Gamma herpesvirus impact on required B cell:CD4 T interactions in a B cell-dependent, antibody-independent mouse model of multiple sclerosis - PROJECT ABSTRACT Potential for Epstein-Barr virus (EBV) involvement in multiple sclerosis (MS) etiology is increasingly recognized, but how infection could trigger or augment myelin autoreactivity is unclear. MS is an immune-mediated demyelinating disease of the central nervous system (CNS), and despite first line drugs that limit symptoms, disease remains incurable. Due to its early life onset and rise in prevalence for nearly 1 million Americans, MS imparts an immense health and economic burden on the United States. Adaptive immune cells, particularly CD4 T cells (CD4s), have long been considered integral players in neuroinflammation and demyelination in MS, and B cells have been appreciated as playing a pathobiological role, highlighted by the success of anti-CD20 B cell depletion therapy (BCDT). Mechanistically, B cells are thought to support autoreactive CD4s through antigen presentation. Given EBV is a gamma herpesvirus (gHV) that latently infects human B cells, it is postulated infection may influence disease-driving B:CD4 interactions by enhancing autoantigen presentation. Few MS animal models are well-equipped to dissect B:CD4 interactions in this viral context, as the vast majority of EAE (experimental autoimmune encephalomyelitis) studies feature B cell- independent disease. To circumvent this, we have developed a B cell-dependent, antibody- independent EAE model in WT B6 mice featuring CD4 T cell immunoreactivity to the extracellular domain sequences of the highly abundant and 100% conserved myelin proteolipid protein (PLPECD). Through rigorous experimentation, we have identified B cell-mediated antigen presentation to CD4s through MHC class II as the required pathogenic B cell mechanism in PLPECD-induced EAE, where B cells engage PLPECD through the B cell receptor and are more efficient than dendritic cells at processing and presenting immunodominant residues from within PLPECD to PLP178-191-reactive CD4 T cells. Further mimicking the sustained pathogenic B cell involvement seen in MS and unlike B cell-independent EAE driven by PLP178-191, BCDT robustly ameliorates established PLPECD disease. Thus, we have developed a novel and powerful tool to investigate how gHV infection impacts key pathogenic B:CD4 interactions during development of autoimmune demyelinating disease. We hypothesize that gHV infection of WT B6 mice exacerbates B cell-dependent but not B cell-independent EAE by enhancing B cells’ support of autoreactive CD4s. Specific Aim 1 will determine how gHV infection affects B cells’ support of disease-driving CD4 T cells. Specific Aim 2 will determine how gHV infection impacts B cell- dependent vs. B cell-independent EAE.
