Novel Receptor-Ligand Interactions in Glomerulonephritis

描述(申请人提供)：抗肾小球基底膜肾炎，是一种典型的自身免疫性肾炎，其肾脏靶抗原特征良好，是发现人类肾脏疾病发病机制的关键系统。肾脏致病表位位于肾小球基底膜内的α3(IV)Nc1胶原上。最近令人信服的发现表明，在疾病发病机制中存在一种交叉反应和先前未被怀疑的额外自身抗原，以及各种抗胶原疾病之间的免疫学联系。这些发现表明自身免疫性疾病调控的显著复杂性，其阐明将为疾病的发病、抑制和阻止提供新的见解。这项建议的目的是确定第二抗原和新的受体-配体相互作用的分子基础，并探讨它们在体内参与人类自身免疫和疾病发病机制。这一努力依赖于尖端但经过验证的技术和跨学科合作。具体目标1将使用最先进的和互补的蛋白质组学方法来鉴定与α3(IV)NC1胶原蛋白相互作用并调节其致病活性的未知第二抗原。特定目标2将使用创新的计算预测模型来确定受体-配体结构，这既是为了进一步了解目标1，也是为了对潜在的环境疾病沉淀物和重叠的自身免疫调节回路提供新的见解。具体目标3将开发一种人源化模型，在人类免疫系统的背景下检查体内的自身免疫反应，使用NOD-SCID-伽马株增强造血细胞的植入。该模型还将产生独特的人类免疫试剂和工具，最终目标是为临床前测试提供一个平台，以验证研究结果并测试体内的免疫调节干预措施。 与公共卫生相关：据估计，自身免疫影响了美国7%的人口，全世界大多数免疫性肾炎都是其基础，免疫性肾炎是影响本地和移植器官的慢性肾脏疾病的主要原因。这项建议考察了从抗GBM肾炎研究中出现的新范式，抗GBM肾炎是一种典型的自身免疫性肾炎，人类肾脏靶抗原α3(IV)NC1胶原具有很好的特征。因此，抗肾小球基底膜肾炎是发现人类肾脏疾病发病机制和免疫调节网络的关键系统。此外，抗GBM自身免疫参与ANCA血管炎的发病，可通过免疫调节性单抗治疗而诱导，并与抗II型胶原自身免疫和类风湿性关节炎具有遗传和免疫学联系。因此，拟议中的研究旨在找到这些疾病的根本原因，预计将具有广泛的临床意义。新的见解和新的工具可以应用于大量的患者群体，以推进新的诊断和治疗方法！

DESCRIPTION (provided by applicant): Anti-GBM nephritis, the prototypic autoimmune nephritis for which the kidney target antigen is well characterized, is a key system for discovery involving human kidney disease pathogenesis. Nephritogenic epitopes reside on alpha3 (IV) NC1 collagen within the glomerular basement membrane. Compelling recent discoveries indicate the existence of a crossreactive and previously unsuspected additional self-antigen involved in disease pathogenesis, as well as immunological links between diverse anti-collagen diseases. These findings indicate remarkable complexity in autoimmune disease regulation, the elucidation of which will provide new insights into disease onset, suppression, and arrest. The goals of this proposal are to identify this second antigen and the molecular basis of novel receptor-ligand interactions, and to explore their engagement in human autoimmunity and disease pathogenesis in vivo. This effort relies on cutting edge but validated technologies and cross-disciplinary collaborations. Specific Aim 1 will use state-of-the- art and complementary proteomics approaches to identify the unknown second antigen that engages and regulates pathogenic reactivity to alpha3(IV)NC1 collagen. Specific Aim 2 will use innovative computational prediction modeling to determine receptor-ligand structure, both to further inform Aim 1 and to provide new insight into potential environmental disease precipitants and overlapping autoimmune regulatory circuits. Specific Aim 3 will develop a humanized model to examine autoimmune responses in vivo in the context of a human immune system, using the NOD-scid-gamma strain for enhanced engraftment of hematopoietic cells. The model will also generate unique human immune reagents and tools, with the ultimate goal of providing a platform for preclinical testing to validate research findings and to test immune modulating interventions in vivo. PUBLIC HEALTH RELEVANCE: Autoimmunity affects an estimated 7% of the U.S. population and worldwide underlies most immune nephritis, a leading cause of chronic kidney disease affecting native and transplanted organs. This proposal examines new paradigms that emerged from the study of anti-GBM nephritis, the prototypic autoimmune nephritis for which the human kidney target antigen, alpha3(IV)NC1 collagen, is well characterized. Anti- GBM nephritis thus is a key system for discovery involving human kidney disease pathogenesis and immune regulatory networks. Moreover, anti-GBM autoimmunity contributes to disease in ANCA vasculitis, can be induced by immune modulating mAb therapies, and shares genetic and immunological links with anti-collagen II autoimmunity and rheumatoid arthritis. Thus the proposed studies, designed to find the root cause of these diseases, are anticipated to have broad clinical relevance. Novel insights and new tools can be applied to a large patient population to advance new diagnostic and therapeutic approaches!