T cells in Lupus

导致耐受性普遍破坏和器官病理学的多种机制， 患有系统性红斑狼疮（SLE）的患者挑战了基础免疫学家 和翻译研究人员。感染仍然是发病的主要原因之一， 尽管我们的诊断能力显著提高， 及早有效地治疗感染。 对SLE患者T细胞中表达的基因的研究表明，CD38与SLE患者的T细胞中表达的基因相关。 疾病更严重，基因表达更广泛异常。CD8 + CD38 + T细胞为 发现在SLE患者中扩大，并与感染增加密切相关 rates. CD8 + CD38+细胞显示出受损的细胞毒活性，烟酰胺的量较少 腺嘌呤二核苷酸（NAD+），减少糖酵解和氧化磷酸化， 降低负责细胞毒性细胞功能的分子的表达。 此外，CD38的抑制似乎恢复了细胞毒性细胞功能的各个方面。 将指导拟议研究的假设是： SLE患者和狼疮易感小鼠中的CD8+细胞降低了其细胞毒活性， 容易感染并引发自身免疫。三组使用人类细胞的实验 并且将使用新的小鼠来测试该假设。第一个将确定CD38 表达限制了CD8细胞中的细胞毒性。第二个阶段将探讨如何加强 SLE CD8+细胞的细胞毒性应答，包括靶向递送药物至T细胞。然而， 在第三部分，我们将进行一项前瞻性研究，以确定CD38表达的价值， 识别易感染的SLE患者。 系统性红斑狼疮患者CD8 + CD38 + T细胞亚群的鉴定及免疫调节作用 CD38在限制其细胞毒活性方面沿着新小鼠的设计代表了新的 狼疮领域的概念。寻找恢复其细胞毒活性的方法， 临床研究将其定义为SLE患者易感染的生物标志物， 这一研究方向的转化价值

The multitude of mechanisms that lead to general break of tolerance and organ pathology in patients with systemic lupus erythematosus (SLE) have challenged both basic immunologists and translational researchers. Infections remain one of the main causes of morbidity and mortality among patients with SLE despite our significantly improved ability to diagnose and treat infections early and efficiently. Search for genes expressed in T cells from patients with SLE revealed CD38 to be associated with more severe disease and extensive aberrant gene expression. CD8+CD38+ T cells were found expanded in patients with SLE and to be strongly associated with increased infection rates. CD8+CD38+ cells display compromised cytotoxic activity, less amounts of nicotinamide adenine dinucleotide (NAD+), decreased glycolysis and oxidative phosphorylation and decreased expression of molecules responsible for the performance of cytotoxic cell function. In addition, inhibition of CD38 appeared to restore aspects of cytotoxic cell function. The hypothesis which will guide the proposed studies is: increased expression of CD38 on CD8+ cells in patients with SLE and lupus-prone mice compromises their cytotoxic activity and predisposes to infections and drives autoimmunity. Three sets of experiments using human cells and novel mice will be conducted to test the hypothesis. The first will determine how CD38 expression limits cytotoxicity in CD8 cells. The second will explore approaches to enhance cytotoxic responses of SLE CD8+ cells including targeted delivery of drugs to T cells. Whereas, in the third we will conduct a pilot prospective study to determine the value of CD38 expression in identifying patients with SLE prone to infections. The identification of the CD8+CD38+ T cell subset to be expanded in SLE patients and role of CD38 in limiting their cytotoxic activity along with the design of new mice represent novel concepts in the field of lupus. The search for approaches to restore their cytotoxic activity and the clinical study to define them as a biomarker for SLE patients prone to infections represent the translational value of this line of research.