autoantibody sensitivity-specificity pairs:** ANA is sensitive but not specific for SLE; anti-dsDNA and anti-Sm are specific for SLE (dsDNA tracks nephritis activity); anti-CCP is specific for rheumatoid arthritis; anti-centromere for limited systemic sclerosis, anti-Scl-70 for diffuse; anti-Jo-1 for myositis with interstitial lung disease. - **Organ-specific versus systemic:** Hashimoto and Graves at one pole, SLE, Sjögren and systemic sclerosis at the other; type 1 diabetes and autoimmune Addison cluster in polyglandular syndromes. - **Witebsky's (Rose's) postulates:** autoantibody or T cells demonstrable, corresponding antigen identified, disease reproducible in animals by immunisation with the antigen — the framework by which a marker earns pathogenic status. ## How a sunburn lights up lupus nephritis Take the best-worked mechanism chain in the syllabus. Ultraviolet exposure induces keratinocyte apoptosis; apoptotic blebs externalise nucleosomes — DNA and histones normally hidden inside the nucleus. In a susceptible person (complement deficiencies such as C1q or C4 are the strongest monogenic lupus risks), clearance of these blebs is slow, and B cells that escaped tolerance present nucleosomal antigens to T cells. Anti-dsDNA antibodies form, and the classic twisted-story begins: DNA-anti-DNA complexes lodge in glomeruli, bind to nucleosomes trapped in the basement membrane, activate complement, and the full type III picture erupts — proliferative glomerulonephritis with wire-loop deposits on immunofluorescence ("full-house" staining). Photosensitivity, arthritis and cytopenias share one logic. Blocking the terminal pathway (anti-C5, anifrolumab against type I interferon receptor) now treats lupus — mechanism guiding therapy, which is exactly what the examiner rewards. ## Where students slip Treating a positive ANA as disease is the commonest clinical error: at low titre it is frequent in healthy people, and specificity comes only from the confirmatory antibodies. The second slip is assuming autoimmunity is always antibody-mediated: type 1 diabetes, multiple sclerosis and Hashimoto are T-cell diseases, and seronegativity there means nothing. Remember that one disease can stack mechanisms — pemphigus is type II, lupus mixes II and III, and rheumatic fever is type II with molecular mimicry as cause. Finally, the female preponderance (overall roughly 1 in 9 patients with autoimmune disease being female, with huge variation by disease) is examinable as an observation even though its oestrogen-and-X-chromosome explanation remains partly open. ## Frequently asked questions ### What is the difference between central and peripheral tolerance? Central tolerance deletes self-reactive lymphocytes during maturation in marrow and thymus; peripheral tolerance restrains escaped cells through anergy, regulatory T cells and apoptosis. ### Which gene mutations directly cause autoimmune disease? AIRE (APECED) and FOXP3 (IPEX) — disabling thymic self-antigen display and regulatory T cells respectively. ### What is molecular mimicry in autoimmunity? Cross-reactivity between microbial and self antigens, as when streptococcal M protein antibodies attack cardiac myosin in rheumatic fever. ### Why is anti-dsDNA more useful than ANA in SLE? Anti-dsDNA is highly specific for SLE and correlates with nephritis activity, whereas ANA is sensitive but nonspecific. ### Which HLA association is the strongest in humans? HLA-B27 with ankylosing spondylitis, present in the large majority of patients versus a small minority of controls.