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While both cell-mediated and humoral mechanisms contribute to CIDP, the role of complement remains poorly understood. Considering the rise of complement-targeted treatment, it is crucial to examine the role of complement in CIDP. In this cross-sectional, study, sural nerve biopsies from 55 CIDP patients were analyzed using histopathology, gene- and protein-based techniques, comparing them to two non-diseased controls (NDCs), as well as 8 patients with hereditary neuropathy (HN) and idiopathic axonal neuropathy (IPN). Overall, 94% (n\u2009=\u200952) revealed abnormal and prominent deposition of terminal complement complex C5b-9 on endoneurial capillaries. Patients with significant complement deposition presented with a progressive disease course (n\u2009=\u200952) and the number and distribution of infiltrating CD8\u2009+\u2009T cells and CD68\u2009+\u2009macrophages, since a basic immunological paradigm holds that those two may form an immunological synapse, correlated with clinical disease severity as measured by inflammatory neuropathy cause and treatment sensory sum (INCAT) score (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Furthermore, changes in abundances of complement proteins as unveiled by untargeted proteomics accord with changes on transcript level as identified by targeted gene expression studies. In contrast, there was no complement deposition in NDC nor DC. This study provides an extensive evaluation of sural nerve specimens of CIDP patients finding a marked involvement of complement supporting the postulated concept of complement mediated demyelination in CIDP. Our results support the approach of targeting the complement system as a new and promising therapeutic strategy\u2014at least in a subgroup of CIDP. Further research is warranted to unravel the functional implications and role of complement in CIDP progression and optimize patient care. <jats:italic>Clinical Trial Registration<\/jats:italic>: The study is registered under the German clinical trial registry (<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"https:\/\/www.drks.de\" ext-link-type=\"uri\">https:\/\/www.drks.de<\/jats:ext-link>), DRKS0003245.<\/jats:p>","DOI":"10.1007\/s00401-025-02936-w","type":"journal-article","created":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T14:59:09Z","timestamp":1758293949000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Complement profiling of sural nerves in chronic-inflammatory demyelinating polyneuropathy"],"prefix":"10.1007","volume":"150","author":[{"given":"Frauke","family":"Stascheit","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Roos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina B.","family":"Schroeter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna Katrin","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Pre\u00dfler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Hentschel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beate","family":"Schlotter-Weigel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Schoser","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Ruck","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Meisel","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":[[2025,9,19]]},"reference":[{"key":"2936_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jns.2019.116497","volume":"408","author":"JA Allen","year":"2020","unstructured":"Allen JA, Gelinas DF, Freimer M, Runken MC, Wolfe GI (2020) Immunoglobulin administration for the treatment of CIDP: IVIG or SCIG? 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She receives financial research support (paid to her institution) from Alexion Pharmaceuticals and argenx. She serves as a member of the medical advisory of the German Myasthenia Gravis Society e.V. KH received financial reimbursement for consulting, advisory board activities, speaker fees and\/or contributions to congresses and travel support to attend scientific meetings by Akcea Therapeuticals Inc., Alnylam Pharmaceuticals Inc., Amicus, AstraZeneca, GSK, Hormosan, Takeda Pharmaceutical Inc., Pfizer Pharmaceuticals Inc., Swedish Orphan Biovitrum Inc. and ViiV. KH further received research funding by the foundation Charit\u00e9 (BIH clinical fellow, digital accelerator), Alnylam Pharmaceuticals Inc., and Pfizer Pharmaceuticals. None of this were related to this project. T.R. reports grants from the German Ministry of Education, Science, Research and Technology, grants and personal fees from Sanofi, Alexion and argenx, personal fees from Roche and Merck outside the submitted work. A.M. received speaker or consultancy honoraria or financial research support (paid to his institution) from Alexion Pharmaceuticals, argenx, Axunio, Destin, Grifols, Hormosan Pharma, Janssen, Merck, Octapharma, UCB, and Xcenda. He serves as medical advisory board chairman of the German Myasthenia Gravis Society. C.P. received travel\/accommodation\/meeting expenses from Janssen Pharmaceutica NV, a Johnson and Johnson company and received speaking honoraria from argenx. BS received travel expenses and speaker honoraria from Alexion, argenx, and Johnson and Johnson. The remaining authors report no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"Ethical approval was granted by the ethics committee of Charit\u00e9-Universit\u00e4tsmedizin Berlin (EA4\/166\/23). The patients provided their written informed consent to participate in this study according to the Declaration of Helsinki. This article follows the Strengthening the Reporting of Observational Studies in Epidemiology reporting guidelines [].","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"32"}}