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Patterns I and II show signs of immune-mediated demyelination, but only pattern II is associated with antibody\/complement deposition. In pattern III lesions, which include Bal\u00f3\u2019s concentric sclerosis, primary oligodendrocyte damage was proposed. Serum antibody reactivities could reflect disease pathogenesis and thus distinguish histopathologically defined MS patterns. We established a customized microarray with more than 700 peptides that represent human and viral antigens potentially relevant for inflammatory demyelinating CNS diseases, and tested sera from 66 patients (pattern I<jats:italic>n<\/jats:italic>\u2009=\u200912; II<jats:italic>n<\/jats:italic>\u2009=\u200929; III<jats:italic>n<\/jats:italic>\u2009=\u200925, including 8 with Bal\u00f3\u2019s), healthy controls, patients with Sj\u00f6gren\u2019s syndrome and stroke patients. Cell-based assays were performed for aquaporin 1 (AQP1) and AQP4 antibody detection. No single peptide showed differential binding among study cohorts. Because antibodies can react with different peptides from one protein, we also analyzed groups of peptides. Patients with pattern II showed significantly higher reactivities to Nogo-A peptides as compared to patterns I (<jats:italic>p<\/jats:italic>\u2009=\u20090.02) and III (<jats:italic>p<\/jats:italic>\u2009=\u20090.02). Pattern III patients showed higher reactivities to AQP1 (compared to pattern I<jats:italic>p<\/jats:italic>\u2009=\u20090.002, pattern II<jats:italic>p<\/jats:italic>\u2009=\u20090.001) and varicella zoster virus (VZV, compared to pattern II<jats:italic>p<\/jats:italic>\u2009=\u20090.05). In patients with Bal\u00f3\u2019s, AQP1 reactivity was also significantly higher compared to patients without Bal\u00f3\u2019s (<jats:italic>p<\/jats:italic>\u2009=\u20090.04), and the former revealed distinct antibody signatures. Histologically, Bal\u00f3\u2019s patients showed loss of AQP1 and AQP4 in demyelinating lesions, but no antibodies binding conformational AQP1 or AQP4 were detected. In summary, higher reactivities to Nogo-A peptides in pattern II patients could be relevant for enhanced axonal repair and remyelination. Higher reactivities to AQP1 peptides in pattern III patients and its subgroup of Bal\u00f3\u2019s patients possibly reflect astrocytic damage. Finally, latent VZV infection may cause peripheral immune activation.<\/jats:p>","DOI":"10.1007\/s00401-019-02120-x","type":"journal-article","created":{"date-parts":[[2020,1,16]],"date-time":"2020-01-16T15:03:18Z","timestamp":1579186998000},"page":"547-564","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Antibody signatures in patients with histopathologically defined multiple sclerosis patterns"],"prefix":"10.1007","volume":"139","author":[{"given":"Lidia","family":"Stork","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Ellenberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Klemens","family":"Ruprecht","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Reindl","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Bei\u00dfbarth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tim","family":"Friede","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tania","family":"K\u00fcmpfel","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lisa A.","family":"Gerdes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mareike","family":"Gloth","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Liman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friedemann","family":"Paul","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wolfgang","family":"Br\u00fcck","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6571-7630","authenticated-orcid":false,"given":"Imke","family":"Metz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,1,16]]},"reference":[{"key":"2120_CR1","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1016\/j.humimm.2013.06.009","volume":"74","author":"H Ahsan","year":"2013","unstructured":"Ahsan H (2013) 3-Nitrotyrosine: A biomarker of nitrogen free radical species modified proteins in systemic autoimmunogenic conditions. 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Stork has nothing to disclose.D. Ellenberger has nothing to disclose.K. Ruprecht was supported by the German Ministry of Education and Research (BMBF\/KKNMS, Competence Network Multiple Sclerosis) and has received research support from Novartis and Merck Serono as well as speaking fees and travel grants from Guthy Jackson Charitable Foundation, Bayer Healthcare, Biogen Idec, Merck Serono, sanofi-aventis\/Genzyme, Teva Pharmaceuticals, Roche and Novartis.M. Reindl\u00a0was\u00a0supported by research grants from the Austrian Science Funds (FWF), Austrian\u00a0Science Promotion Agency (FFG) and the Austrian\u00a0Multiple Sclerosis Research\u00a0Society. The University Hospital and Medical University of Innsbruck\u00a0(Austria; M.R.) receives payments for antibody\u00a0assays (MOG, AQP4, and\u00a0other autoantibodies) and for MOG and AQP4 antibody validation\u00a0experiments organized by Euroimmun (L\u00fcbeck,\u00a0Germany).T. Bei\u00dfbarth has nothing to disclose.T. Friede has received personal fees for consultancies (including data monitoring committees) in the past three years from Bayer, BiosenseWebster, Boehringer Ingelheim, Cardialysis, CSL Behring, DaiichiSankyo, Enanta, Feldmann Patent Attorneys, Fresenius Kabi, Galapagos, IQVIA, Janssen, Mediconomics, Novartis, Penumbra, Roche, SGS, Vifor; all outside the submitted work.T. K\u00fcmpfel has received travel expenses and speaker honoraria from Bayer Healthcare, Teva Pharma, Merck, Novartis Pharma, Sanofi-Aventis\/Genzyme, CLB Behring, Roche Pharma and Biogen as well as grant support from Bayer-Schering AG, Novartis and Chugai Pharma.LA. Gerdes has received travel expenses and speaker honoraria from Merck, Sanofi-Aventis\/Genzyme and Roche Pharma.M. Gloth has nothing to disclose.F. Paul serves on the scientific advisory board for Novartis; received speaker honoraria and travel funding from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis\/Genzyme, Merck Serono, Alexion, Chugai, MedImmune, and Shire; is an academic editor for PLoS ONE; is an associate editor for Neurology Neuroimmunology and Neuroinflammation; consulted for SanofiGenzyme, Biogen Idec, MedImmune, Shire, and Alexion; and received research support from Bayer, Novartis, Biogen Idec, Teva, Sanofi-Aventis\/Genzyme, Alexion, Merck Serono, German Research Council, Werth Stiftung of the City of Cologne, German Ministry of Education and Research, Arthur Arnstein Stiftung Berlin, EU FP7 Framework Program, Arthur Arnstein Foundation Berlin, Guthy Jackson Charitable Foundation.W. Br\u00fcck is supported from the German Ministry of Education and Research (BMBF \u201cGerman Competence Network Multiple Sclerosis (KKNMS)\u201d). Dr. Br\u00fcck has received, outside the submitted work, honoraria for lectures by Bayer Vital, Biogen, Merck Serono, Teva Pharma, Genzyme, Sanofi-Aventis, Celgene and Novartis and is a member of scientific advisory boards for Teva Pharma, Biogen, Novartis and Genzyme. He received funding for research projects by Teva Pharma, Biogen, Novartis and Genzyme. Dr. Br\u00fcck serves on the editorial boards of Neuropathology and Applied Neurobiology, Multiple Sclerosis International and Therapeutic Advances in Neurological Disorders.I. Metz reports grants from German Ministry for Education and Research (BMBF, \"German Competence Network Multiple Sclerosis\", Pattern MS\/NMO), during the conduct of the study; personal fees from BiogenIdec, Bayer Healthcare, TEVA, Serono, Novartis, Genzyme, Roche, grants from BiogenIdec, Genzyme, Novartis, grants from N-RENNT 2 (Niedersachsen Research Network on Neuroinfectiology), outside the submitted work.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}