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Role of Complement Receptor 1 in the Modulation of B Cell Tolerance

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Autoimmune diseases affect more than 2% of the US population, with effects on morbidity and mortality and associated health care costs that rival those of cancer and heart disease. Both genetic and environmental factors influence the development of autoimmune diseases, which result from an imbalance between activation and regulation of the immune system. As our understanding of the immunological mechanisms that drive these diseases has grown, the impetus has been to develop specific therapies that restore immune tolerance to disease-associated autoantigens. We recently identified by trans-ancestral mapping a single nucleotide polymorphism (SNP), rs1876453, located just inside the first intron of the immune-associated complement receptor 2 (CR2) gene that was enriched in controls rather than lupus cases, suggesting that it had a protective effect. CR2 is located directly 5? of complement receptor 1 (CR1) at chromosome 1q32. We found that B cells from individuals with the protective SNP had increased transcription of the CR1 gene but no changes in CR2 transcriptional levels. We hypothesize that increased transcription of CR1 associated with the protective CR2 SNP results in the active induction of antigen-specific immune tolerance. We will evaluate the mechanism for this using several immunological and transcriptional approaches and ultimately test whether forced overexpression of CR1 restores tolerance in a model of systemic lupus erythematosus. We propose that CR1 is a viable target for the early treatment of lupus and other autoimmune diseases during the preclinical phase in which autoantibodies are present in the absence of symptoms. With rising enlistment into the military of young minority women who are at increased risk of developing lupus, the future extension of our findings into tangible interventions will have a substantial impact on veteran health.
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