{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE316nnn/GSE316688/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":[" Other","Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE316688"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Multimodal discovery of a pathogenic B cell-dependent T cell state in multiple sclerosis","description":"B cell depleting therapies in multiple sclerosis (MS) have transformed disease management, yet the immunological mechanisms linking B cells to chronic compartmentalised CNS inflammation, the key pathological driver of disability accrual, remain poorly defined. Here, we leverage anti-CD20 therapy as an in vivo perturbational probe to disentangle MS immunobiology. We combine longitudinal, high-dimensional multimodal immune profiling in patients initiating ocrelizumab with a novel machine learning pipeline to resolve treatment-induced shifts in continuous immune cell states, revealing treatment-associated modulation of shared biological processes that act across the boundaries of discretely partitioned cell types. We identify a distinct chronically activated, proinflammatory–cytotoxic T cell state with CNS-homing properties that is selectively depleted following B cell ablation. Importantly, across independent datasets, the same T cell state is enriched in the circulation of patients with clinically aggressive relapsing disease, in CSF-enriched expanded clonotypes, including a subset with proven Epstein–Barr virus-specificity, and in chronically inflamed lesion rims in end-stage MS. Finally, we demonstrate that blockade of lymphocyte trafficking across the blood–brain barrier with the anti-integrin α4 therapy natalizumab leads to enrichment of this cell state in the circulation, demonstrating a mechanistically concordant effect across distinct high-efficacy MS therapies. Together, our findings support a B cell-dependent, pathogenic T cell state which links peripheral immune activation to CNS-compartmentalised smouldering neuroinflammation across disease stages. Direct therapeutic manipulation of this T cell state may represent a key opportunity for targeting chronic neuroinflammation and facilitate a strategic shift away from broad immune cell ablation.","dates":{"publication":"2026/09/11"},"accession":"GSE316688","cross_references":{"GSM":["GSM9458350","GSM9458319","GSM9458316","GSM9458359","GSM9458315","GSM9458318","GSM9458317","GSM9458279","GSM9458356","GSM9458312","GSM9458311","GSM9458355","GSM9458278","GSM9458314","GSM9458358","GSM9458357","GSM9458313","GSM9458352","GSM9458351","GSM9458354","GSM9458277","GSM9458310","GSM9458276","GSM9458353","GSM9458282","GSM9458281","GSM9458284","GSM9458361","GSM9458360","GSM9458283","GSM9458280","GSM9458327","GSM9458326","GSM9458329","GSM9458328","GSM9458323","GSM9458322","GSM9458289","GSM9458325","GSM9458324","GSM9458286","GSM9458285","GSM9458288","GSM9458321","GSM9458320","GSM9458287","GSM9458293","GSM9458292","GSM9458295","GSM9458294","GSM9458291","GSM9458290","GSM9458338","GSM9458337","GSM9458339","GSM9458334","GSM9458333","GSM9458336","GSM9458335","GSM9458297","GSM9458330","GSM9458296","GSM9458299","GSM9458332","GSM9458331","GSM9458298","GSM9458309","GSM9458308","GSM9458305","GSM9458349","GSM9458348","GSM9458304","GSM9458307","GSM9458306","GSM9458345","GSM9458301","GSM9458300","GSM9458344","GSM9458303","GSM9458347","GSM9458346","GSM9458302","GSM9458341","GSM9458340","GSM9458343","GSM9458342"],"GPL":["34281"],"GSE":["316688"],"taxon":["Homo sapiens"],"PMID":["[42714077]"]}}