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LRP4 antibodies (LRP4-ab) are typically of the IgG1 or IgG2 subclass, implying distinct capacities to activate complement. The extent and pattern of complement involvement in LRP4-ab\u207a MG remain insufficiently characterized at the human neuromuscular junction (NMJ). We examined intercostal muscle biopsies from seven patients with LRP4-ab\u207a generalized MG using immunohistochemistry, immunofluorescence including IgG-subtyping, electron microscopy (EM), and qPCR for complement-associated gene expression. AChR-ab\u207a MG patients and non-disease controls served as comparators. C5b-9 deposition at NMJs was observed in all LRP4-ab\u207a biopsies, affecting 6\u201396% of identified endplates. Co-localization with IgG1 was consistently detected, whereas IgG2 and IgG4 were absent. One double-seropositive patient showed focal IgG3 staining. Complement transcript levels (\n                    <jats:italic>C1QC<\/jats:italic>\n                    ,\n                    <jats:italic>C3<\/jats:italic>\n                    ) were higher in LRP4-ab\u207a and AChR-ab\u207a MG compared with controls. Ultrastructural analysis revealed reduced and shortened postsynaptic clefts in 3\/4 evaluable LRP4-ab\u207a patients. One therapy-refractory LRP-ab\u2009+\u2009MG patient with complement deposition and endplate destruction improved after targeted complement inhibition was introduced to his therapeutic regimen, which was based on the biopsy finding. Our findings provide in situ evidence of classical complement pathway activation and associated structural alterations at the human NMJ in LRP4-ab\u207a MG. These tissue-based data contribute to a better understanding of the pathophysiology in this rare MG subgroup.\n                  <\/jats:p>","DOI":"10.1186\/s40478-026-02284-0","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T21:35:08Z","timestamp":1776807308000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Complement deposition, IgG subtyping and endplate destruction in LRP4-ab-positive myasthenia gravis"],"prefix":"10.1186","volume":"14","author":[{"given":"Sarah","family":"Hoffmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katharina","family":"Brokamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Meisel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Doksani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lissy","family":"Helmig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Schuelke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jens-Carsten","family":"R\u00fcckert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Pumberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Friederike","family":"Sch\u00f6mig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene","family":"Wolfsgruber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inga","family":"Koneczny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Mayrhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Bl\u00fcthner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Ruck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Pawlitzki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Werner","family":"Stenzel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Preusse","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"issue":"10","key":"2284_CR1","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1016\/S1474-4422(15)00145-3","volume":"14","author":"NE Gilhus","year":"2015","unstructured":"Gilhus NE, Verschuuren JJ (2015) Myasthenia gravis: subgroup classification and therapeutic strategies. 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All procedures were approved by the official institutional ethics review committee (EA1\/144\/21) at the Charit\u00e9 - University Hospital Berlin. This manuscript follows the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines for reporting observational studies.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"S. Hoffmann, K. Brokamp, A. Meisel, P. Doksani, L. Helmig, J.C. R\u00fcckert, M. Pumberger, F. Sch\u00f6mig, M. Wolfsgruber, I. Koneczny, M. Mayrhofer, M. Bl\u00fcthner, Ruck, M. Pawlitzki, W. Stenzel, C. Preusse declare no conflict of interest related to this paper, M. Schuelke received funding from the DFGOther (e.g. grants, consulting fee, honoraria, as well as leadership roles): S. Hoffmann: argenx, Janssen, Alexion Pharmaceuticals, Kyverna, Novartis, Roche, Grifols, Member of the Medical Advisory Board of the German Myasthenia Society (DMG); A. Meisel: Alexion (AstraZeneca Rare Disease), argenx, Axunio Pharma GmbH, Octapharma, UCB, Deutsche Forschungsgemeinschaft, Leducq Foundation, Einstein Foundation Berlin, Janssen Pharmaceuticals, Merck, Xcenda, Boehringer, Desitin, Dierks, Grifols, Hormosan, Pfizer\/BMS, Deutsche Myasthenie Gesellschaft (DMG), Bundesinstitut f\u00fcr Qualit\u00e4t und Patientensicherheit (BQS)\/ DMG, Berliner Schlaganfall-Allianz; P. Doksani: UCB Pharma, Alexion; M. Schuelke: UCB, Medizinische Marktforschung Berlin, Atheneum, DGM, Khondrion; T. Ruck: argenx, Alexion, Merck, Roche, UCB, Member of the Medical Advisory Board of the German Myasthenia Society (DMG); M. Pawlitzki: Argenx, Alexion, Bayer Health Care, Biogen, Demecan, Hexal AG, Janssen Cilag, Merck Serono, Neuraxpharm, Novartis, Roche, Sanofi-Aventis, Teva, Viatris, Takeda, Amicus Therapeutics; W. Stenzel: Alexion, GSK, Member of the programme committee and the executive board of the World Muscle Society; C. Preusse: DGM, DFG, Myositis-Netz e.V., Alexion, argenx, WMS, Supporting scientific committee ICN conference.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"102"}}