{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T08:11:57Z","timestamp":1790237517207,"version":"4.1.0"},"reference-count":51,"publisher":"National Academy of Sciences","issue":"7","license":[{"start":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T00:00:00Z","timestamp":1707177600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000265","name":"UKRI | Medical Research Council","doi-asserted-by":"publisher","award":["MR\/V007173\/1"],"award-info":[{"award-number":["MR\/V007173\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["104079\/Z\/14\/Z"],"award-info":[{"award-number":["104079\/Z\/14\/Z"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100014437","name":"Wenner-Gren Stiftelserna","doi-asserted-by":"publisher","award":["WGF2018-0020"],"award-info":[{"award-number":["WGF2018-0020"]}],"id":[{"id":"10.13039\/100014437","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008349","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","award":["MIJR"],"award-info":[{"award-number":["MIJR"]}],"id":[{"id":"10.13039\/100008349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,2,13]]},"abstract":"<jats:p>\n                    Intrathecal synthesis of central nervous system (CNS)-reactive autoantibodies is observed across patients with autoimmune encephalitis (AE), who show multiple residual neurobehavioral deficits and relapses despite immunotherapies. We leveraged two common forms of AE, mediated by leucine-rich glioma inactivated-1 (LGI1) and contactin-associated protein-like 2 (CASPR2) antibodies, as human models to comprehensively reconstruct and profile cerebrospinal fluid (CSF) B cell receptor (BCR) characteristics. We hypothesized that the resultant observations would both inform the observed therapeutic gap and determine the contribution of intrathecal maturation to pathogenic B cell lineages. From the CSF of three patients, 381 cognate-paired IgG BCRs were isolated by cell sorting and scRNA-seq, and 166 expressed as monoclonal antibodies (mAbs). Sixty-two percent of mAbs from singleton BCRs reacted with either LGI1 or CASPR2 and, strikingly, this rose to 100% of cells in clonal groups with \u22654 members. These autoantigen-reactivities were more concentrated within antibody-secreting cells (ASCs) versus B cells (\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001), and both these cell types were more differentiated than LGI1- and CASPR2-unreactive counterparts. Despite greater differentiation, autoantigen-reactive cells had acquired few mutations intrathecally and showed minimal variation in autoantigen affinities within clonal expansions. Also, limited CSF T cell receptor clonality was observed. In contrast, a comparison of germline-encoded BCRs versus the founder intrathecal clone revealed marked gains in both affinity and mutational distances (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.004 and\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001, respectively). Taken together, in patients with LGI1 and CASPR2 antibody encephalitis, our results identify CSF as a compartment with a remarkably high frequency of clonally expanded autoantigen-reactive ASCs whose BCR maturity appears dominantly acquired outside the CNS.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2311049121","type":"journal-article","created":{"date-parts":[[2024,2,6]],"date-time":"2024-02-06T13:36:19Z","timestamp":1707226579000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":46,"title":["Ultrahigh frequencies of peripherally matured LGI1- and CASPR2-reactive B cells characterize the cerebrospinal fluid in autoimmune encephalitis"],"prefix":"10.1073","volume":"121","author":[{"given":"Jakob","family":"Theorell","sequence":"first","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford","place":["Oxford, United Kingdom"]},{"name":"Department of Medicine Huddinge, Karolinska Institutet","place":["Stockholm, Sweden"]},{"name":"Department of Neurology, Karolinska University Hospital","place":["Stockholm, Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruby","family":"Harrison","sequence":"additional","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn","family":"Williams","sequence":"additional","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford","place":["Oxford, United Kingdom"]},{"name":"Department of Neurology, John Radcliffe Hospital, Oxford University Hospitals","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5663-5297","authenticated-orcid":false,"given":"Matthew I. J.","family":"Raybould","sequence":"additional","affiliation":[{"name":"Department of Statistics, Oxford Protein Informatics Group, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9967-7075","authenticated-orcid":false,"given":"Meng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4667-4345","authenticated-orcid":false,"given":"Hannah","family":"Fox","sequence":"additional","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford","place":["Oxford, United 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Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0848-0195","authenticated-orcid":false,"given":"Eleanor","family":"Browne","sequence":"additional","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Mgbachi","sequence":"additional","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5507-6657","authenticated-orcid":false,"given":"Bo","family":"Sun","sequence":"additional","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rohini","family":"Mopuri","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic","place":["Jacksonville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Quantitative Health Sciences, Mayo Clinic","place":["Jacksonville"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Waters","sequence":"additional","affiliation":[{"name":"Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, University of Oxford","place":["Oxford, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1388-2252","authenticated-orcid":false,"given":"Charlotte M.","family":"Deane","sequence":"additional","affiliation":[{"name":"Department of Statistics, Oxford Protein Informatics 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Theorell LGI1_CASPR2_BCR_CSF. Github. https:\/\/github.com\/jtheorell\/LGI1_CASPR2_BCR_CSF. Deposited 3 December 2023."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2311049121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T17:49:31Z","timestamp":1742579371000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2311049121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,6]]},"references-count":51,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2024,2,13]]}},"alternative-id":["10.1073\/pnas.2311049121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2311049121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,6]]},"assertion":[{"value":"2023-07-02","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-12-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-02-06","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2311049121"}}