Date of Award

January 2015

Document Type

Open Access Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

David A. Hafler

Second Advisor

Kevin O'Connor

Subject Area(s)

Immunology, Medicine

Abstract

Multiple sclerosis is an autoimmune, demyelinating disorder of the central nervous system that afflicts nearly 2.5 million people worldwide and is among the most common causes of permanent disability in young adults. Although a number of treatments for multiple sclerosis have emerged in recent years, no cure currently exists. From a pathophysiological standpoint, murine models and human genomic studies have established the contribution of T-lymphocytes to multiple sclerosis. However, evidence suggests that B-lymphocytes are also involved in the development of this disease. Immunoglobulins (also known as oligoclonal bands) are routinely measured in the cerebrospinal fluid of patients at the time of diagnosis of multiple sclerosis. In addition, several small-scale clinical trials have demonstrated benefit with B-cell depleting therapies (such as rituximab and ocrelizumab). Prior work has also established the presence of shared B lymphocyte clones in multiple sclerosis lesions as well as in other locations in the CNS, such as meninges. The purpose of this study was to investigate whether shared B lymphocyte clones are also observed in peripheral lymphoid tissues to elucidate the natural history and migration patterns of these cells. Applying conventional DNA sequencing of the B cell receptors (BCRs) to autopsy samples from five patients, we found that B lymphocyte clonal variants are indeed shared between the CNS and periphery. Subsequent work building on this thesis employing high-throughput sequencing (published in Stern et al. [1]) confirmed these findings and found that these cells predominantly mature in the periphery. These results shed light on the role of B cells in multiple sclerosis pathogenesis, clarify the mechanism of current therapeutics that function by modulating lymphocyte migration, and suggest new avenues of investigation for multiple sclerosis treatment.

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