Experimental Autoimmune Nephritis: Epitope Spreading in Pathogenesis and Control

描述(申请人提供)：终末期肾脏疾病是美国的主要医疗保健问题。肾小球肾炎是终末期肾脏疾病的第三大原因。大多数肾小球肾炎都是自身免疫性肾炎，但病因通常不清楚。在自身免疫性肾小球肾炎古德帕斯病中，已知的病原性抗原是在肾小球基底膜中发现的IV型胶原链A3(IV)Nc1。尽管鉴定出了这种抗原，但关于起始、疾病进展和控制仍有许多未知之处。我们开发了一种实验性自身免疫性肾小球肾炎的模型，它概括了古德帕斯普雷的疾病。我们已经确定了A3(IV)NC1上的免疫优势T细胞表位，并表明该抗原可以扩散到A3和A4(IV)NC1上的其他表位，但不会扩散到额外的肾小球抗原(分子内和分子间表位扩散)。我们还提出证据表明，肾脏和其引流淋巴结之间的反馈环可能参与了表位的扩散和调节性T细胞的产生，这些T细胞出现在肾炎肾脏中。其他模型已经表明，表位扩散与免疫反应的放大和疾病的进展有关，而阻断表位扩散可以改善疾病的表达。我们假设，表位扩散发生在离散数量的可识别表位上，效应和调节性T细胞在肾脏和肾脏引流淋巴结闭环环境中的招募与局部抗原处理是疾病诱导和调节的机制，早期调节性T细胞反应的诱导可能改善疾病的自然进程。在本方案中，我们将1)确定A3(IV)和A3(IV)NC1蛋白上的T细胞免疫优势和亚优势扩散表位，2)研究表位扩散的机制，3)评估调节性T细胞在实验性自身免疫性肾小球肾炎发生和发展中的作用。我们假设，阻断局部肾淋巴结反馈环和放大调节性T细胞反应将改善病程并下调疾病的表达。由于实验性自身免疫性肾小球肾炎重演了人类的古德帕斯病，这些信息应该有助于更好地理解人类疾病的发病机制和可能的干预措施。

DESCRIPTION (provided by applicant): End stage renal disease is a major health care problem in the U.S. Glomerulonephritis is the third leading cause of end stage renal disease. Most cases of glomerulonephritis are of autoimmune origin but the etiologic antigen is usually not known. In the autoimmune glomerulonephritis Goodpasture's disease, the etiologic antigen is known to be a chain of type IV collagen, a3(IV) NC1, found in the glomerular basement membrane of the kidney. Despite identification of this antigen, much remains unknown about initiation, disease progression, and control. We have developed a model, experimental autoimmune glomerulonephritis, which recapitulates Goodpasture's disease. We have identified the immunodominant T cell epitope on a3(IV) NC1 and showed that the antigen causes spreading to other epitopes on a3 and a4 (IV)NC1 but not to additional glomerular antigens, (intra- and intermolecular epitope spreading). We also present evidence that a feedback loop between the kidney and its draining lymph node may be involved in epitope spreading and generation of regulatory T cells which appear in the nephritic kidneys. Other models have shown that epitope spreading is associated with amplification of immune response and disease progression, and that interruption of epitope spreading can ameliorate disease expression. We hypothesize that epitope spreading occurs to a discrete number of identifiable epitopes, that recruitment of effector and regulatory T-cells in the closed-loop environment of the kidney and kidney draining lymph node with local antigen processing are mechanisms of disease induction and regulation, and that induction of an early regulatory T cell response may ameliorate the natural course of the disease. In the present proposal we will 1) identify T cell immunodominant and subdominant spread epitopes on a3(IV) and a3(IV)NC1 proteins, 2) study the mechanisms involved in epitope spreading, and 3) assess the effect of regulatory T cells on the initiation and progression of experimental autoimmune glomerulonephritis. We hypothesize that interruption of the local kidney lymph node feed back loop and amplification of regulatory T cell response will ameliorate the course and down-regulate disease expression. Since experimental autoimmune glomerulonephritis recapitulates Goodpasture's disease in man, the information should lead to a better understanding of the pathogenesis and possible intervention in human disease.