B Cell Modulation of T Cell Responses in Multiple Sclerosis
Harp, Christopher Todd
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Until recently, a definitive role for B cells in the pathogenesis of the autoimmune neurological disorder multiple sclerosis (MS), had not been widely accepted, and remains poorly understood. B cells have multiple functions in the immune system and can both positively and negatively modulate immune responses through the production of antibody, cytokine secretion, and/or antigen presentation. Several studies indirectly suggest that B cell-T cell cooperation may be paramount in MS disease pathogenesis, although this interaction has not been well studied in MS. Therefore, the focus of my thesis project was to test the hypothesis that B cells could be efficient neuro-antigen presenting cells in the context of MS. My work has demonstrated that the cerebrospinal fluid (CSF) B cell population in MS shows characteristics of both auto-reactivity and antigen driven selection in a germinal center reaction. These findings suggest that neuro-antigen driven selection had occurred in the periphery and prompted investigation of B cells as neuro-antigen presenting cells. Examination of CD40 ligand (CD40L) and interleukin-4 (IL-4) activated peripheral B cells demonstrated for the first time that B cells could efficiently elicit myelin basic protein (MBP) specific CD8+ and CD4+ T cell proliferation from resting T cells in vitro through a mechanism that was partially dependent on presentation through HLA-DR. Further inquiry into the antigen presentation capacity of specific subpopulations of resting B cells revealed that memory B cells from MS patients (but not healthy donors (HDs)) were significantly better neuro-antigen specific presenting cells than their na?ve counter parts. This data indicated that a specific peripheral immune response had been generated in response to neuro-antigens in RRMS patients but not HDs. Taken together, these data provide a model where antigen experienced peripheral B cells from MS patients (but not HDs) provide important T cell support through antigen presentation and add to our understanding of the role of B cells in the pathogenesis of this autoimmune disease of the CNS.