B cell costimulatory signals in the pathogenesis of SLE

项目摘要 尽管有现代免疫抑制治疗，系统性红斑狼疮（SLE）患者仍处于高水平。 进行性器官损伤的高风险，强调需要更好的，有针对性的治疗这种疾病。 除了产生致病性自身抗体外，最近的研究表明，B细胞可以 通过启动免疫耐受性破坏和促进 自发生发中心（GC）。在这种情况下，不同的共刺激受体家族已被联系在一起， 自身免疫的发病机制然而，尽管有令人信服的SLE临床前数据和临床获益， 在其它自身免疫性疾病中，用CTLA 4-IG（阿巴西普）进行共刺激阻断不能控制 狼疮临床试验这些数据强调了我们对细胞内在机制的理解， B7：CD 28共刺激信号影响狼疮患者自身反应性B细胞活化不完全本课题 将使用充分表征的小鼠狼疮模型和嵌合抗原受体（CAR）T的新应用， 细胞技术来剖析免疫机制的启动，繁殖和细胞输出 SLE中滤泡外（EF）与GC B细胞活化途径。在目标1中，我们将研究是否致病 自身抗体可以通过T细胞依赖性的EF B细胞活化途径产生，但CD 28 独立，方式。在目标2中，我们将测试B细胞共刺激信号是否促进了细胞周期的起始或 维持自身免疫性GC反应。最后，在目标3中，我们将测试另一种共刺激因子是否 受体对，ICOS：ICOS配体，补偿狼疮发病过程中CD 28信号的损失。在一起， 这些研究有望促进我们对狼疮发病机制的理解，并可能为设计 SLE和其他体液自身免疫性疾病中共刺激阻断的未来人类临床试验。

Project abstract Despite modern immunosuppressive therapies, patients with systemic lupus erythematosus (SLE) remain at high risk for progressive organ damage, emphasizing the need for better, targeted treatments for this disease. In addition to the production of pathogenic autoantibodies, recent studies have demonstrated that B cells can promote lupus pathogenesis by initiating immune tolerance breaks and facilitating the generation of spontaneous germinal centers (GC). In this context, distinct costimulatory receptor families have been linked with the pathogenesis of autoimmunity. However, despite compelling preclinical data in SLE and clinical benefit in other autoimmune diseases, costimulatory blockade with CTLA4-Ig (Abatacept) failed to control disease in lupus clinical trials. These data emphasize that our understanding of the cell-intrinsic mechanisms whereby B7:CD28 costimulatory signals impact autoreactive B cell activation in lupus is incomplete. In this project, we will use well-characterized murine lupus models and the novel application of chimeric antigen receptor (CAR) T cell technology to dissect the immune mechanisms underlying the initiation, propagation and cellular output of extra-follicular (EF) vs. GC B cell activation pathways in SLE. In Aim 1, we will study whether pathogenic autoantibodies can be generated via an EF B cell activation pathway in a T cell-dependent, but CD28 independent, manner. In Aim 2, we will test whether B cell costimulatory signals promote the initiation or maintenance of autoimmune GC responses. Finally, in Aim 3, we will test whether another costimulatory receptor pair, ICOS:ICOS ligand, compensates for loss of CD28 signals during lupus pathogenesis. Together, these studies promise to advance our understanding of lupus pathogenesis and may inform the design of future human clinical trials of costimulatory blockade in SLE and other humoral autoimmune diseases.