Proximal Determinants of Nephritogenic Autoimmunity

自身免疫是大多数肾小球肾炎的前驱，肾小球肾炎是终末期肾病的最常见原因。 全球范围内的疾病。然而，对病因学的初步了解迫使依赖于非特异性毒性 免疫抑制治疗我们开发了IG转基因（Tg）小鼠，该小鼠携带B细胞， 致肾炎抗原（Ag）作为工具来剖析控制体液自身免疫的机制， 肾我们推测：a）B细胞与结构多样的与肾损伤相关的自身抗原反应， 由不同的机制调节; B）维持B细胞增殖的分子途径存在差异 自身免疫与非自身免疫个体以及个体间对致肾炎抗原的耐受性 携带不同的易感基因星座;以及，c）在以下方面存在根本差异： 调节B细胞，促进系统性与器官限制性疾病中的肾炎。这预示着， 在不同的自身免疫性肾炎中，不同的调节机制被破坏。我们将使用IG Tg模型 本研究的主要目的是：1）确定缺失和无反应性在调节B细胞中的作用 与基底膜反应，这是人类自身免疫性肾炎中唯一确认的靶点。细胞命运将 使用抗层粘连蛋白LamH/LamL和双特异性LamH/VSR“单克隆”H+L IG Ig与Ag特异性连接 通过灭活Rag或内源性IG基因消除了间接调节影响的Tg小鼠。 2)剖析B细胞耐受性遗传修饰的分子基础。微阵列将用于监测 并分析来自自身免疫性MRL和非MRL的受体刺激的耐受性Tg细胞中的转录谱。 易感B6小鼠揭示中枢调节通路。LamH Tg，具有明确的公差 表型，也将建立在肾炎倾向（NZBxNZW）F1和BXSB菌株，以确定是否有一个 单一Ag-受体相互作用在遗传上不同的疾病易感宿主中是差异性致耐受性的。 3)确定并比较肾反应性238 H IG和抗α 3（IV）NC 1胶原Tg B细胞的命运 与肾炎相关的系统性与肾限制性自身免疫。这将评估 核酸交叉反应性和Ag螯合的贡献，已知影响免疫的因素 沉积，调节致肾炎B细胞。总的来说，这些研究将确定调控途径 作为免疫性肾病的定制药物干预的靶点。

Autoimmunity is the antecedent to most glomerulonephritis, the most common cause of end stage renal disease worldwide. Yet rudimentary understanding of etiology compels reliance on non-specific toxic immunosuppressive therapy. We developed Ig transgenic (Tg) mice bearing B cells reactive with nephritogenic antigens (Ag) as tools to dissect mechanisms controlling humoral autoimmunity that destroys kidney. We postulate that: a) B cells reactive with structurally diverse self-Ag relevant to renal injury are regulated by diverse mechanisms; b) There are differences in molecular pathways maintaining B cell tolerance to nephritogenic Ag in autoimmune vs nonautoimmune individuals, and between individuals bearing different constellations of susceptibility genes; and, c) There are fundamental differences in regulation of B cells that promote nephritis in systemic versus organ-restricted disease. This predicts that different regulatory mechanisms are breached in different autoimmune nephritides. We will use Ig Tg models to pursue the following Specific Aims: 1) Determine the role of deletion and anergy in regulating B cells reactive with basement membrane, the only confirmed target in human autoimmune nephritis. Cell fate will be linked to Ag specificity using anti-laminin LamH/LamL and duat specific LamH/VSR "monoclonal" H+L Ig Tg mice in which collateral regulatory influences are eliminated by inactivated Rag or endogenous Ig genes. 2) Dissect the molecular basis of genetic modification of B cell tolerance. Microarray will be used to monitor and analyze transcriptional profiles in receptor-stimulated tolerant Tg cells from autoimmune MRL and non- susceptible B6 mice to reveal central regulatory pathways. The LamH Tg, with a well defined tolerance phenotype, will also be established on nephritis-prone (NZBxNZW)F1 and BXSB strains to determine if a single Ag-receptor interaction is differentially tolerogenic in genetically disparate disease-susceptible hosts. 3) Determine and compare the fate of kidney-reactive 238H Ig and anti-alpha3(IV) NC1 collagen Tg B cells associated with nephritis in systemic versus renal-limited autoimmunity, respectively. This will assess contributions of nucleic acid crossreactivity and Ag sequestration, factors known to impact immune deposition, to regulation of nephritogenic B cells. Collectively these studies will identify regulatory pathways to be targeted for tailored pharmacologic intervention in immunologic renal disease.