{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,5]],"date-time":"2026-09-05T01:09:15Z","timestamp":1788570555383,"version":"build-2803163510"},"reference-count":76,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100005202","name":"Muscular Dystrophy Association","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005202","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003157","name":"Myasthenia Gravis Foundation of America","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003157","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Neuromuscular Study Group"},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R00AI159302"],"award-info":[{"award-number":["R00AI159302"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01-AI114780"],"award-info":[{"award-number":["R01-AI114780"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Rare Diseases Clinical Research Consortia of the NIH and MGNet","award":["U54-NS115054"],"award-info":[{"award-number":["U54-NS115054"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016650","name":"Rare Diseases Clinical Research Network","doi-asserted-by":"publisher","award":["U54NS115054"],"award-info":[{"award-number":["U54NS115054"]}],"id":[{"id":"10.13039\/100016650","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Rare Diseases Clinical Research Consortia of the NIH and MGNet","award":["U54-NS115054"],"award-info":[{"award-number":["U54-NS115054"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Patients with muscle-specific tyrosine kinase (MuSK) myasthenia gravis (MG) develop muscle weakness due to functionally monovalent immunoglobulin (Ig) G4 autoantibodies (Abs) that target MuSK and disrupt acetylcholine receptor (AChR) clustering. Emerging evidence from other autoimmune conditions suggests that Abs of the IgA class\u2014the archetypal immunoglobulin isotype at mucosal sites\u2014may synergize with IgG Abs, contributing to pathology. In MuSK MG, however, the presence of disease-specific IgA Abs has not yet been recognized, limiting a broader understanding of IgG4-driven autoimmunity. To address this knowledge gap, we leveraged cell-based binding assays, patient-derived recombinant monoclonal autoantibodies (mAbs), high-throughput B-cell receptor sequencing, C2C12 mouse myotube cultures and passive immunization experiments.<\/jats:p>\n                  <jats:p>Among 112 sera collected from 25 patients with MuSK MG (discovery cohort), MuSK-specific IgA Abs were detected in eight samples, corresponding to 3\/25 (12%) patients. This finding was validated in a second, independent cohort (validation cohort; n = 14 individuals), wherein one additional patient (1\/14; 7.1%) harboured MuSK IgA Abs. Across all cases, MuSK IgA Abs coexisted with MuSK IgG Abs, while domain mapping demonstrated a polyclonal IgA response in 2\/4 (50%) patients. Notably, in a paradigmatic case with longitudinal samples spanning over a decade, MuSK IgA seropositivity was persistent, and clonally expanded MuSK IgA B cells showed remarkable resistance to therapeutic B-cell depletion.<\/jats:p>\n                  <jats:p>We generated three patient-derived MuSK-specific IgA mAbs for in-depth molecular profiling. These mAbs were highly hypermutated, bound to distinct MuSK domains and shared target epitopes with MuSK IgG4 mAbs. Two IgA mAbs cross-reacted with murine MuSK, enabling functional studies with C2C12 myotubes. Mechanistically, individual IgA mAbs promoted AChR clustering (indicative of MuSK agonism) and partially antagonized the pathogenic effects of MuSK IgG4 monovalency. When modelling a polyclonal response, however, the combination of the same IgA mAbs significantly impaired cluster formation, demonstrating cooperative pathogenic potential. Consistent with this, passive transfer of both IgA clones into mice induced a myasthenic phenotype characterized by progressive weight loss, muscle weakness and structural disruption of the neuromuscular junction (effects similar to those elicited by a functionally monovalent MuSK IgG4 mAb).<\/jats:p>\n                  <jats:p>These findings uncover a previously unrecognized pathogenic Ab isotype in a subset of patients with MuSK MG and show a mechanism through which bivalent MuSK Abs may synergize to induce pathology. The identification of MuSK-specific IgA B cells could signal a role of mucosal or environmental factors in the pathogenesis of MuSK MG and other IgG4-mediated diseases, offering a worthy avenue for future research.<\/jats:p>","DOI":"10.1093\/brain\/awaf410","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T09:16:40Z","timestamp":1761643000000},"page":"2091-2106","source":"Crossref","is-referenced-by-count":9,"title":["IgA autoantibodies demonstrate a novel mechanism of MuSK myasthenia gravis pathology"],"prefix":"10.1093","volume":"149","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4754-2141","authenticated-orcid":false,"given":"Gianvito","family":"Masi","sequence":"first","affiliation":[{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT 06511 ,","place":["USA"]},{"name":"Department of Immunobiology, Yale School of Medicine , New Haven, CT 06510 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangzhi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT 06511 ,","place":["USA"]},{"name":"Department of Neurology, Xiangya Hospital, Central South University , Changsha, Hunan 41008 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra C","family":"Bayer","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT 06511 ,","place":["USA"]},{"name":"Department of Immunobiology, Yale School of Medicine , New Haven, CT 06510 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Bayarri-Olmos","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine , New Haven, CT 06510 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minh C","family":"Pham","sequence":"additional","affiliation":[{"name":"Department of Neurology, Yale School of Medicine , New Haven, CT 06511 ,","place":["USA"]},{"name":"Department of Immunobiology, Yale School of Medicine , New Haven, CT 06510 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabel","family":"Wallace","sequence":"additional","affiliation":[{"name":"Yale College , New Haven, CT 06511 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Falso","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore , Rome 00168 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Evoli","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore , Rome 00168 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaele","family":"Iorio","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e0 Cattolica del Sacro Cuore , Rome 00168 ,","place":["Italy"]},{"name":"Neurology Unit, Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS, Rome 00168 ,","place":["Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth B","family":"Hoehn","sequence":"additional","affiliation":[{"name":"Department of Biomedical Data Science and Dartmouth Cancer Center, Geisel School of Medicine at Dartmouth , Hanover, NH 03756 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7824-9856","authenticated-orcid":false,"given":"Akiko","family":"Iwasaki","sequence":"additional","affiliation":[{"name":"Department of Immunobiology, Yale School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Center for Infection and Immunity, Yale School of Medicine , New Haven, CT 06510 ,","place":["USA"]},{"name":"Howard Hughes Medical Institute , Chevy Chase, MD 20815 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8438-482X","authenticated-orcid":false,"given":"Richard 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