{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:59:00Z","timestamp":1792803540893,"version":"4.5.0"},"reference-count":44,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T00:00:00Z","timestamp":1680220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["2017\u20137722209_PREVENT RA"],"award-info":[{"award-number":["2017\u20137722209_PREVENT RA"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000781","name":"European Research 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Frimurarestiftelse","award":["777357_RTCure"],"award-info":[{"award-number":["777357_RTCure"]}],"id":[{"id":"https:\/\/ror.org\/03n9z2d15","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse","award":["2019-01506"],"award-info":[{"award-number":["2019-01506"]}],"id":[{"id":"https:\/\/ror.org\/03n9z2d15","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse","award":["2020-02260"],"award-info":[{"award-number":["2020-02260"]}],"id":[{"id":"https:\/\/ror.org\/03n9z2d15","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Knut and Alice Wallenberg Foundation","award":["2017\u20137722209_PREVENT RA"],"award-info":[{"award-number":["2017\u20137722209_PREVENT RA"]}],"id":[{"id":"https:\/\/ror.org\/004hzzk67","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Knut and Alice Wallenberg Foundation","award":["777357_RTCure"],"award-info":[{"award-number":["777357_RTCure"]}],"id":[{"id":"https:\/\/ror.org\/004hzzk67","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Knut and Alice Wallenberg Foundation","award":["2019-01506"],"award-info":[{"award-number":["2019-01506"]}],"id":[{"id":"https:\/\/ror.org\/004hzzk67","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Knut and Alice Wallenberg Foundation","award":["2020-02260"],"award-info":[{"award-number":["2020-02260"]}],"id":[{"id":"https:\/\/ror.org\/004hzzk67","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Swedish Medical Research Council","award":["2017\u20137722209_PREVENT RA"],"award-info":[{"award-number":["2017\u20137722209_PREVENT RA"]}]},{"name":"Swedish Medical Research Council","award":["777357_RTCure"],"award-info":[{"award-number":["777357_RTCure"]}]},{"name":"Swedish Medical Research Council","award":["2019-01506"],"award-info":[{"award-number":["2019-01506"]}]},{"name":"Swedish Medical Research Council","award":["2020-02260"],"award-info":[{"award-number":["2020-02260"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Background: Why the adaptive immune system turns against citrullinated antigens in rheumatoid arthritis (RA) and whether anti-citrullinated protein antibodies (ACPAs) contribute to pathogenesis are questions that have triggered intense research, but still are not fully answered. Neutrophils may be crucial in this context, both as sources of citrullinated antigens and also as targets of ACPAs. To better understand how ACPAs and neutrophils contribute to RA, we studied the reactivity of a broad spectrum of RA patient-derived ACPA clones to activated or resting neutrophils, and we also compared neutrophil binding using polyclonal ACPAs from different patients. Methods: Neutrophils were activated by Ca2+ ionophore, PMA, nigericin, zymosan or IL-8, and ACPA binding was studied using flow cytometry and confocal microscopy. The roles of PAD2 and PAD4 were studied using PAD-deficient mice or the PAD4 inhibitor BMS-P5. Results: ACPAs broadly targeted NET-like structures, but did not bind to intact cells or influence NETosis. We observed high clonal diversity in ACPA binding to neutrophil-derived antigens. PAD2 was dispensable, but most ACPA clones required PAD4 for neutrophil binding. Using ACPA preparations from different patients, we observed high patient-to-patient variability in targeting neutrophil-derived antigens and similarly in another cellular effect of ACPAs, the stimulation of osteoclast differentiation. Conclusions: Neutrophils can be important sources of citrullinated antigens under conditions that lead to PAD4 activation, NETosis and the extrusion of intracellular material. A substantial clonal diversity in targeting neutrophils and a high variability among individuals in neutrophil binding and osteoclast stimulation suggest that ACPAs may influence RA-related symptoms with high patient-to-patient variability.<\/jats:p>","DOI":"10.3390\/biom13040630","type":"journal-article","created":{"date-parts":[[2023,3,31]],"date-time":"2023-03-31T02:30:20Z","timestamp":1680229820000},"page":"630","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Anti-Citrullinated Protein Antibody Reactivity towards Neutrophil-Derived Antigens: Clonal Diversity and Inter-Individual Variation"],"prefix":"10.3390","volume":"13","author":[{"given":"Alexandra","family":"C\u00eerciumaru","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"},{"name":"Center for Rheumatology, Academic Specialist Center, Stockholm Health Services, 11365 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6661-4158","authenticated-orcid":false,"given":"Marcelo Gomes","family":"Afonso","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi","family":"W\u00e4h\u00e4maa","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akilan","family":"Krishnamurthy","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5481-1557","authenticated-orcid":false,"given":"Monika","family":"Hansson","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linda","family":"Mathsson-Alm","sequence":"additional","affiliation":[{"name":"Thermo Fisher Scientific, 75450 Uppsala, Sweden"},{"name":"Department of Immunology, Genetics and Pathology, Uppsala University, 75185 Uppsala, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M\u00e1rton","family":"Keszei","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 17165 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ragnhild","family":"St\u00e5lesen","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Ottosson","sequence":"additional","affiliation":[{"name":"Division of Pediatric Endocrinology, Department of Women\u2019s and Children\u2019s Health, Karolinska Institutet, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4513-4128","authenticated-orcid":false,"given":"Charlotte","family":"de Vries","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8842-0303","authenticated-orcid":false,"given":"Miriam A.","family":"Shelef","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9251-8082","authenticated-orcid":false,"given":"Vivianne","family":"Malmstr\u00f6m","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lars","family":"Klareskog","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anca I.","family":"Catrina","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"},{"name":"Center for Rheumatology, Academic Specialist Center, Stockholm Health Services, 11365 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caroline","family":"Gr\u00f6nwall","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7669-3777","authenticated-orcid":false,"given":"Aase","family":"Hensvold","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"},{"name":"Center for Rheumatology, Academic Specialist Center, Stockholm Health Services, 11365 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8220-5015","authenticated-orcid":false,"given":"Bence","family":"R\u00e9thi","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, 17176 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"178ra40","DOI":"10.1126\/scitranslmed.3005580","article-title":"NETs Are a Source of Citrullinated Autoantigens and Stimulate Inflammatory Responses in Rheumatoid Arthritis","volume":"5","author":"Khandpur","year":"2013","journal-title":"Sci. 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