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Farooq, R.* ; Cutler, B.* ; Pisa, M.* ; Balaram Kuttikkatte, S.* ; Palace, J.* ; DeLuca, G.C.* ; Gold, R.* ; Theis, F.J. ; Fugger, L.* ; Attfield, K.E.*

Multimodal discovery of a pathogenic B cell-dependent T cell state in multiple sclerosis.

Brain, DOI: 10.1093/brain/awag303 (2026)
Postprint DOI PMC
Open Access Green
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter B Cells ; T Cells ; Machine Learning ; Multiple Sclerosis ; Neuroimmunology ; Single-cell Transcriptomics
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Zeitschrift Brain: A Journal of Neurology
Verlag Oxford University Press
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Computational Biology (ICB)