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，其特征是产生 抗广谱自身抗原的自身抗体，尤其是来自细胞核的。遗传 易感性是人类和动物对SLE易感性的重要因素。基因 多种途径参与介导疾病的发病机制，以及这些途径之间的上位性相互作用。 基因影响疾病的严重程度。一组基因的产物在细胞内活跃， 体内废物处理机制的生理途径，包括参与清除的基因 循环免疫复合物和凋亡细胞的单核吞噬细胞系统。第二 组编码调节T和B淋巴细胞耐受和活化阈值的基因。 该项目是互动PPG的一部分，旨在解决突变的总体假设， 在7个SLAM家族基因中的一个或多个中，影响有助于对自身抗原耐受的途径 在人类和老鼠身上。总的来说，我们在人类和小鼠身上的观察强烈支持 这 具体而言，我们将： 目标1.检验SLAM家族基因座{CD 244 <->Ly 108}控制CD 4 T细胞和抗原的假设 C57 BL/6小鼠中的呈递细胞功能。 目的2.验证{CD 244 <->Ly 108}基因组间隔缺失导致耐受性丧失的假设 在C57 BL/6小鼠中， 目的3.验证来源于129 Sv小鼠的SLAM家族基因是否与129 Sv小鼠的发育有关。 在引入到{CD 244 <->Ly 108}-/-C57 BL/6小鼠中后， 总之，这些实验应该澄清APC，T和B细胞之间的相互作用， 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 提出了可应用于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.