Elevated frequencies of activated memory B cells in multiple sclerosis are reset to healthy control levels after B cell depletion with Ocrelizumab
doi: 10.1016/j.jneuroim.2024.578502.
Online ahead of print.
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J Neuroimmunol.
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Abstract
In multiple sclerosis (MS) the B cell depleting drug ocrelizumab has shown high efficacy in reducing inflammatory activity. Its mechanism of action is unclear due to B cell subset complexity and unknown roles in pathogenesis. Here, we comprehensively phenotyped and quantitated peripheral blood B cell subsets before and after ocrelizumab infusion to gain insight into the fate of B cell subsets with pathogenic potential. Peripheral blood B cells were collected from treatment naïve patients at baseline and months one, three, and six following the first course of ocrelizumab treatment; at 6 months following the second treatment cycle; ∼14 months following their last infusion; and from healthy controls. Flow cytometry combined with cluster analysis was used to track depletion and repletion of naïve, memory, and antibody secreting cells. By month one, naïve B cells were depleted, but a small subset of memory B cells were retained with no depletion of antibody secreting cells. Uniform manifold approximation and projection for dimension reduction analysis of flow cytometry data revealed two non-class switched naïve clusters and two class switched memory clusters. One class switched cluster was activated in MS patients but largely absent in healthy controls. Both memory B cell subsets underwent depletion after a single six-month course of ocrelizumab treatment after which their proportions were reset to heathy control levels. These observations suggest that activated class-switched memory B cells could serve as a biomarker of recent or ongoing MS disease activity to guide redosing.
Keywords:
B cell depletion; Flow cytometry; Memory B cells; Multiple sclerosis.
Copyright © 2024. Published by Elsevier B.V.
Conflict of interest statement
Declaration of competing interest CJG, ZH, AJV, KF, SO and BND have no contact or competing interests to declare. AZO reports receiving personal compensation for participation in scientific advisory boards, steering committees, and/or speaking engagements from Alexion Pharmaceuticals, Amgen, Banner Life Sciences, BD Biosciences, Biogen, Biologix Solutions, Bristol Myers Squibb, Celgene, EMD Serono, Genentech (The manufacturer of ocrelizumab), GW Pharmaceuticals, Horizon Therapeutics, Jazz Pharmaceuticals, Novartis, Sandoz, Sanofi Genzyme, TG Therapeutics, and Viela Bio; Also, received honoraria from Medscape, MJH Life Sciences, and WebMD; has served as a site principal investigator for studies funded (directly paid to the Medical College of Wisconsin) by Atara Biotherapeutics, Biogen, Bristol Myers Squibb, Celgene, CorEvitas, EMD Serono, Genentech, GW Pharmaceuticals, Immunic Therapeutics, National Multiple Sclerosis Society/Patient-Centered Outcomes Research Institute, Novartis, Sanofi Genzyme, and TScan Therapeutics.
Fonte original PubMed