Implications of Dysregulated Antibody Hypermutation Patterns in Multiple Sclerosis Patients

The potential role of B cells in contributing to the pathology of the human autoimmune neurological disease multiple sclerosis (MS) has recently become of significant interest. MS is a complex disorder of the central nervous system (CNS) with various presentation types, symptoms, and damage that involves many different components of the immune system. Historically, the role of B cells was considered minimal and overshadowed by the impact of T cells. The main effector function of a B cell is mediated by the downstream production of antibodies, that bind to their cognate antigens.. Thus, detailed investigation of antibody genomics reveals important information regarding the response of a B cell to its environment. We previously discovered a pattern of somatic hypermutation in the antibody genes expressed isolated from cerebrospinal fluid (CSF) B cells of patients with MS and those at high risk for developing MS. The focus of this thesis project was to further characterize this pattern of mutation termed the antibody gene signature (AGS) and determine the biological significance of this shared AGS among patients. Secondly, I aimed to discover differences in B cell subtypes and antibody genomics in the two of the most common initial presentations of clinically isolated syndrome (CIS) patients at high risk for converting to MS: optic neuritis (ONCIS) and transverse myelitis (TMCIS). Through my work in analyzing antibody genomics, I demonstrated that the AGS is present at the site of MS disease, within the CNS tissue. This provides support for the study of CSF B cells since it recapitulates what is present within the parenchyma. I also determined that both ONCIS and TMCIS patients are enriched for AGS positive B cells within the CSF. This exemplifies that regardless of initial presentation, patients at high risk for converting to MS share this AGS. Further characterization of TMCIS patients revealed that a subset harbor an expansion of plasmablasts in both the periphery and the CSF compared to ONCIS patients. Furthermore, in depth analyses of the peripheral plasmablasts uncovered altered genomic selective pressures in the periphery. This differential expansion of plasmablasts may offer insight for future studies of the possible varied underlying biological processes between these two patient groups. I aimed to determine the biological significance of this shared genomic pattern of the AGS by examining the CNS targeting potential. Immunohistochemical experiments revealed that AGS-enriched antibodies from ONCIS, TMCIS, and MS patients target neurons and astrocytes within the gray matter. These novel findings provide future directions for elucidating the auto-antigen(s) responsible for eliciting the shared AGS. Furthermore, identifying the AGS-enriched antibody binding patterns could aid in identifying potential therapeutic targets to help reduce CNS damage in both CIS and MS patients.