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

自身免疫性疾病影响超过2%的美国人口，影响发病率和死亡率， 与癌症和心脏病相媲美的相关医疗费用。遗传和环境 影响自身免疫性疾病发展的因素， 和免疫系统的调节。正如我们对免疫机制的理解， 疾病的增长，推动力一直是开发特定的疗法，恢复免疫耐受， 疾病相关自身抗原。我们最近通过跨代定位发现了一个核苷酸 多态性（SNP），rs1876453，位于免疫相关补体的第一个内含子内 受体2（CR2）基因在对照组而不是狼疮病例中富集，这表明它具有保护作用。 效果CR2直接位于染色体1q32上补体受体1（CR1）的5 ′端。我们发现B细胞 具有保护性SNP的个体的CR1基因转录增加，但CR2基因没有变化。 转录水平。我们假设CR1转录的增加与保护性CR2 SNP导致抗原特异性免疫耐受的主动诱导。我们将评估该机制， 这使用了几种免疫学和转录方法，并最终测试是否被迫 CR1的过表达恢复了系统性红斑狼疮模型的耐受性。我们建议CR1 是临床前阶段早期治疗狼疮和其他自身免疫性疾病的可行靶点 其中自身抗体在没有症状的情况下存在。随着越来越多的人应征入伍， 年轻的少数民族妇女谁是在发展狼疮的风险增加，未来的扩展，我们的研究结果， 切实的干预措施将对退伍军人的健康产生重大影响。

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.