Determining Enhanced Inflammatory B cell Function in African Americans with MS

点击翻译按钮获取中文摘要

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.