NEPHRITOGENIC EPITOPES IN GOODPASTURES SYNDROME

描述(摘自《研究人员摘要》)：人的肾小球肾炎是导致透析或移植的发病率、死亡率和终末期肾病(ESRD)的主要原因。自身免疫性疾病导致大多数形式的肾小球肾炎。肾小球肾炎的最终表达涉及多种致病因素，包括抗体的沉积和细胞免疫。许多模型已经被广泛研究以阐明致病机制，但最有可能的是由与人类没有直接关系的方法诱导的。这位研究人员开发了一个模型来研究古德帕斯氏综合征的发病机制，这是一种与肾小球基底膜抗体、进行性新月体肾炎和肺出血相关的疾病。他的研究表明，在用负责的抗原免疫后，会产生各种抗体，而且只有这些抗体中的一部分实际上会导致疾病。翻译后修饰可能是致病抗原表达的关键。PI假设构成免疫抗原的氨基酸的转录后修饰影响其引起肾炎的能力。其具体目的是利用生化和分子方法来1)鉴定引起肾小球肾炎的抗原，2)确定是否存在氨基酸的翻译后修饰以及这些修饰可能是什么，以及3)检查这些修饰的交替对疾病诱导和病程的影响。强有力的证据表明，在该模型中导致肾小球肾炎的抗原与导致人类古德帕斯图氏综合征的抗原或位于相同的蛋白质上。该模型为进一步研究自身免疫性肾小球肾炎的发病机制提供了机会，并允许研究在体外无法完成的发病机制。从该模型获得的信息将为更好地了解古德帕斯氏综合征和其他类型的自身免疫性肾小球肾炎提供信息。此外，从这些研究中获得的知识可能为最终开发针对古德帕斯图尔综合征的特定治疗干预措施提供基础。

Description (Adapted from Investigator's Abstract): Glomerulonephritis in man is a major cause of morbidity, mortality and end stage renal disease (ESRD) leading to dialysis or transplantation. Autoimmune disease causes most forms of glomerulonephritis. Multiple pathogenic factors are involved in the final expression of glomerulonephritis including the deposition of antibodies and cell mediated immunity. Numerous models have been extensively studied to clarify pathogenic mechanisms, but most likely are induced by methods not directly relevant to man. This investigator has developed a model to examine the pathogenesis of Goodpasture's syndrome, a disease associated with antibody to the glomerular basement membrane, progressive crescentic glomerulonephritis and pulmonary hemorrhage. His studies suggest that a variety of antibodies develop after immunization with the responsible antigen, and that only a subset of these antibodies actually cause disease. Post-translational modification may be critical for expression of the pathogenic antigen. The PI hypothesizes that post-transcriptional modification of the amino acids constituting the immunizing antigen influences its ability to cause nephritis. The specific aims are to utilize biochemical and molecular methods to 1) identify the antigens which induce the glomerulonephritis, 2) determine if post-translational modification of the amino acids are present and what these modifications might be, and 3) examine the effect of alternation of these modifications on disease induction and course. Strong evidence indicates that the antigen which causes glomerulonephritis in this model is the same antigen or is located on the same protein that causes Goodpasture's syndrome in man. This model provides an opportunity for further study of pathogenic events in autoimmune glomerulonephritis and permits investigations of pathogenesis that cannot be accomplished in vitro. Information derived from this model will provide a better understanding of Goodpasture's syndrome and other types of autoimmune glomerulonephritis. Further, the knowledge resultant from these investigations may provide a basis for the eventual development of specific therapeutic interventions for Goodpasture's syndrome.