The Blimp-1 SLE risk variant regulates inflammatory function in dendritic cells

描述（由申请人提供）：全基因组关联研究（GWAS）已经确定了许多与SLE相关的遗传位点；然而，我们仍然需要了解每一种对疾病起源或发病机制的贡献。具体而言，GWAS发现B淋巴细胞诱导成熟蛋白-1 （Blimp-1）在系统性红斑狼疮（SLE） rs548234中具有易感多态性，但该多态性对Blimp-1表达和功能的意义以及对SLE发病机制的意义尚未确定。我们已经建立了一种新的SLE小鼠模型，其中Blimp-1以树突状细胞（DC）特异性的方式被删除（DCBlimp-1ko小鼠）。与其他已建立的模型相比，dclimp -1ko小鼠显示出更明显的性别依赖性疾病发展，类似于人类疾病。此外，dclimp -1ko小鼠的狼疮样表型取决于雌激素的存在。Blimp-1缺陷dc在toll样受体（TLR）刺激后表现出活化的表型和促炎细胞因子的表达增加。我们发现Blimp-1直接调控dc中Let-7c的表达，因此Blimp-1诱导导致Let-7c的异常升高和Let-7c靶分子、细胞因子信号传导抑制因子-1 （SOCS-1）的降低。我们研究了具有SLE风险等位基因Blimp-1的健康个体的dc功能。我们的初步研究表明，在风险等位基因携带者的dc中，Blimp-1水平下降，Let-7c水平上升。Blimp-1和Let-7c的差异表达是DC特异性的，因为没有

DESCRIPTION (provided by applicant): Genome wide association studies (GWAS) have identified many genetic loci which are associated with SLE; however, we still need to understand the contribution of each to disease initiation or pathogenesis. Specifically, GWAS identified that B lymphocyte induced maturation protein-1 (Blimp-1) has a susceptibility polymorphism for systemic lupus erythematosus (SLE) rs548234 but neither the significance of the polymorphism for Blimp-1 expression and function, nor its significance for SLE pathogenesis has been identified. We have generated a novel mouse model of SLE in which Blimp-1 is deleted in a dendritic cell (DC) specific manner (DCBlimp-1ko mice). Compared to the other established models, DCBlimp-1ko mice show a more pronounced gender dependent disease development, similar to the human disease. Moreover, the lupus-like phenotype in DCBlimp-1ko mice depends on the presence of estrogen. Blimp-1 deficient DCs show an activated phenotype and increased expression of proinflammatory cytokines following toll-like receptor (TLR) stimulation. We determined that Blimp-1 directly regulates expression of microRNA Let-7c in DCs, thus Blimp-1 induction leads to an aberrant increase of Let-7c and a decrease in the Let-7c target molecule, suppressor of cytokine signaling-1 (SOCS-1). We investigated the function of DCs from healthy individuals with the SLE risk allele of Blimp-1. Our preliminary studies demonstrate that there is a decrease in the level of Blimp-1 and increase in Let-7c in DCs of risk allele carriers. The differential expression of Blimp-1 and Let-7c is DC specific since there is no significant difference in Blimp-1 expression between B cells of risk allele and non-risk allele carriers. DCs of risk allele carriers also secrete an increased level of IL-6 following TLR stimulation. Finally, these phenotypic and functional changes depend on gender, since male risk allele carriers exhibit a much milder phenotype. We hypothesize that Blimp-1 has a critical immune tolerogenic function in DCs. In this proposal, we will identify how the risk allele affects the expression of Blimp-1 in DCs. We will identify target molecules of Blimp-1 which regulate the proinflammatory phenotype in DCs. We will also investigate the role of estrogen in Blimp-1 expression or function. Where limitations to human studies are great, we will employ the DCBlimp-1ko mouse model. There are strong similarities between human Blimp-1 risk allele carriers and DCBlimp-1ko mice and these similarities give us a unique opportunity to understand its contribution to human disease pathogenesis.