Ethnicity-associated, differential CNS demyelinating autoimmune disease severity: reconciling identity, ancestry and neurotoxic antibody response

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Black African multiple sclerosis (BA-MS) patients exhibit double the neurodegeneration rates of Caucasian patients (CA-MS). Socioeconomic factors do not completely account for this disparity, pointing to biological mediators. Antibody-secreting cells (ASC)s are associated with MS disease activity and production of neurotoxic demyelinating and axopathic antibodies. Intrathecal antibody levels strongly correlate with neurodegeneration among Black African but not Caucasian MS patients. This suggests that ethnicity-associated differences in neurotoxic antibody function may promote the heightened clinical severity reported for BA-MS patients. However, no study has examined whether the prevalence or quality of neurotoxic antibodies differs according to ethnicity. Determining how neurotoxic antibody responses in MS vary by ethnicity will improve our understanding of antibody-mediated CNS degeneration. This will better position us to address inordinate CNS disease burden faced by MS patients from underserved backgrounds. The mentored phase (Aim 1) includes: generating recombinant human antibodies (rhAb) derived from individually sorted ASCs; culturing these rhAbs with myelinating central nervous system tissue; and, measuring rhAb-mediated demyelination and axon loss through immunohistochemical analysis. Sequencing data collected as a byproduct of single cell rhAb generation will provide the candidate opportunity to gain high-level knowledge of antibody genetic repertoire analysis. During the independent phase, the above approaches will be applied to other B cell subsets that feature in MS disease activity; double negative 2 (DN2) B cells in Aim2, and repopulating B cells after depletion therapy in Aim3. Each of the three aims employs subject cohorts that correspond to different stages of MS: early MS patients experiencing their first symptoms (Aim1); established clinically- managed MS patients (Aim2); and established clinically-managed MS patients after B cell depletion therapy (Aim3). For each cohort we will determine the quality, quantity and cellular sources of neurotoxic antibodies in relation to self-identified ethnicity and genetic ancestry. Employing similar technical approaches across all aims establishes complementary phenotypic, functional and genetic antibody repertoire datasets for different B cell subsets and stages of MS. This facilitates future research avenues for the candidate. The proposed work will provide competencies for an independent research career. The mentoring team: Drs Vartanian, Monson, Elemento, & Pascual, will supervise the candidate in experimental methodology. Through regular meetings, they will advise the candidate in securing a faculty position and developing a research program. Advisor team members: Drs. Bennett, Nussenzweig, Davis, Kittles, Sanz & Kister will provide additional technical & professional guidance through their extensive experience with methods & approaches outlined in the Research Strategy; such as, neuroimmunologic assays, molecular genetic approaches, as well as with studying differential ethnicity or ancestry-associated clinical disparities.