Experimental Autoimmune Nephritis: Epitope Spreading in Pathogenesis and Control

描述（由申请人提供）：终末期肾脏疾病是美国主要的医疗保健问题，肾小球肾炎是终末期肾脏疾病的第三大原因。大多数肾小球肾炎的病例是自身免疫性的，但病因抗原通常是未知的。在自身免疫性肾小球肾炎Goodpasture病中，病因抗原已知是在肾脏肾小球基底膜中发现的IV型胶原链a3(IV) NC1。尽管确定了这种抗原，但关于发病、疾病进展和控制仍有许多未知之处。我们已经开发了一个模型，实验性自身免疫性肾小球肾炎，它概括了Goodpasture病。我们已经确定了a3(IV) NC1上的免疫显性T细胞表位，并表明抗原会扩散到a3和a4 (IV)NC1上的其他表位，但不会扩散到其他肾小球抗原（分子内和分子间表位扩散）。我们还提供证据表明，肾脏及其引流淋巴结之间的反馈回路可能参与肾脏病肾中出现的表位扩散和调节性T细胞的产生。其他模型表明，表位扩散与免疫反应的扩增和疾病进展有关，并且表位扩散的中断可以改善疾病表达。我们假设表位扩散发生在离散数量的可识别表位上，肾脏闭环环境中效应T细胞和调节性T细胞的募集和局部抗原处理的肾引流淋巴结是疾病诱导和调节的机制，诱导早期调节性T细胞反应可能改善疾病的自然过程。在本研究中，我们将1)鉴定a3（IV）和a3(IV)NC1蛋白上的T细胞免疫显性和亚显性扩散表位，2)研究表位扩散的机制，以及3)评估调节性T细胞在实验性自身免疫性肾小球肾炎的发生和进展中的作用。我们假设局部肾淋巴结反馈回路的中断和调节性T细胞反应的扩增将改善病程并下调疾病表达。由于实验性自身免疫性肾小球肾炎是人类good牧草病的再现，这些信息应该有助于更好地了解其发病机制和可能的人类疾病干预措施。

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.