Date of Award

January 2015

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Kevin C. O'Connor

Second Advisor

Emily Gilmore

Subject Area(s)

Neurosciences, Immunology

Abstract

Myasthenia gravis (MG) is an autoimmune disorder of neuromuscular transmission with an estimated annual incidence of 1-2 per 100,000 and prevalence as high as 20-50 per 100,000 [1]. The immunopathology of the disease is related to the presence of autoantibodies most commonly directed to acetylcholine receptors (AChR) or less commonly to muscle specific tyrosine kinase (MuSK) [2], both of which cluster on muscle cells at the neuromuscular junction and initiate muscle contraction. The cause of these autoantibodies' production is still unknown. We hypothesize that B cells in MG carry intrinsic defects in central or peripheral B cell tolerance checkpoints that lead to autoreactivity and that this defect is present in patients with ocular and generalized MG, who are either anti-AChR or anti-MuSK antibody positive, contributing to the pathogenesis of disease. This was tested by creating recombinant antibodies from five MG patients and determining the frequency of polyreactivity and HEp2 reactivity, as markers for central and peripheral tolerance defects, respectively, compared to healthy donors. It was found that all MG patients show significantly higher frequency of reactivity in both assays, indicating a break in both central and peripheral tolerance checkpoints. Overall, this demonstrates the likely cause of autoimmunity in these patients and a potential target for future directed pharmacologic intervention.

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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