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Since their initial recognition as immunofluorescence patterns, ANCA have evolved into well\u2010characterized pathogenic autoantibodies directed primarily against proteinase 3 (PR3) and myeloperoxidase (MPO). This review integrates the historical evolution of ANCA discovery with current understanding of disease pathogenesis and contemporary diagnostic practice. We summarize key biological mechanisms underlying AAV, including genetic susceptibility, epigenetic dysregulation, neutrophil priming, complement activation via the alternative pathway, and neutrophil extracellular trap formation, which together drive endothelial injury and necrotizing vasculitis. Recognition of PR3 ANCA and MPO ANCA as pathogenic entities has reshaped disease classification and supports the concept of biologically distinct disease subsets. In parallel, laboratory diagnostics have undergone a major paradigm shift. We critically review the transition from indirect immunofluorescence\u2010first algorithms to immunoassay\u2010first strategies endorsed by the 2017 revised international consensus, highlighting the improved diagnostic performance of contemporary antigen\u2010specific immunoassays. The roles of automated immunofluorescence, biochip mosaic platforms, and multiparametric testing are discussed within harmonized diagnostic workflows. Emphasis is placed on strict clinical gating, quantitative antibody interpretation, and likelihood ratio\u2010based reporting to enhance diagnostic accuracy and reduce false\u2010positive results. By integrating historical, biological, and diagnostic perspectives, this review provides a practical reference framework for evidence\u2010based ANCA testing and interpretation in clinical practice.<\/jats:p>","DOI":"10.1111\/1756-185x.70910","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T18:25:03Z","timestamp":1791656703000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Antineutrophil Cytoplasmic Antibodies: Integrating History, Pathogenesis, and Modern Diagnostics"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7368-0323","authenticated-orcid":false,"given":"Aravind","family":"Radhakrishnan","sequence":"first","affiliation":[{"name":"Department of Pathology Postgraduate Institute of Medical Education and Research (PGIMER)  Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7181-6064","authenticated-orcid":false,"given":"Biman","family":"Saikia","sequence":"additional","affiliation":[{"name":"Department of Immunopathology Postgraduate Institute of Medical Education and Research (PGIMER)  Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aman","family":"Sharma","sequence":"additional","affiliation":[{"name":"Division of Clinical Immunology and Rheumatology, Department of Internal Medicine Postgraduate Institute of Medical Education and Research (PGIMER)  Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2925-5608","authenticated-orcid":false,"given":"Seema","family":"Chhabra","sequence":"additional","affiliation":[{"name":"Department of Immunopathology Postgraduate Institute of Medical Education and Research (PGIMER)  Chandigarh India"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,10]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V89.10.3503"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2009121238"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1080\/00325481.2022.2102368"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm11092573"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/rmdopen\u20102022\u2010002949"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/keaf052"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10157\u2010013\u20100869\u20106"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev\u2010pathol\u2010011811\u2010132453"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1523\u20101755.2000.00080.x"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014090903"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1108735"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI103987"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.285.6342.606"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140\u20106736(85)91147\u2010X"},{"key":"e_1_2_13_16_1","first-page":"16","article-title":"Indirect Immunofluorescence Examination for IgG\u2010ANCA in Sera Submitted for the 1st International Workshop on ANCA, 1988","volume":"6","author":"Rasmussen N.","year":"1989","journal-title":"APMIS. 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