Expanded Double Negative T cells in SLE.

系统性红斑狼疮折磨着1 - 2百万美国人，并与显著的 发病率和死亡率。虽然更明智地使用免疫抑制剂和及时治疗 并发症提高了总体生存率和生活质量，但我们仍然缺乏特效药， 充分了解所涉及的致病过程和有价值的疾病生物标志物。在 此外，我们对参与执行的局部器官特异性机制的理解， 组织损伤有限。扩增的T细胞群体从T细胞中缺失CD 4和CD 8， 系统性狼疮患者外周血中的表面（双阴性T细胞） 红斑，帮助自体B细胞产生免疫球蛋白和dsDNA抗体， 产生促炎性白细胞介素17并侵入组织引起炎症。这 该申请提出了使用包括光谱细胞计数的最新技术， 单细胞RNA测序和一系列新的工程小鼠，以研究 狼疮易感小鼠外周血和肾脏中的双阴性T细胞群， 系统性红斑狼疮患者了解炎症环境 为他们这一代做出贡献。与此同时，提出实验来了解如何 炎性细胞因子作用于肾驻留细胞以使炎症得以建立。 所提出的实验将为开发抑制这种疾病的方法提供信息。 产生致病性双阴性T细胞并阻止组织的建立 炎症

Systemic lupus erythematosus afflicts 1 to 2 million Americans and is associated with significant morbidity and mortality. While wiser use of immunosuppressive drugs and prompt treatment of complications have improved the overall survival and quality of life, we still lack specific drugs, full understanding of the involved pathogenic processes and valuable disease biomarkers. In addition, our understanding of local, organ-specific mechanisms involved in the execution of tissue injury is limited. An expanded population of T cells missing CD4 and CD8 from the surface (double negative T cells) in the peripheral blood of patients with systemic lupus erythematosus, helps autologous B cells to produce immunoglobulin and dsDNA antibodies, produces the proinflammatory interleukin 17 and invades tissues to cause inflammation. This application proposes the use of state-of-the-art new technologies including spectral cytometry, single cell RNA sequencing and series of novel engineered mice to study the diversity of the double negative T cell population in the peripheral blood and kidneys of lupus-prone mice and people with systemic lupus erythematosus and understand how an inflammatory environment contributes to their generation. In parallel, experiments are proposed to understand how inflammatory cytokines act on kidney resident cells to enable the establishment of inflammation. The proposed experiments will inform the development of approaches to suppress the generation of pathogenic double negative T cells and prevent the establishment of tissue inflammation.