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.
Lupus disproportionally affects young women and minorities. In 2015, women comprised 15.5% of the active duty force and 19% of the Selected Reserve force, and minorities made up 31.3% of the active duty force and 26% of the Selected Reserve force (Department of Defense 2015 Demographics Profile of the Military Community). The number of women receiving care at the VA has doubled since 2000, and although the total veteran population continues to decrease, the female veteran population has been increasing each year and this trend is expected to continue through 2044 (Office of the Actuary, Veteran Population Projections Model (VetPop2014)). Current treatments for lupus are often ineffective and have substantial short- and long-term toxicity. This project is relevant to veteran health because it will characterize the mechanism by which a disease-associated genetic variant reduces risk of lupus. Since this variant is associated with phenotypic effects that influence immune tolerance, understanding its mechanisms has important therapeutic implications.
