Investigating Immunoglobulin CSR as a Novel Therapeutic Target for SLE

 描述(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，导致产生自身抗体和免疫复合体，最终导致潜在的致命器官损害。自身反应性B淋巴细胞是这种异常免疫反应的中心，产生大量的致病自身抗体。FDA几十年来批准的第一种治疗SLE的药物直接靶向并耗尽B淋巴细胞，使这种方法具有吸引力，值得进一步探索。B淋巴细胞经历了独特的类开关重组(CSR)和体细胞高突变过程，在此过程中会发生永久性的DNA变化。这些变化是由AID分子引发的双链DNA断裂引起的，随后通过同源重组修复。使用这些基因修饰，B淋巴细胞能够改变它们产生的抗体类别，以更有效地应对病原体入侵。在系统性红斑狼疮中，B淋巴细胞主动接受艾滋病引发的CSR，以产生致病的自身抗体。我们的实验室最近观察到AID在BXSB.Yaa小鼠中上调，BXSB.Yaa小鼠可以说是与人类SLE最相关的动物模型。这些小鼠产生的大多数致病抗体来自经历过CSR的B淋巴细胞。由于CSR是B淋巴细胞所特有的，这一过程的治疗性靶向将提供一种直接的方法来消除仅产生致病抗体的激活的B淋巴细胞。本项目的目的是探索在BXSB.Yaa SLE小鼠模型中进行治疗干预的新研究策略，该策略可用于未来旨在改进SLE患者治疗方法的转译研究。我们假设AID介导的CSR在SLE的发病机制中起重要作用，这一过程可以作为治疗干预的靶点。为了检验我们的假设，我们提出了两个目标。目的1：检测Aicda(编码AID的基因)基因缺失是否能消除BXSB.Yaa小鼠SLE样病的发病机制。我们预计，在这些小鼠中，SLE的进展将会减弱，从而验证了这一途径的靶向性，以进行治疗干预。目的2：检测新型治疗药物对AID诱导的DNA损伤的修复是否能抑制BXSB.Yaa小鼠SLE样疾病的进展。一种治疗选择是阻断AID诱导的DNA断裂的修复，这已被证明会导致B淋巴细胞死亡。小鼠将接受DNA断裂修复小分子抑制剂DIDS和C-1523-1a的治疗，并监测疾病进展。这些化合物是一类药物的成员，目前正在测试其对白血病和淋巴瘤的潜在治疗作用。这项研究的结果有望提供确凿的证据，证明CSR在SLE的发病机制中发挥关键作用，并成为治疗干预的潜在靶点。这种方法在系统性红斑狼疮中的成功将是自身免疫性疾病治疗的新方法，并将为未来的治疗探索提供途径。

 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.