{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T05:45:05Z","timestamp":1791438305277,"version":"4.3.3"},"reference-count":64,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T00:00:00Z","timestamp":1741132800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010795","name":"Chugai Pharmaceutical Co., Ltd","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100010795","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Neuromyelitis optica (NMO) is an acute inflammatory demyelinating disease of the CNS. The presence of astrocyte-targeted AQP4-immunoglobulin G (IgG) in peripheral blood is a major factor in its diagnosis. Previous studies show that AQP4-IgG contributes directly to CNS inflammation and that B cells play a central pathogenic role in NMO. However, where and how the B-cell response is altered remains controversial.<\/jats:p>\n               <jats:p>In this study, we used high-parameter flow cytometry to carry out a comprehensive analysis of the immune cell populations in the CSF samples obtained from first-episode acute-phase NMO patients, compared with those from patients with acute-phase multiple sclerosis and other neurological diseases. Among 10 immune cell populations defined in the analysis, the frequency only of B cells and antibody-secreting cells (ASC) was higher in the CSF of acute-phase NMO compared with other neurological diseases. Detailed assessments of B-cell and ASC subsets in the CSF revealed differences in the dominant subsets between NMO and multiple sclerosis. In NMO, a series of CD21lo B-cell subsets, including \u2018activated\u2019 na\u00efve B, double-negative and switched memory subsets, considered as ASC precursors, were dominant. A majority of these CD21lo B-cell subsets expressed CD69 and CXCR3, suggesting their CNS residency. An increase of CD21lo B-cell subsets was also observed in the CSF of treatment-refractory NMO patients. Furthermore, two B-helper T-cell subsets, T peripheral helper type 1 and T follicular helper type 1 cells, both highly expressing CD69 and CXCR3, were enriched in the CSF of NMO patients, suggesting their interactions with ASC precursors in the CNS.<\/jats:p>\n               <jats:p>In vitro culture experiments using blood samples from patients with NMO showed that CD21lo B cells included AQP4-IgG-producing cells and displayed a high propensity to differentiate into ASCs. We also found that CD21lo B-cell subsets in NMO upregulated the expression of C5a receptors, and C5a signals promoted their differentiation into ASCs. ASCs derived from CD21lo B cells expressed high levels of CXCR3 and CD138. The increase in CD21lo B-cell subsets was significantly correlated with the annual relapse rate.<\/jats:p>\n               <jats:p>Collectively, our study strongly suggests that the mechanism to promote the generation of CD21lo B cells, probably via the extrafollicular pathway, becomes activated during the acute phase of NMO and that the generated CD21lo B-cell subsets contribute to the pathogenesis. Targeting CD21lo B-cell subsets might be useful for the development of novel therapeutic approaches.<\/jats:p>","DOI":"10.1093\/brain\/awaf086","type":"journal-article","created":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T11:28:31Z","timestamp":1741174111000},"page":"2995-3010","source":"Crossref","is-referenced-by-count":8,"title":["CD21lo B-cell subsets are recruited to the central nervous system in acute neuromyelitis optica"],"prefix":"10.1093","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2555-1899","authenticated-orcid":false,"given":"Ryusei","family":"Nishigori","sequence":"first","affiliation":[{"name":"Department of Neurology, Kyoto University Graduate School of Medicine , Kyoto 6068507 ,","place":["Japan"]},{"name":"Department of Immunology, Kyoto University Graduate School of Medicine , Kyoto 6068501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mio","family":"Hamatani","sequence":"additional","affiliation":[{"name":"Institute for the Advanced Study of Human Biology, Kyoto University , Kyoto 6068501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yoshitomi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Kyoto University Graduate School of Medicine , Kyoto 6068501 ,","place":["Japan"]},{"name":"Institute for the Advanced Study of Human Biology, Kyoto University , Kyoto 6068501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8359-2886","authenticated-orcid":false,"given":"Kimitoshi","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kyoto University Graduate School of Medicine , Kyoto 6068507 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Takata","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kyoto University Graduate School of Medicine , Kyoto 6068507 ,","place":["Japan"]},{"name":"Department of Immunology, Kyoto University Graduate School of Medicine , Kyoto 6068501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinji","family":"Ashida","sequence":"additional","affiliation":[{"name":"Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine , Kyoto 6028566 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chihiro","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kansai Medical University Medical Center , Moriguchi 5708507 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Ochi","sequence":"additional","affiliation":[{"name":"Department of Intractable Disease and Aging Science, Ehime University Graduate School of Medicine , Ehime 7910295 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1407-9640","authenticated-orcid":false,"given":"Ryosuke","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kyoto University Graduate School of Medicine , Kyoto 6068507 ,","place":["Japan"]},{"name":"Kyoto University Research Administration Center, Kyoto University , Kyoto 6068501 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Kondo","sequence":"additional","affiliation":[{"name":"Department of Neurology, Kansai Medical University Medical Center , Moriguchi 5708507 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