Ocrelizumab Modulates Both B and T Cell Immune Capacities in Multiple Sclerosis

Wu, Q.; Gurrea-Rubio, M.; Wang, Q.; Dwyer, D.; Mills, E. A.; Garton, J.; Mytych, J. S.; Lundy, S. K.; Scharer, C. D.; Boss, J.; Cooney, L.; Draayer, D. E.; Campbell, P. L.; Fox, D. A.; Mao-Draayer, Y.

doi:10.64898/2026.03.24.713043

bioRxiv · 10.64898/2026.03.24.713043

Ocrelizumab Modulates Both B and T Cell Immune Capacities in Multiple Sclerosis

Wu, Q.·Gurrea-Rubio, M.·Wang, Q.·Dwyer, D.·Mills, E. A.·Garton, J.·Mytych, J. S.·Lundy, S. K.·Scharer, C. D.·Boss, J.·Cooney, L.·Draayer, D. E.·Campbell, P. L.·Fox, D. A.·Mao-Draayer, Y.

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Abstract

To understand the molecular and cellular mechanisms beyond B-cell depletion with the anti-CD20 monoclonal antibody ocrelizumab, we used comprehensive muti-modal flow cytometry and functional assays in a prospective longitudinal multiple sclerosis (MS) cohort. Ocrelizumab depleted the vast majority of B cells and showed selective effects on different B cells subsets. Analysis of residual/replenished B cells revealed relative enrichment of regulatory B cells like CD27+CD43+ B1 and CD24hiCD38hi transitional B cells, and reduction of CD27+ memory B cell subsets and CD19+IgD+CD27-naive B cells at early time points (1-3 month) and before subsequent infusions at 4-7 months, 11-14 months, and >18 months. CD20+ T cells and peripheral helper T-cells (Tph) were also reduced. RNA sequencing analysis showed B1 cells have significantly higher expression of LGALS1, KCNN4, ITGB1, and IL2RB. Compared to transitional B cells, B1 cells also displayed significantly higher expression of tissue homing molecules ITGAX (CD11c), S100A4, ITGB1, and CXCR3. IL10 signaling pathway is increased in these B cells. Ex vivo B cell functional assays indicated the residual/replenishing B cells were anergic following ocrelizumab, with increased IL10/TNF and IL10/IL6 ratios under BCR stimulation. Ocrelizumab treatment may create a self-reinforcing regulatory circuit: the reduction of Tph cells could alleviate suppression of regulatory B cells, which subsequently expand and further promote regulatory T cell networks via IL2RB, LGALS1, and an increased IL-10 signaling pathway.

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Wu, Q., Gurrea-Rubio, M., Wang, Q., Dwyer, D., Mills, E. A., Garton, J., Mytych, J. S., Lundy, S. K., Scharer, C. D., Boss, J., Cooney, L., Draayer, D. E., Campbell, P. L., Fox, D. A., Mao-Draayer, Y.. 2026-03-26. Ocrelizumab Modulates Both B and T Cell Immune Capacities in Multiple Sclerosis. https://doi.org/10.64898/2026.03.24.713043

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