Why African American and Latin Americans present with greater multiple sclerosis (MS) disease severity has not been investigated beyond retrospective clinical chart review, and risk association studies. B cells inform MS diagnostic, severity and prognostic assessments through their immunobiological activity. Thanks to the dramatic efficacy of B cell depletion therapy, we now know that B cells are principal drivers of MS clinical activity. We propose that B cell-based, ancestry-dependent functional difference in MS holds clinically valuable mechanistic insight. Such insight would be supportive of an emergent pattern where ancestry-mediated immunobiological differences underlie ancestry-disparate clinical severity, heterogeneity and prevalence. In this study, we test our hypothesis that MS patients of African ancestry possess greater T- dependent inflammatory B cell function relative to those of Caucasian ancestry. Our preliminary findings support this hypothesis. At steady-state ex vivo (directly from subject peripheral blood) circulating antibody secreting cell (ASC) subset frequencies are increased in BA/LAwMS relative to CAwMS. Further, isolated B cells more readily differentiate into ASCs compared to CAwMS upon in vitro T-dependent stimulation. These differences are absent amongst healthy donors. Our preliminary findings imply that underlying ancestry-mediated differences drive B cell differentiation toward ASC fate. We will specify mechanisms associated with these findings, ultimately applying fine-resolution SNP-based ancestral analysis to ex vivo and in vitro assay readouts. Specifically, we will conduct longitudinal ex vivo assessment of ASC as well as antigen presenting function-associated proteins on memory B cells. We will also delineate in vitro T-dependent and T-independent ASC differentiation, expression of class- switched memory B cell inflammatory products and enhanced STAT3 signaling amongst this population. This project (1) directly investigates inflammatory B-cell function comparing BA/LAwMS and CAwMS for the first time, and (2) builds upon a nascent paradigm (to our knowledge) initially demonstrated in limited fashion within systemic lupus erythematosus. Our project thus fits key criteria of the R21 mechanism by nuancing the emergent idea of B cell-driven ancestry- dependent disease disparity. As for impacting clinical research, our project is in-line with current and future precision medicine initiatives geared towards identifying and responding to biological variation across formerly subsumed or otherwise underrepresented ethnic groups.