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Hydralazine exposure has been linked to autoimmune diseases, including antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Our hypothesis posits that hydralazine covalently binds to myeloperoxidase (MPO), triggering the autoimmune response in ANCA vasculitis. In vitro, we observed formation of carbonyl derivatives on amine groups in the presence of acrolein. This facilitated the subsequent binding of hydralazine to heme-containing proteins, including MPO, via a Michael addition. Our studies demonstrated that carbonyl derivatives and hydrazone adducts induced conformational changes in the MPO heavy chain, potentially changing its immunogenicity. We identified hydrazone adducts on circulating MPO in patients with hydralazine-associated ANCA vasculitis. These patients exhibited elevated anti-MPO IgM levels, while anti-MPO IgG levels were comparable between hydralazine-associated and nonhydralazine-associated vasculitis patients. IgM isolated from patients with hydralazine-associated MPO ANCA demonstrated a heightened affinity to hydralazine-modified MPO and activated neutrophil-like HL-60 cells. Hydralazine-modified MPO was pathogenic, as demonstrated by splenocyte transfer in a mouse model of ANCA vasculitis. Our findings unveil a mechanism of drug-induced autoimmunity wherein stepwise chemical modifications of MPO lead to conformational changes and hydrazone adduct formation, producing a neoantigen that generates pathogenic autoantibodies.<\/jats:p>","DOI":"10.1172\/jci178813","type":"journal-article","created":{"date-parts":[[2025,2,28]],"date-time":"2025-02-28T14:08:48Z","timestamp":1740751728000},"source":"Crossref","is-referenced-by-count":13,"title":["Sequential carbonyl derivatives and hydrazone adduct formation on myeloperoxidase contribute to development of ANCA vasculitis"],"prefix":"10.1172","volume":"135","author":[{"given":"Gang","family":"Xi","sequence":"first","affiliation":[{"name":"University of North Carolina Kidney Center, Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Mclnnis","sequence":"additional","affiliation":[{"name":"University of North Carolina Kidney Center, Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Lardinois","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Research and Support Group, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiqi","family":"Hu","sequence":"additional","affiliation":[{"name":"University of North Carolina Kidney Center, Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."},{"name":"Department of Pathology and Laboratory Medicine,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John S.","family":"Poulton","sequence":"additional","affiliation":[{"name":"University of North Carolina Kidney Center, Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meghan E.","family":"Free","sequence":"additional","affiliation":[{"name":"University of North Carolina Kidney Center, Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhruti P.","family":"Chen","sequence":"additional","affiliation":[{"name":"University of North Carolina Kidney Center, Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evan M.","family":"Zeitler","sequence":"additional","affiliation":[{"name":"University of North Carolina Kidney Center, Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6394-6843","authenticated-orcid":true,"given":"Eveline Y.","family":"Wu","sequence":"additional","affiliation":[{"name":"Division of Pediatric Rheumatology, Department of Pediatrics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole M.","family":"Orzechowski","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Allergy, and Immunology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7662-7497","authenticated-orcid":true,"given":"Vimal K.","family":"Derebail","sequence":"additional","affiliation":[{"name":"University of North Carolina Kidney Center, Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8081-6565","authenticated-orcid":true,"given":"J. 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