{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,15]],"date-time":"2026-08-15T04:34:54Z","timestamp":1786768494515,"version":"build-2736575974"},"reference-count":46,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,11,25]],"date-time":"2022-11-25T00:00:00Z","timestamp":1669334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000691","name":"Academy of Medical Sciences","doi-asserted-by":"publisher","award":["SGL023\/1071"],"award-info":[{"award-number":["SGL023\/1071"]}],"id":[{"id":"10.13039\/501100000691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010876","name":"Vasculitis UK","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010876","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2023,1]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG\u2013mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA\u2010induced myeloid cell activation and vasculitis pathogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Phosphorylation of Syk in myeloid cells from healthy controls and ANCA\u2010associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)\u2013ANCA IgG activation of cells was investigated using functional assays (interleukin\u20108 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO\u2010ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA\u2010mediated cellular responses. Using targeted gene expression analysis, we identified up\u2010regulation of FcR\u2010 and Syk\u2010dependent signaling pathways following MPO\u2010ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings indicate that Syk plays a critical role in MPO\u2010ANCA IgG\u2013induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.42321","type":"journal-article","created":{"date-parts":[[2022,8,1]],"date-time":"2022-08-01T00:05:14Z","timestamp":1659312314000},"page":"84-97","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Syk Activation in Circulating and Tissue Innate Immune Cells in Antineutrophil Cytoplasmic Antibody\u2013Associated Vasculitis"],"prefix":"10.1002","volume":"75","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7048-7457","authenticated-orcid":false,"given":"Maria","family":"Prendecki","sequence":"first","affiliation":[{"name":"Department of Immunology and Inflammation Centre for Inflammatory Disease, Imperial College London, Hammersmith Campus, and Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, Hammersmith Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2651-593X","authenticated-orcid":false,"given":"Kavita","family":"Gulati","sequence":"additional","affiliation":[{"name":"Department of Immunology and Inflammation Centre for Inflammatory Disease, Imperial College London, Hammersmith Campus, and Imperial College Renal and Transplant Centre, Imperial College Healthcare NHS Trust, Hammersmith Hospital  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noelle","family":"Pisacano","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damilola","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Department of Immunology and Inflammation Centre for Inflammatory Disease, Imperial College London  Hammersmith Campus London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tejal","family":"Bhatt","sequence":"additional","affiliation":[{"name":"Department of Immunology and Inflammation Centre for Inflammatory Disease, Imperial College London  Hammersmith Campus London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie\u2010Anne","family":"Mawhin","sequence":"additional","affiliation":[{"name":"Department of Immunology and Inflammation Centre for Inflammatory Disease, Imperial College London  Hammersmith Campus London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederic","family":"Toulza","sequence":"additional","affiliation":[{"name":"Department of Immunology and Inflammation Centre for Inflammatory Disease, Imperial College London  Hammersmith Campus London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esteban S.","family":"Masuda","sequence":"additional","affiliation":[{"name":"Rigel Pharmaceuticals  South San Francisco California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Cowburn","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharine M.","family":"Lodge","sequence":"additional","affiliation":[{"name":"National Heart and Lung Institute, Imperial College  London UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick W. 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