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

Blimp-1 SLE 风险变异体调节树突状细胞的炎症功能

• 批准号: 8847283
• 负责人: Sun Jung Kim
• 金额: $ 44.48万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8847283
• 关键词: Address; Affect; Alleles; Antibodies; Antigen Presentation; Autoantibodies; Autoimmune Diseases; B lymphocyte-induced maturation protein 1; B-Lymphocytes; CISH gene; Cell Differentiation process; Cell physiology; Cells; Cellular biology; Characteristics; Clinical; Collaborations; Complex; Dendritic Cells; Development; Disease; Down-Regulation; Environmental Risk Factor; Estrogens; Exhibits; Female; Gender; Generations; Genetic; Genetic Polymorphism; Genetic Transcription; Glomerulonephritis; Health; Hereditary Disease; Human; Immune; Immune Tolerance; Individual; Inflammatory; Institutes; Interleukin-6; Lupus; MicroRNAs; Modeling; Molecular; Molecular Target; Mus; Nuclear Antigens; Organ; PRDM1 gene; Pathogenesis; Patients; Phenotype; Predisposition; Proteinuria; Regulation; Risk; Role; Specificity; Systemic Lupus Erythematosus; T-Lymphocyte Subsets; Toll-like receptors; Transcription Repressor/Corepressor; Translating; Variant; Woman; base; cell type; cytokine; differential expression; ds-DNA; genetic variant; genome wide association study; human disease; individualized medicine; lupus-like; male; mouse model; new therapeutic target; novel; protein B; risk variant; young woman

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.

描述（由申请人提供）：全基因组关联研究（GWAS）已鉴定出许多与 SLE 相关的遗传位点；然而，我们仍然需要了解每种因素对疾病发生或发病机制的贡献。具体而言，GWAS 发现 B 淋巴细胞诱导成熟蛋白 1 (Blimp-1) 具有系统性红斑狼疮 (SLE) rs548234 的易感性多态性，但该多态性对于 Blimp-1 表达和功能的意义及其对 SLE 发病机制的意义尚未确定。我们建立了一种新的 SLE 小鼠模型，其中以树突状细胞 (DC) 特异性方式删除 Blimp-1（DCBlimp-1ko 小鼠）。与其他已建立的模型相比，DCBlimp-1ko 小鼠表现出更明显的性别依赖性疾病发展，类似于人类疾病。此外，DCBlimp-1ko 小鼠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) 刺激后表现出激活表型和促炎细胞因子表达增加。我们确定Blimp-1直接调节DC中microRNA Let-7c的表达，因此Blimp-1诱导导致Let-7c的异常增加和Let-7c靶分子（细胞因子信号传导1（SOCS-1）的抑制因子）的减少。我们研究了带有 Blimp-1 SLE 风险等位基因的健康个体的 DC 的功能。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 水平增加。 Blimp-1 和 Let-7c 的差异表达是 DC 特异性的，因为没有 风险等位基因和非风险等位基因携带者的B细胞之间Blimp-1表达存在显着差异。 TLR 刺激后，风险等位基因携带者的 DC 也会分泌增加水平的 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 中具有重要的免疫耐受功能。在本提案中，我们将确定风险等位基因如何影响 DC 中 Blimp-1 的表达。我们将鉴定调节 DC 促炎表型的 Blimp-1 靶分子。我们还将研究雌激素在 Blimp-1 表达或功能中的作用。当人类研究受到很大限制时，我们将采用 DCBlimp-1ko 小鼠模型。人类 Blimp-1 风险等位基因携带者和 DCBlimp-1ko 小鼠之间存在很强的相似性，这些相似性为我们提供了一个独特的机会来了解其对人类疾病发病机制的贡献。