Role of CD48:CD244 Pathway in Systemic Lupus Erythematosus

项目概述本K08奖的主要目的是研究SLAM家族成员CD48和CD244在小鼠和人类系统性红斑狼疮(SLE)中的作用。K08奖将由T细胞共刺激和耐受领域的专家Arlene Sharpe博士指导。我们的初步数据表明CD244和CD48在调节耐受和自身免疫中起作用。C57BL/6 CD244缺陷(-/-)小鼠和C57BL6 x 129 CD48-/-小鼠均表现为狼疮。拟议的研究将检验CD48：CD244相互作用调节免疫激活和耐受之间的平衡的假设。研究CD244在T细胞和B细胞耐受中的作用。CD244-/-小鼠自发产生自身抗体。当CD244-/-小鼠被培育到Y连锁自身免疫加速器基因座(YAA)时，所产生的菌株患上了增殖性肾小球肾炎，这与没有发生肾脏疾病的YAA小鼠形成了鲜明的对比。CD244-/-小鼠也表现出调节性T细胞的变化。Aim1A将阐明CD244在调节性T细胞发育和功能中的作用。目的研究CD244在BCR转基因小鼠B细胞耐受中的作用。2.鉴定CD48基因缺陷小鼠的获得性免疫反应，并评估CD48在系统性红斑狼疮小鼠模型中的自身免疫作用。尽管C57BL6x129 CD48-/-小鼠自发地产生活化的T和B细胞、抗DNA抗体和肾小球肾炎，但这种表型的解释由于小鼠1号染色体上129个区间(包含CD48基因)和C57BL/6基因之间可能的上位性相互作用而变得复杂，C57BL/6基因可能介导了耐受性的丧失。在这里，我将使用我们最近培育的CD48缺陷的C57BL/6小鼠来研究CD48在调节T和B细胞反应中的作用，并确定B6.CD48-/-小鼠是否会患上类SLE疾病。3.验证SLAM家族成员调节失调在人类系统性红斑狼疮发病中的作用这一假说。研究SLE患者SLAM家族成员CD48、CD58、CD244的表达水平。将尝试将表达水平与细胞因子的产生联系起来。这些研究将与乔治·托科斯博士合作进行，他是我的K08科学咨询委员会的临床导师和成员。在这项提议中，我计划在人类免疫学、自身免疫的小鼠模型和分子生物学领域获得新的技能。我的长期目标是将我在基础科学和儿科风湿学方面的背景结合起来，成为一名学术内科科学家和独立研究员，研究自身免疫中免疫失调的机制，并将这些发现转化为新的治疗方法。

DESCRIPTION (provided by applicant): Project Summary The main goal of this K08 Award is to investigate the roles of the SLAM family members CD48 and CD244 in murine and human Systemic Lupus Erythematosus (SLE). The K08 Award will be mentored by Dr. Arlene Sharpe, an expert in the field of T cell costimulation and tolerance. Our preliminary data implicate CD244 and CD48 in regulating tolerance and autoimmunity. C57BL/6 CD244 deficient (-/-) mice and C57BL6 x 129 CD48-/- mice both develop features of lupus. The proposed studies will test the hypothesis that CD48:CD244 interactions regulate the balance between immune activation and tolerance. Our specific aims are: 1. Study the role of CD244 in mediating T cell and B cell tolerance. CD244-/- mice spontaneously develop autoantibodies. When CD244-/- mice were bred to the Y-linked autoimmune accelerator locus (Yaa), the resulting strain developed proliferative glomerulonephritis, in marked contrast to Yaa mice that do not develop renal disease. CD244-/- mice also exhibit alterations in regulatory T cells. Aim1A will elucidate the role of CD244 in regulatory T cell development and function. Aim1B will dissect the role of CD244 in B cell tolerance using BCR transgenic mice. 2. Characterize the adaptive immune response in CD48-deficient mice and assess how CD48 contributes to autoimmunity in a murine model of SLE. Although C57BL6 x 129 CD48-/- mice spontaneously develop activated T and B cells, anti- DNA antibodies and glomerulonephritis, the interpretation of this phenotype is complicated by possible epistatic interactions between 129 interval on mouse chromosome 1, which encompasses the CD48 gene, and C57BL/6 genes which could have mediated the loss of tolerance. Here, I will use our recently generated CD48-deficient C57BL/6 mice to investigate the roles of CD48 in regulating T and B cell responses, and determine whether B6.CD48-/- mice develop SLE-like disease. 3. Test the hypothesis that dysregulation of SLAM family member's plays a role in human SLE. I will study the expression level of SLAM family members CD48, CD58, and CD244 in patient with SLE. Attempts will be made to correlate expression levels with cytokine production. These studies will be performed in collaboration with Dr. George Tsokos, a clinical mentor and member of my K08 scientific advisory committee. In this proposal, I plan to acquire new skills in the areas of human immunology, mouse models of autoimmunity and molecular biology. My long term goal is to combine my background in basic science and pediatric rheumatology to be an academic physician-scientist and independent investigator, studying mechanisms of immune dysregulation in autoimmunity and translating these findings to new therapies.