Proximal Determinants of Nephritogenic Autoimmunity

免疫性肾炎折磨自体肾和移植肾，是慢性肾功能衰竭的主要原因。 疾病系统性红斑狼疮患者中有高达74%会发生肾炎， 自身炎症性疾病的衰弱。对疾病发病机制的见解正在出现， 人类和小鼠狼疮的补充研究，尽管快速进展受到阻碍， 这种疾病广泛的临床异质性和遗传复杂性。该提案使用新的 在过去的五年中开发了一个模型系统，用于跟踪体内离散的自身免疫细胞群。 狼疮易感基因的不同星座的背景。广泛的初步研究表明， 四种典型的狼疮毒株NZB、BWF 1、BXSB和MRL/lpr中的每一种都被修饰以表达 相同的肾炎相关受体，显示出独特的耐受表型。这个目标 这项提案的目的是剖析破坏肾脏的自身免疫调节的分子机制。这 这一努力依赖于尖端但经过验证的技术和跨学科合作。具体 目的1将使用体外和体内方法来鉴定改变的细胞和分子基础。 NZB是一种发展血液学和肾脏疾病的菌株， 暴发性肾炎的主要易感位点。具体目标2将使用现有的子区间同源性 和基因组定位，以确定功能性遗传变异， 表型。具体目标3将剖析改变耐受性的细胞、分子和遗传基础 在加速性狼疮性肾炎的情况下，包括确定独特的基础 BXSB中过度增殖和边缘带样表型。总的来说，这些菌株模拟了 人类狼疮的遗传异质性，他们的研究最终应该提供对调控的洞察力。 和适用于患者的疾病机制。

Immune nephritis afflicts both native and transplanted kidneys and is a leading cause of chronic renal disease. Nephritis occurs in up to 74% of patients with systemic lupus erythematosus, one of the most debilitating of the autoinflammatory diseases. Insights into disease pathogenesis are emerging from the complementary study of human and mouse lupus, although rapid progress has been hindered by the extensive clinical heterogeneity and genetic complexity of this disease. This proposal uses a new model system developed over the past five years to track discrete autoimmune cell populations within the context of distinct constellations of lupus susceptibility genes. Extensive preliminary studies reveal that each of the four classic lupus strains, NZB, BWF1, BXSB, and MRL/lpr, modified to express the identical nephritis-associated receptor, displays a unique tolerance phenotype. The goal of this proposal is to dissect the molecular mechanisms regulating autoimmunity that destroys kidneys. This effort relies on cutting edge but validated technologies and cross-disciplinary collaboration. Specific Aim 1 will use in vitro and in vivo approaches to identify the cellular and molecular basis of altered tolerance revealed in NZB, a strain that develops hematologic and renal disease and contributes major susceptibility loci to fulminant nephritis. Specific Aim 2 will use existing subinterval congenics and genome mapping to localize functional genetic variants that determine the defective tolerance phenotype. Specific Aim 3 will dissect the cellular, molecular, and genetic basis of altered tolerance in the setting of accelerated lupus nephritis, including determining the basis of the unique hyperproliferation and marginal zone-like phenotype in BXSB. Collectively, these strains model the genetic heterogeneity of human lupus, and their study should ultimately provide insight into regulatory and disease mechanisms applicable to patients.