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相关的遗传基因座;然而，我们仍然需要了解每个基因座对疾病发生或发病机制的贡献。具体而言，GWAS鉴定了B淋巴细胞诱导成熟蛋白-1（Blimp-1）具有系统性红斑狼疮（SLE）rs 548234的易感性多态性，但该多态性对Blimp-1表达和功能的意义以及其对SLE发病机制的意义均未被鉴定。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）特异性方式缺失（DCBlimp-1 ko小鼠）。与其他已建立的模型相比，DCBlimp-1 ko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，DCBlimp-1 ko小鼠中的狼疮样表型取决于雌激素的存在。Blimp-1缺陷型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。我们确定Blimp-1直接调节DC中microRNA Let-7 c的表达，因此Blimp-1诱导导致Let-7 c的异常增加和Let-7 c靶分子（细胞因子信号传导抑制因子-1（SOCS-1））的减少。我们研究了来自具有SLE危险等位基因Blimp-1的健康个体的DC的功能。我们的初步研究表明，在危险等位基因携带者的DC中，Blimp-1水平降低，Let-7 c水平升高。Blimp-1和Let-7 c的差异表达是DC特异性的，因为在DC中不存在Blimp-1和Let-7 c。 Blimp-1在危险等位基因携带者和非危险等位基因携带者的B细胞中的表达差异有统计学意义。危险等位基因携带者的DC在TLR刺激后也分泌增加水平的IL-6。最后，这些表型和功能变化取决于性别，因为男性风险等位基因携带者表现出更温和的表型。我们假设Blimp-1在DC中具有关键的免疫耐受性功能。在这个提议中，我们将确定风险等位基因如何影响Blimp-1在DC中的表达。我们将鉴定Blimp-1的靶分子，其调节DC中的促炎表型。我们还将研究雌激素在Blimp-1表达或功能中的作用。最后，我们将比较危险等位基因或非危险等位基因SLE患者，以确定是否在所有SLE患者中发生类似的DC功能模式。如果人类研究的局限性很大，我们将采用DCBlimp-1 ko小鼠模型。人类Blimp-1风险等位基因携带者和DCBlimp-1 ko小鼠之间存在很强的相似性，这些相似性为我们了解其对人类疾病发病机制的贡献提供了独特的机会。

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. Finally, we will compare risk allele or non-risk allele SLE patients to determine whether a similar pattern of DC function occurs in all SLE patients. 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.