Defining the Pathogenic Contribution of High Genotypic MIF Expression

项目总结 类风湿性关节炎(RA)尽管有生物治疗，但仍无法治愈。我们之前确定了一个 细胞因子巨噬细胞移动抑制因子基因功能启动子多态性研究 我们的小组首次克隆了与RA侵蚀性关节破坏有关的基因。众所周知，MIF可以调节 通过抑制糖皮质激素的作用，抑制激活诱导的细胞凋亡的先天反应，以及 促进组织中巨噬细胞的滞留。MIF和高表达的MIF等位基因的作用还不完全 然而，理解，特别是关于长期存在的适应性反应的变化 炎症、病理进展和疾病持久性。我们发现了一种新的T细胞 表达MIF受体(CD74)的亚群，在关节炎期间扩张，并重现疾病 当转移到幼稚的宿主时。在人类类风湿滑膜中也存在类似的人群。我们 假设CD4 CD74 T细胞在类风湿性炎症、疾病进展和 旧病复发。我们将在这项提议中追求三个具体目标：1.界定小说的致病作用， 炎性关节炎患者外周血中表达MIF受体的T细胞亚群(CD4、CD74、T细胞)我们 假设CD4 CD74 T细胞表达炎性细胞因子和趋化受体 导致滑膜关节破坏。我们将描述MIF信号和效应器的反应 小鼠和人CD4 CD74 T细胞，鉴定运输因子/受体，并建立其致病机制 潜力。2.明确高基因MIF表达对小鼠关节免疫病理的影响 新颖的人性化MIF小鼠模型。我们假设MIF的表达驱动了病理性的CD4 CD74 T细胞运输和效应器反应，以及顽固性关节炎。我们将使用小说来验证这一假设 人源化的MIF小鼠，表达低表达和高表达的人MIF等位基因。3.评估 ICBP90抑制对人源化MIF小鼠和高基因MIF小鼠MIF表达的影响 表达人类细胞。我们鉴定了上调MIF的转录因子(ICBP90) 在其变异启动子微卫星(-794CATT5-8)和类药物分子(CMFT)上转录 阻断ICBP90与该启动子位点的结合。我们假设抑制ICBP90将改善MIF- CD4 CD74 T细胞的依赖扩增和效应反应我们将在以下方面测试这种可能性 实验性关节炎并检测ICBP90对高基因MIF表达的人细胞的抑制作用 从外周血和类风湿滑膜组织中提取。这些目标的实现将 深入了解一种表达T细胞群的新型MIF受体的病理作用 MIF风险等位基因在类风湿炎症中的作用。这些研究也将加速考虑 一种基于精确的方法来治疗RA关节破坏。

PROJECT SUMMARY Rheumatoid arthritis (RA) remains incurable despite biologic therapies. We previously identified a functional promoter polymorphism in the gene for macrophage migration inhibitory factor (MIF) - a cytokine our group first cloned, that is associated with erosive joint destruction in RA. MIF is known to regulate the innate response by inhibiting glucocorticoid action, suppressing activation-induced apoptosis, and promoting macrophage retention in tissues. The role of MIF and high expression MIF alleles is not fully understood however, especially with respect to alterations in the adaptive response that perpetuate inflammation, pathologic progression, and disease persistence. We have discovered a novel T cell subpopulation that expresses the MIF receptor (CD74), expands during arthritis, and recapitulates disease when transferred into naïve hosts. A similar population exists in human rheumatoid synovium. We hypothesize that CD4+CD74+ T cells play a key role in rheumatoid inflammation, disease progression, and relapse. We will pursue three Specific Aims in this proposal: 1. Define the pathogenic role of a novel, MIF receptor expressing T cell sub-population (CD4+CD74+ T cells) in inflammatory arthritis. We hypothesize that CD4+CD74+ T cells express inflammatory cytokines and chemotactic receptors that contribute to synovial joint destruction. We will characterize the MIF signaling and effector responses of mouse and human CD4+CD74+ T cells, identify trafficking factors/receptors, and establish their pathogenic potential. 2. Define the impact of high-genotypic MIF expression on joint immunopathology in a novel humanized MIF mouse model. We hypothesize that MIF expression drives pathologic CD4+CD74+ T cell trafficking and effector responses, and unremitting arthritis. We will test this hypothesis using novel humanized MIF mice that express low-expression and high-expression human MIF alleles. 3. Evaluate the impact of ICBP90 inhibition on MIF expression in humanized MIF mice and in high genotypic MIF expressing human cells. We identified both the transcription factor (ICBP90) that upregulates MIF transcription at its variant promoter microsatellite (-794 CATT5-8), and a drug-like molecule (CMFT) that blocks ICBP90 binding to this promoter site. We hypothesize that ICBP90 inhibition will ameliorate the MIF- dependent expansion and effector response of CD4+CD74+ T cells. We will test this possibility in experimental arthritis and examine ICBP90 inhibition in high-genotypic MIF expressing human cells obtained from peripheral blood and from rheumatoid synovial tissue. The completion of these Aims will provide insight into the pathologic role of a novel, MIF receptor expressing T cell population and the contribution of MIF risk alleles to rheumatoid inflammation. These studies also will accelerate consideration of a precision-based approach for treating RA joint destruction.