{"doi":"10.1172/jci.insight.188543","title":"Early multiple sclerosis activity associated with TBX21+CD21loCXCR3+ B cell expansion resembling EBV-induced phenotypes","abstract":"Epstein-Barr virus (EBV) infection precedes multiple sclerosis (MS) onset and plays a poorly understood etiologic role. To investigate possible viral pathogenesis, we analyzed single-cell expression in peripheral B cells from people with early MS collected longitudinally during the Immune Tolerance Network STAyCIS Trial. Expression profiles were compared with single-cell RNA-Seq (scRNA-Seq) from in vitro EBV models, autoimmune disorders, chronic infectious diseases, and healthy controls. Analyses focused on CD19+CD20+CD21loCD11c+T-bet+ atypical B cells (ABCs). ABCs were significantly enriched in early MS PBMCs versus healthy controls by scRNA-Seq and flow cytometry, establishing ABC expansion as a clinical feature. EBV-associated ABC expression, including CXCR3, programmed cell death ligand 1 (PD-L1), and PD-L2, was enriched in early MS; however, direct EBV infection of ABCs was not detected. Early MS ABCs exhibited significantly upregulated inflammatory cytokine mRNAs (CXCL8, IL18, VEGFA). Further, de novo EBV-infected B cells secreted IL-8 and VEGF. MS activity stratification revealed rare, distinctive inflammatory ABCs significantly underrepresented in individuals with no evidence of activity long-term versus people with additional relapsing-remitting MS activity at the primary endpoint. Moreover, CXCR3+ ABCs increased after baseline diagnosis and were significantly enriched in people with disease exacerbation during the study. Thus, ABC expansion and inflammatory responses correlate to early MS activity, possibly as a bystander response to EBV.","journal":"JCI Insight","year":2025,"id":512518,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9578,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1164916,"name":"Ellora Haukenfrers","orcid":null,"position":1,"is_corresponding":false},{"id":618424,"name":"Gillian Q. Horn","orcid":"0000-0003-4571-1933","position":2,"is_corresponding":false},{"id":1056188,"name":"Vaibhav Jain","orcid":"0000-0002-8505-9778","position":3,"is_corresponding":false},{"id":1372000,"name":"James Giarraputo","orcid":"0000-0002-3639-1985","position":4,"is_corresponding":false},{"id":997222,"name":"Karen Abramson","orcid":"0000-0002-3504-5933","position":5,"is_corresponding":false},{"id":59322,"name":"Emily Hocke","orcid":"0000-0002-0976-5814","position":6,"is_corresponding":false},{"id":927813,"name":"Laura A. Cooney","orcid":"0000-0001-7307-2548","position":7,"is_corresponding":false},{"id":256536,"name":"Kristina M. Harris","orcid":"0000-0002-6957-514X","position":8,"is_corresponding":false},{"id":246282,"name":"Scott S. Zamvil","orcid":"0000-0003-2720-9915","position":9,"is_corresponding":false},{"id":59323,"name":"Simon G. Gregory","orcid":"0000-0002-7805-1743","position":10,"is_corresponding":false},{"id":395715,"name":"Micah A. Luftig","orcid":"0000-0002-2964-1907","position":11,"is_corresponding":false},{"id":577327,"name":"Elliott D. SoRelle","orcid":"0000-0002-3362-1028","position":0,"is_corresponding":true}],"reference_count":124,"raw_metadata":null,"created_at":"2026-07-19T02:48:06.263458Z","pmid":"40359016","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}