{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:04:43Z","timestamp":1789729483521,"version":"4.0.1"},"reference-count":49,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Multiple sclerosis (MS) is a chronic autoimmune disease where B cells play a central pathogenic role. Cladribine, an oral therapy, provides durable benefits by reshaping lymphocyte populations, yet its specific long\u2010term impact on distinct B\u2010cell subsets is not fully understood. This study aimed to define cladribine's longitudinal effects on B\u2010cell subsets and characterize their inflammatory properties.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a 48\u2010month longitudinal study of 36 persons with relapsing\u2013remitting MS treated with cladribine who had completed 2 annual treatment cycles, using high\u2010parameter flow cytometry to track B\u2010cell subset dynamics. In a parallel cross\u2010sectional analysis, B cells from 16 untreated patients and 16 healthy donors were profiled for polyfunctional cytokine production granulocyte\u2010macrophage colony stimulating factor (GM\u2010CSF), interleukin\u20106 (IL\u20106), tumor necrosis factor\u2010\u03b1 (TNF\u2010\u03b1) and key surface markers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Cladribine induced profound, sustained depletion of memory B cells, with marginal zone\u2010like (MZ\u2010like) cells showing the deepest and most persistent loss, alongside reconstitution of transitional and na\u00efve populations. Functionally, MZ\u2010like B cells were the most potent polyfunctional producers of proinflammatory cytokines and immunoglobulin M (IgM), a capacity significantly enhanced in persons with MS compared to healthy donors, and expressed the highest levels of CD1c and CD1d, consistent with specialization in lipid antigen presentation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>MZ\u2010like B cells are a dominant, polyfunctional inflammatory subset in MS, equipped for non\u2010canonical lipid antigen presentation and IgM secretion. They represent a preferential pharmacological target of cladribine. Sustained reduction of this pathogenic memory pool, followed by repopulation with less inflammatory B cells, offers a mechanistic basis for cladribine's durable clinical benefit and nominates MZ\u2010like cells as biomarkers of response and therapeutic targets. ANN NEUROL 2026;100:808\u2013823<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ana.78277","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T12:40:20Z","timestamp":1781786420000},"page":"808-823","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["From Marginal to Central: Marginal Zone\u2010like B Cells as Critical Targets in Cladribine\u2010Treated Multiple Sclerosis"],"prefix":"10.1002","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9907-2279","authenticated-orcid":false,"given":"Marta","family":"Pirronello","sequence":"first","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2529-6456","authenticated-orcid":false,"given":"Mario","family":"Picozza","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3467-6469","authenticated-orcid":false,"given":"Gisella","family":"Guerrera","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7360-6570","authenticated-orcid":false,"given":"Silvia","family":"Corbisiero","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-5019-5400","authenticated-orcid":false,"given":"Andrea","family":"Misiti","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6083-8292","authenticated-orcid":false,"given":"Roberta C.","family":"Placido","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9367-9574","authenticated-orcid":false,"given":"Alice","family":"Verdiani","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4995-9752","authenticated-orcid":false,"given":"Lorenzo","family":"de Marco","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1124-7327","authenticated-orcid":false,"given":"Manolo","family":"Sambucci","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"},{"name":"Department of Internal Medicine and Medical Specialities (DIMI) University of Genova  Genoa Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6236-7975","authenticated-orcid":false,"given":"Elena","family":"Olivieri","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4552-9226","authenticated-orcid":false,"given":"Daniela F.","family":"Angelini","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Esmeralda","family":"Quartuccio","sequence":"additional","affiliation":[{"name":"Neuroscience Department San Camillo\u2010Forlanini Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3237-6267","authenticated-orcid":false,"given":"Luca","family":"Prosperini","sequence":"additional","affiliation":[{"name":"Neuroscience Department San Camillo\u2010Forlanini Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9037-7300","authenticated-orcid":false,"given":"Carla","family":"Tortorella","sequence":"additional","affiliation":[{"name":"Neuroscience Department San Camillo\u2010Forlanini Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4839-1528","authenticated-orcid":false,"given":"Maria C.","family":"Buscarinu","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3948-2534","authenticated-orcid":false,"given":"Valeria","family":"Zancan","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs Sapienza University of Rome  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"de Masi","sequence":"additional","affiliation":[{"name":"Neuroimaging Unit Fondazione Santa Lucia IRCSS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0501-8803","authenticated-orcid":false,"given":"Marco","family":"Salvetti","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Mental Health and Sensory Organs Sapienza University of Rome  Rome Italy"},{"name":"Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Neurologico Mediterraneo Neuromed  Pozzilli Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3959-4067","authenticated-orcid":false,"given":"Claudio","family":"Gasperini","sequence":"additional","affiliation":[{"name":"Neuroscience Department San Camillo\u2010Forlanini Hospital  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4227-6481","authenticated-orcid":false,"given":"Giovanna","family":"Borsellino","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6488-4891","authenticated-orcid":false,"given":"Luca","family":"Battistini","sequence":"additional","affiliation":[{"name":"Neuroimmunology Unit European Centre for Brain Research, Fondazione Santa Lucia IRCCS  Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.01.021"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000007032"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0274565"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1986.00520110029009"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-015-1500-6"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.59.4.555"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1177\/1352458508095729"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2025.578622"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0706383"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1401483"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.21363"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-01-331462"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502448"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61649-8"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneuroim.2019.576966"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111675"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20130699"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aab4176"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2004.tb00049.x"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm038"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.102027"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00415-018-8830-y"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0902533"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2019.01.038"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2024.110380"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1177\/17562864231211077"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1133967"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.abl5344"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/vaccines11111705"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.msard.2020.102666"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms252313153"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2019.04.006"},{"key":"e_1_2_9_34_1","first-page":"1","article-title":"B cells in central nervous system disease: diversity, locations and pathophysiology","volume":"22","author":"Jain RW","year":"2021","journal-title":"Nat Rev Immunol"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000200048"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awr128"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031389"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20051625"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI22833"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-023-00838-7"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01639"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXI.0000000000200185"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.adn2784"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2021.102627"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06708-y"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.08.015"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1001145"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1014209"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20031175"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-024-46024-1"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78277","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ana.78277","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.78277","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T10:31:03Z","timestamp":1789727463000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.78277"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,18]]},"references-count":49,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/ana.78277"],"URL":"https:\/\/doi.org\/10.1002\/ana.78277","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,18]]},"assertion":[{"value":"2025-11-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-05","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}