Date of Award

Summer 2011

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Betty Diamond

Abstract

Anti-DNA antibodies are a hallmark of systemic lupus. These antibodies are not only a specific marker of the disease, but have also been shown to directly contribute to the pathogenesis of lupus kidney and brain disease. Using a novel murine model that incorporates genetic susceptibility and an exogenous trigger, we have dissected the pathogenesis of anti-DNA autoimmunity, and have discovered that the gene Csk can contribute to autoimmunity by abrogating B cell negative selection. Having previously identified a highly-linked lupus susceptibility locus on chromosome 9, we identified the Csk gene as a culprit by both a candidate gene and positional approach. The autoimmune-associated allele of Csk is over-expressed within B cells, and this is due to an Oct transcription factor binding site. Over-expression of Csk decreases BCR signaling and BCR-mediated apoptosis in immature B cells. Lastly, we demonstrate that the locus containing Csk is responsible for increased autoantibody production in another model of autoimmunity: the proteoglycan-induced model of inflammatory arthritis. Csk is the biologic partner of PTPN22, a gene that has been implicated in the pathogenesis of lupus, rheumatoid arthritis, type I diabetes, and autoimmune thyroid disease. Preliminary evidence from a human association study demonstrates association between Csk variants and lupus in humans. Thus, Csk may prove to be a highly important gene in human autoimmunity, and BCR signaling is further emerging as a pathway that is central to self-tolerance.

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