Genetic Dissection of the defect in the SLAM-receptor.........

系统性红斑狼疮(SLE)是一种慢性自身免疫性疾病，其特征是 抗多种自身抗原的自身抗体，尤其是来自细胞核的自身抗体。遗传 易感性是人类和动物系统性红斑狼疮易感性的重要因素。中的基因 多种途径参与介导疾病的发病机制，并在这些途径之间上位性的相互作用 基因影响疾病的严重程度。其中一组包括其产物活跃在 体内废物处理机制的生理途径，包括参与清除的基因 单核巨噬细胞系统对循环免疫复合体和凋亡细胞的影响。第二 该组编码调节T和B淋巴细胞耐受和激活阈值的基因。 这个项目是交互式PPG的一部分，该PPG试图解决突变 在七个SLAM家族中的一个或多个中，基因影响对自身抗原耐受的途径 在人类和老鼠身上。总的来说，我们在人类和老鼠身上所做的观察有力地支持了 这 具体来说，我们会： 目的1.验证SLAM家族基因座控制CD4T细胞和抗原的假设 介绍C57BL/6小鼠的细胞功能。 目的2.验证{CD244；-&gt；Ly108}基因组区间缺失会导致耐受性丧失的假设 C57BL/6小鼠对染色质的亲和力。 目的3.验证来自129Sv小鼠的SLAM家族基因对发育有贡献的假设 将狼疮导入{CD244；-&gt；Ly108}-/-C57BL/6小鼠。 总之，这些实验应该澄清APC、T和B细胞之间的相互作用，这些细胞受 SLAM家族基因及其对小鼠狼疮易感性的控制。这些研究的结果应该是 建议可应用于SLE患者的治疗策略。

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies against a wide spectrum of self-antigens, especially from the cell nucleus. Genetic predisposition is an important contributor to susceptibility to SLE in both humans and animals. Genes in multiple pathways participate in mediating disease pathogenesis, and epistatic interactions amongst these genes influence the severity of disease. One group includes genes whose products are active in physiologic pathways of waste disposal mechanisms in the body, and includes genes involved in removal of circulating immune complexes and apoptotic cells by the mononuclear phagocyte system. The second group encodes genes that regulate thresholds for tolerance and activation of T and B lymphocytes. This project is part of an interactive PPG, which seeks to address the overall hypothesis that mutations in one or more of the seven SLAM-family genes affect pathways that contribute to tolerance to selfantigens in humans and mice. Collectively, our observations made in humans and mice strongly support this Specifically we will: Aim 1. test the hypothesis that the SLAM-Family-locus {CD244<->Ly108} governs CD4 T cell and antigen presenting cell functions in the C57BL/6 mouse. Aim 2.test the hypothesis that deletion of the {CD244<->Ly108} genomic interval causes loss of tolerance toward chromatin in C57BL/6 mice. Aim 3.test the hypothesis that SLAM-family genes derived from 129Sv mice contribute to the development of lupus upon introduction into the {CD244<->Ly108}-/- C57BL/6 mouse. Together these experiments should clarify the interplay between APC, T and B cells governed by the SLAM-Family genes and their control of susceptibility to murine lupus. The results of these studies should suggest therapeutic strategies that can be applied to SLE patients.