Investigating Immunoglobulin CSR as a Novel Therapeutic Target for SLE

 描述（由申请人提供）：系统性红斑狼疮（SLE）是一种严重的系统性自身免疫性疾病，其特征是免疫耐受性丧失，导致自身抗体和免疫复合物的产生，最终导致潜在的致命性器官损伤。自身反应性B淋巴细胞是这种异常免疫反应的中心，产生大量的致病性自身抗体。这是几十年来FDA批准的第一种直接靶向和消耗B淋巴细胞治疗SLE的药物，使这种方法具有吸引力，并阻止了进一步的探索。B淋巴细胞经历类别转换重组（CSR）和体细胞超突变的独特过程，在此期间发生永久性DNA变化。这些变化是由于双链DNA断裂，由分子AID引发，随后通过同源重组修复。利用这些遗传修饰，B淋巴细胞能够改变它们产生的抗体种类，以更有效地响应病原体入侵。在SLE中，B淋巴细胞积极进行AIDS启动的CSR以产生致病性自身抗体。我们的实验室最近观察到AID在BXSB.Yaa小鼠中上调，BXSB.Yaa小鼠可以说是人类SLE最相关的动物模型。在这些小鼠中产生的大多数致病性抗体来源于经历了CSR的B淋巴细胞。由于CSR对B淋巴细胞是独特的，因此该过程的治疗靶向将提供仅消除产生病原性抗体的活化的B淋巴细胞的直接方法。本项目的目的是研究BXSB.Yaa SLE小鼠模型中治疗干预的新研究策略，这些策略可用于未来旨在改善SLE患者治疗方法的转化研究。我们推测，艾滋病介导的CSR在SLE的发病机制中起着重要作用，这一过程可以有针对性的治疗干预。为了验证我们的假设，我们提出了两个目标。目的1：检测Aicda（编码AID的基因）的基因缺失是否消除BXSB.Yaa小鼠中SLE样疾病的发病机制。我们预期SLE进展将在这些小鼠中减弱，从而验证了该途径的治疗干预靶向。目标二：在BXSB.Yaa小鼠中测试预防AIDS诱导的DNA损伤修复的新型治疗剂的施用是否抑制SLE样疾病进展。一种治疗选择是阻断艾滋病诱导的DNA断裂的修复，这已被证明会导致B淋巴细胞死亡。将用DNA断裂修复的小分子抑制剂DIDS和C- 1523-1a处理小鼠，并监测疾病进展。这些化合物是目前作为白血病和淋巴瘤的潜在治疗药物进行测试的一类药物的成员。本研究的结果有望提供结论性证据，证明CSR在SLE的发病机制中起着关键作用，并可作为治疗干预的潜在靶点。这种方法在SLE中的成功将是自身免疫性疾病治疗的新方法，并将为治疗探索提供未来的途径。

 DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a severe systemic autoimmune disease characterized by a loss of immune tolerance which results in the production of autoantibodies and immune complexes, and culminating in potentially fatal organ damage. Autoreactive B lymphocytes are at the center of this aberrant immune response, producing copious amounts of pathogenic autoantibodies. The first FDA drug in decades approved for the treatment of SLE directly targets and depletes B lymphocytes, making this approach appealing and warranting further exploration. B lymphocytes undergo the unique processes of class switch recombination (CSR) and somatic hypermutation, during which permanent DNA changes occur. These changes are due to double-stranded DNA breaks that are initiated by the molecule, AID, and subsequently repaired through homologous recombination. Using these genetic modifications, B lymphocytes are able to change the class of antibody they produce to more effectively respond to pathogenic invasion. In SLE, B lymphocytes actively undergo AID-initiated CSR to produce pathogenic autoantibodies. Our laboratory recently observed that AID is upregulated in the BXSB.Yaa mouse, which is arguably the most relevant animal model for human SLE. Most pathogenic antibodies produced in these mice originate from B-lymphocytes having undergone CSR. Since CSR is unique to B lymphocytes, therapeutic targeting of this process would provide a directed approach to eliminating only activated B lymphocytes producing pathogenic antibodies. The objective of this project is to investigate novel research strategies of therapeutic intervention in the BXSB.Yaa SLE mouse model that could be used in future translational studies aimed at improved therapeutic approaches for SLE patients. We hypothesize that AID-mediated CSR plays an important role in the pathogenesis of SLE, and that this process can be targeted for therapeutic intervention. To test our hypothesis, we propose two aims. Aim 1: Test if genetic deletion of Aicda (the gene encoding AID) abrogates the pathogenesis of SLE-like disease in the BXSB.Yaa mouse. We anticipate that SLE progression will be attenuated in these mice validating the targeting of this pathway for therapeutic intervention. Aim 2: Test whether administrations of novel therapeutic agents that prevent the repair of AID-induced DNA damage inhibit SLE-like disease progression in BXSB.Yaa mice. One therapeutic option is blocking the repair of AID-induced DNA breaks, which has been shown to result in B lymphocyte death. Mice will be treated with the small molecule inhibitors of DNA break repair, DIDS and C- 1523-1a, and monitored for disease progression. These compounds are members of a class of drugs currently being tested as a potential therapeutic for leukemia and lymphoma. The results of this study are expected to provide conclusive evidence that CSR plays a critical role in the pathogenesis of SLE and serves as a potential target for therapeutic intervention. Success of this approach in SLE would be novel for autoimmune disease therapy and would present future avenues for therapeutic exploration.