Experimental Induction of SLE by Altered Ia

B细胞耐受性的丧失是SLE自身免疫发病机制的核心。在……里面 为了探讨这一过程中涉及的机制，我们利用了慢性移植物 与移植MHC II类血型不合的bm12脾的SLE宿主模型的比较 细胞或纯化的CD4脾T细胞给C57BL/6小鼠，利用不同的受体 转基因变种。这一系统使我们能够详细地调查损失的机理 B细胞耐受性是SLE的特征。我们之前在这个项目上的工作和我们的 最近的初步数据确定了我们正在提出的几个令人兴奋的方向 在当前的应用程序中继续进行。我们将解决以下问题：为什么SLE 用单抗使B细胞抵抗耗竭？受体编辑和 等位基因包涵体在B细胞耐受性丧失中起作用？CD4T细胞如何调控 B细胞的个体发育，这样它们才能对同种异体反应的T细胞产生反应？什么是 自身抗体形成细胞的表型和分布，以及这与 临床疾病？我们将继续这项工作，具体有四个目标：(1)什么是 B细胞耗竭作为SLE潜在治疗方法的机制？(2)在什么情况下 个体发育：B细胞会失去耐受性吗？(3)CD4T细胞如何影响机体的个体发育 B细胞？(4)在系统性红斑狼疮中发现的自身抗体形成细胞在哪里，特别是关于 肾脏？ 更好地了解B细胞在系统性自身免疫中的作用 B细胞耗尽的治疗效果将允许更有效地使用现有的B细胞 靶向治疗，如利妥昔单抗，以及更合理的新B- 细胞疗法或多种疗法的组合。新的生物标记物很可能需要 被确定为允许合理监测B细胞定向治疗和 适当选择可能有反应的患者。该项目将使用一种复杂的自身免疫性疾病的实验小鼠模型 系统性红斑狼疮。这些研究将特别调查其中一项的作用 参与这种疾病的关键细胞：B淋巴细胞。所获得的知识将 提高对系统性红斑狼疮发病机制的认识 我们如何在治疗中靶向B淋巴细胞。

The loss of B-cell tolerance is central to the pathogenesis of autoimmunity in SLE. In order probe the mechanisms involved in this process, we have utilized the chronic graft versus host model of SLE in which we transfer MHC class II-incompatible bm12 spleen cells or purified CD4 splenic T cells to C57BL/6 mice, utilizing various recipient transgenic variants. This system allows us to investigate in detail the mechanism of loss of B-cell tolerance that characterizes SLE. Our previous work on this project and our recent preliminary data have identified several exciting directions that we are proposing to pursue in the current application. We will address questions such as: Why does SLE make B cells resistant to depletion with mAb? What role does does receptor editing and allelelic inclusion play in the loss of B cell tolerance? How do CD4 T cells control the ontogeny of B cells, so that they can respond to alloreactive T cells? What is the phenotype and distribution of autoantibody forming cells, and how does that relate to clinical disease? We will continue this work with four specific aims: (1) What are the mechanisms of B-cell depletion as a potential therapy for SLE? (2) At what point in ontogeny can B cells lose tolerance? (3) How do CD4 T-cells influence the ontogeny of B cells? (4) Where are autoantibody forming cells found in SLE, particularly as regards the kidneys? The better understanding of the role of B cells in systemic autoimmunity and the therapeutic effects of B-cell depletion will permit the more efficient use of exisitent B-cell targeted therapies, such as rituximab, and the more rationale development of newer B- cell therapies or combinations of therapies. It is likely that new biomarkers will need to be identified to allow the rational monitoring of B-cell directed therapies and the appropriate selection of patients who are likely to respond. This project will use an experimental mouse model of the complex autoimmune disease systemic lupus erythematosus. The studies will particularly investigate the role of one of the key cells involved in this disorder: the B lymphocyte. The knowledge gained will improve of our understanding of the pathogenesis of systemic lupus erythematosus and how we can target the B lymphocytes in treatment.