{"doi":"10.1126/scitranslmed.ady0210","title":"Epstein-Barr virus reprograms autoreactive B cells as antigen-presenting cells in systemic lupus erythematosus","abstract":"Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by antinuclear antibodies (ANAs). Epstein-Barr virus (EBV) infection has been epidemiologically associated with SLE, yet its role in pathogenesis remains incompletely defined. Here, we developed an EBV-specific single-cell RNA-sequencing platform and used it to demonstrate that EBV infection reprograms autoreactive antinuclear antigen B cells to drive autoimmunity in SLE. We demonstrated that, in SLE, EBV + B cells are predominantly CD27 + CD21 low memory B cells that are present at increased frequencies and express ZEB2 , TBX21 (T-bet), and antigen-presenting cell transcriptional pathways. Integrative analysis of chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase-accessible chromatin sequencing (ATAC-seq), and RNA polymerase II occupancy data revealed EBV nuclear antigen 2 (EBNA2) binding at the transcriptional start sites and regulatory regions of CD27 , ZEB2 , and TBX21 , as well as the antigen-presenting cell genes demonstrated to be up-regulated in SLE EBV + B cells. We expressed recombinant antibodies from SLE EBV + B cells and demonstrated that they bind prototypical SLE nuclear autoantigens, whereas those from healthy individuals do not. We further found that SLE EBV + B cells can serve as antigen-presenting cells to drive activation of T peripheral helper cells with concomitant activation of related EBV − antinuclear double-negative 2 B cells and plasmablasts. Our results provide a mechanistic basis for EBV being a driver of SLE through infecting and reprogramming nuclear antigen-reactive B cells to become activated antigen-presenting cells with the potential to promote systemic disease–driving autoimmune responses.","journal":"Science Translational Medicine","year":2025,"id":508947,"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":60,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9589,"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":1361459,"name":"Salvinaz Islam Moutusy","orcid":"0009-0001-7206-2185","position":1,"is_corresponding":false},{"id":983414,"name":"Sajede Rasouli","orcid":"0000-0002-9235-0336","position":2,"is_corresponding":false},{"id":651068,"name":"Shaghayegh Jahanbani","orcid":"0000-0001-7789-4856","position":3,"is_corresponding":false},{"id":1361460,"name":"Mahesh Pandit","orcid":"0009-0007-9111-444X","position":4,"is_corresponding":false},{"id":16855,"name":"Xiaohao Wu","orcid":"0000-0002-0984-7414","position":5,"is_corresponding":false},{"id":1361461,"name":"Suman Acharya","orcid":"0000-0002-2141-2210","position":6,"is_corresponding":false},{"id":1010870,"name":"Orr Sharpe","orcid":"0000-0003-1986-7555","position":7,"is_corresponding":false},{"id":447168,"name":"Tilini U. 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Harley","orcid":null,"position":14,"is_corresponding":false},{"id":395328,"name":"Eric Meffre","orcid":"0000-0003-4326-0171","position":15,"is_corresponding":false},{"id":490962,"name":"Lawrence Steinman","orcid":"0000-0002-2437-2250","position":16,"is_corresponding":false},{"id":533236,"name":"Ann Marshak‐Rothstein","orcid":"0000-0003-2136-8130","position":17,"is_corresponding":false},{"id":226234,"name":"Judith A. James","orcid":"0000-0002-9574-7355","position":18,"is_corresponding":false},{"id":385287,"name":"Olivia M. Martinez","orcid":"0000-0002-2798-0251","position":19,"is_corresponding":false},{"id":22091,"name":"Paul J. Utz","orcid":"0000-0003-1181-1565","position":20,"is_corresponding":false},{"id":226245,"name":"Dana E. Orange","orcid":"0000-0001-9859-7199","position":21,"is_corresponding":false},{"id":376526,"name":"Tobias V. Lanz","orcid":"0000-0001-7106-8801","position":22,"is_corresponding":false},{"id":226251,"name":"William H. 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