Proximal Determinants of Nephritogenic Autoimmunity

自身免疫性肾炎是世界范围内慢性肾脏疾病和肾功能衰竭的主要原因，也是同种异体移植损伤和损失的主要来源。然而，可用的治疗方法仅限于非特异性毒性方案。抗原和细胞特异性治疗具有很大的前景，但这些新的基于机制的干预措施的发展需要了解潜在的发病机制。拟议的研究将确定调节肾源性淋巴细胞的耐受性机制，重点是自身抗体和B细胞。一个重要的假设是，在维持肾限制性和全身性自身免疫耐受的过程中存在共性。目的1使用一种针对good牧草抗原的新型抗体（Ig）转基因（Tg）模型来验证以下假设：1)识别胶原蛋白致病表位的B细胞在体内受到调节；ii) α 3(IV)NC1胶原是一种耐受性原，iii)抗α 3(IV)NC1 B细胞的一个亚群容易逃避或逃避耐受性。免疫表型将在转基因和信息突变回交株中测量。目的2将确定遗传自身免疫易感性在改变嗜肾性B细胞命运中的作用。这一目的验证了宿主修饰基因在细胞和分子水平上调节耐受性的假设。这些研究是可能的，因为已经在狼疮易感菌株MRL、NZB和BXSB上建立了具有良好耐受性表型的LamH Ig Tg，每个菌株都携带独特的疾病易感基因群，并发生类似于人类疾病的严重肾炎。免疫表型将测量和比较这些和相关的BWF1 Tg菌株。凝集素1和3的调节作用是最近才被确定为B细胞耐受性调节剂的重要蛋白质，将通过遗传凝集素缺乏来确定。最后，通过探索现有的阵列数据库，探索由寡阵列决定的在B6或狼疮MRL小鼠中维持B细胞能量的关键调控分子或途径与人类自身免疫的相关性。预计对肾源性自身免疫调节机制的深入研究将为免疫性肾炎的治疗提供新的靶点。公共卫生相关性：自身免疫性疾病影响约6%的人口，当表现为肾小球肾炎时，构成慢性肾脏疾病的主要原因，也是世界范围内终末期肾脏疾病的单一最常见原因。肾小球肾炎也占肾移植的50%以上，其中超过8%最终因复发性疾病而损失。我们的研究旨在剖析调节肾脏自身免疫的耐受机制，以及导致疾病的缺陷。这些检查点中的每一个都是针对疾病的新疗法的潜在靶点。

DESCRIPTION (provided by applicant): Autoimmune nephritis is a leading cause of chronic kidney disease and renal failure worldwide and a major source of allograft injury and loss. Yet available therapies are limited to nonspecific toxic regimens. Antigen- and cell-specific therapies hold great promise but development of these novel mechanism-based interventions requires understanding of underlying pathogenesis. The proposed research will determine tolerance mechanisms that regulate nephritogenic lymphocytes with a focus on autoantibodies and B cells. An overarching hypothesis is that commonalities exist in the processes maintaining tolerance in kidney-restricted and systemic autoimmunity. Aim 1 uses a novel antibody (Ig) transgenic (Tg) model that targets the Goodpasture antigen to test the hypotheses that: i) B cells recognizing pathogenic epitopes on collagen are regulated in vivo; ii) alpha3(IV)NC1 collagen is a tolerogen, and iii) a subset of anti-alpha3(IV)NC1 B cells readily evade or escape tolerance. Immune phenotype will be measured in transgenic and informative mutant backcross strains. Aim 2 will determine the role of genetic autoimmune susceptibility in altering the fate of nephrotropic B cells. This aim tests the hypothesis that host modifier genes modulate tolerance at cellular and molecular levels. These studies are possible because the LamH Ig Tg with a well characterized tolerance phenotype has been established on lupus-prone strains MRL, NZB and BXSB, each of which carries a unique constellation of disease susceptibility genes and develops severe nephritis similar to disease in man. Immune phenotype will be measured and compared in these and the related BWF1 Tg strain. The regulatory role of galectins 1 and 3, prominent proteins only recently identified as modifiers of B cell tolerance, will be determined using genetic galectin deficiency. Finally the relevance to human autoimmunity of key regulatory molecules or pathways, determined by oligoarray to maintain B cell anergy in B6 or lupus MRL mice, will be explored through probing existing array databases. It is anticipated that mechanistic insight into regulation of nephritogenic autoimmunity will yield new targets for therapy in immune nephritis. PUBLIC HEALTH RELEVANCE: Autoimmune diseases affect ~6% of the population, and when manifest in the kidney as glomerulonephritis, constitute a leading cause of chronic kidney disease and the single most common cause of end stage renal disease worldwide. Glomerulonephritis also accounts for up to 50% of kidney transplants, over 8% of which are ultimately loss to recurrent disease. Our studies are designed to dissect the tolerance mechanisms that regulate renal autoimmunity, as well as defects that lead to disease. Each of these checkpoints is a potential target for newer more disease specific therapies.