Proximal Determinants of Nephritogenic Autoimmunity

描述（由申请人提供）：自身免疫性肾炎是全球慢性肾脏疾病和肾衰竭的主要原因，也是同种异体移植物损伤和丢失的主要来源。然而，现有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有很大的希望，但这些新的机制为基础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致肾炎淋巴细胞的耐受机制，重点是自身抗体和B细胞。一个总体假设是，在维持肾脏限制性和全身性自身免疫耐受性的过程中存在共性。目的1使用靶向Goodpasture抗原的新型抗体（IG）转基因（Tg）模型来测试以下假设：i）识别胶原蛋白上的致病性表位的B细胞在体内受到调节; ii）α 3（IV）NC 1胶原蛋白是耐受原，以及iii）抗α 3（IV）NC 1 B细胞的子集容易逃避或逃避耐受。将在转基因和信息突变体回交品系中测量免疫表型。目的2将确定遗传性自身免疫易感性在改变嗜肾性B细胞命运中的作用。这一目的测试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LamH IG Tg具有良好的耐受性表型特征，已经建立了狼疮易感菌株MRL，NZB和BXSB，其中每一个携带一个独特的疾病易感基因的星座，并发展严重的肾炎类似于人类的疾病。免疫表型将在这些和相关的BWF 1 Tg菌株进行测量和比较。半乳糖凝集素1和3的调节作用，突出的蛋白质，最近才确定为B细胞耐受性的修饰剂，将确定使用遗传半乳糖凝集素缺乏。最后，将通过探测现有阵列数据库来探索关键调控分子或途径与人类自身免疫的相关性，所述关键调控分子或途径由寡阵列确定以维持B6或狼疮MRL小鼠中的B细胞无反应性。可以预见，对致肾炎自身免疫调节机制的深入了解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%的人群，并且当在肾脏中表现为肾小球肾炎时，构成慢性肾脏疾病的主要原因和全球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%，其中超过8%最终失去复发性疾病。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更新的疾病特异性治疗的潜在目标。

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.