AUTHOR=Silverman Gregg J. , Amarnani Abhimanyu N. , Armini Arnaldo A. , Kim Angie , Kopinsky Hannah , Fenyo David , Kister Ilya 

TITLE=B cell-extrinsic and intrinsic factors linked to early immune repletion after anti-CD20 therapy in patients with multiple sclerosis of African ancestry

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1590165

DOI=10.3389/fimmu.2025.1590165

ISSN=1664-3224

ABSTRACT=IntroductionRecent investigations have identified patients of African ancestry (AA) with Multiple Sclerosis (MS), who display more rapid B-cell repopulation after standard semi-annual infusions with an anti-CD20 monoclonal antibody for B cell depletion. In this study, we explored the immunologic and genetic factors, with, serum drug monitoring that may contribute to a faster rate of B-cell repletion that follows during recovery from treatment with anti-CD20 antibody. MethodsIn AA MS patients treated with an anti-CD20 antibody that had early repopulation of peripheral blood B cells, we assessed for extrinsic factors, including the presence of anti-drug antibodies against ocrelizumab, which may contribute to early repletion. We also documented the associated serum drug levels. In addition, we examined for inheritance of  intrinsic  gene polymorphisms associated with B cell survival and immune function. ResultsOur findings identified a subset of AA patients with early B cell repletion after anti-CD20 treatment associated with anti-drug antibodies and an absence of detectable drug. Furthermore, a separate set of AA patients with the early B cell repletion phenotype without anti-drug antibodies had significant over-representation of genetic polymorphisms that map to genes for the B cell survival factor, BAFF, to antibody-dependent cytotoxicity, and to pathways involved in inflammation, leukocyte activation and B cell differentiation. DiscussionIn AA patients with MS, after anti-CD20 antibody treatment we found an unexpected high occurrence of early B cell replenishment. This was associated with the presence of anti-drug antibodies and/or specific genetic polymorphisms.  Larger studies are now needed to determine whether these factors may lead to impaired therapeutic benefits of B cell targeted therapy and clinical progression, and these findings may be useful to guide future optimized personalized therapeutic strategies.