Role of CD48:CD244 Pathway in Systemic Lupus Erythematosus

K08奖的主要目标是研究SLAM家族成员CD48和CD244在小鼠和人系统性红斑狼疮（SLE）中的作用。K08奖将由T细胞共刺激和耐受性领域的专家Arlene Sharpe博士指导。我们的初步数据表明CD244和CD48参与调节耐受性和自身免疫。C57BL/6 CD244缺陷（-/-）小鼠和C57BL6 × 129 CD48-/-小鼠均表现为狼疮的特征。拟议的研究将验证CD48:CD244相互作用调节免疫激活和耐受性之间平衡的假设。我们的具体目标是：1。研究CD244在介导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-/-小鼠与y连锁自身免疫促进位点（Yaa）杂交时，产生的品系发生增殖性肾小球肾炎，与不发生肾脏疾病的Yaa小鼠明显相反。CD244-/-小鼠也表现出调节性T细胞的改变。Aim1A将阐明CD244在调节性T细胞发育和功能中的作用。Aim1B将利用BCR转基因小鼠解剖CD244在B细胞耐受中的作用。2. 表征CD48缺陷小鼠的适应性免疫反应，并评估CD48如何在SLE小鼠模型中促进自身免疫。尽管C57BL6 x 129 CD48-/-小鼠自发地产生活化的T细胞和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号染色体上包含CD48基因的129间隔和可能介导耐受性丧失的C57BL/6基因之间的可能的epistatic相互作用而变得复杂。在这里，我将使用我们最近生成的CD48缺陷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是否。CD48-/-小鼠发生slea样疾病。3. 验证SLAM家族成员失调在人类SLE中起作用的假设。我将研究SLAM家族成员CD48、CD58、CD244在SLE患者中的表达水平。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George Tsokos博士合作进行，他是我的临床导师和K08科学咨询委员会成员。在这个项目中，我计划在人类免疫学、自身免疫小鼠模型和分子生物学领域获得新的技能。我的长期目标是结合我在基础科学和儿科风湿病学方面的背景，成为一名学术医师科学家和独立研究者，研究自身免疫失调的机制，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.