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ResearchIn-Press PreviewAutoimmunityNephrology Open Access | 10.1172/JCI178813

Sequential carbonyl derivatives and hydrazone adduct formation on myeloperoxidase contribute to development of ANCA-vasculitis

Gang Xi,1 Elizabeth A. Mclnnis,1 Olivier Lardinois,3 Peiqi Hu,1 John S. Poulton,1 Meghan E. Free,1 Dhruti P. Chen,1 Evan M. Zeitler,1 Eveline Y. Wu,4 Nicole M. Orzechowski,5 Vimal K. Derebail,1 J. Charles Jennette,1 and Ronald J. Falk1

1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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1Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chaple Hill, United States of America

2Division of Nephrology and Hypertension, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

3Mass Spectrometry Research and Support Group, NIH, Research Triangle Park, United States of America

4Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

5Division of Rheumatology, Allergy, and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America

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Published February 28, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI178813.
Copyright © 2025, Xi et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 28, 2025 - Version history
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Abstract

Drug-induced autoimmune diseases are increasingly recognized although mechanistic insight into disease causation is lacking. Hydralazine exposure has been linked to autoimmune diseases, including anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis. Our hypothesis posits that hydralazine covalently binds to myeloperoxidase (MPO), triggering the autoimmune response in ANCA vasculitis. We in vitro 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 induce 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 non-hydralazine-associated vasculitis patients. IgM isolated from hydralazine-associated MPO ANCA patients 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 to which pathogenic autoantibodies are generated.

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