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.
Aim1 A will elucidate the role of CD244 in regulatory T cell development and function.
Aim1 B 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.
The studies in this application should provide a greater understanding of the mechanisms contributing to SLE by analyzing a costimulatory pathway recently implicated in SLE pathogenesis. Results will hopefully elucidate general mechanisms of immune dysregulation, allowing more rational design of therapeutics applicable to SLE and other autoimmune diseases.