The alloantigenic sites of α3α4α5(IV) collagen
The alloantigenic sites of α3α4α5(IV) collagen
复制标题
DOI：
10.1074/jbc.m611892200
复制
发表时间：
2007-04-06
影响因子：
4.8
通讯作者：
Borza, Dorin-Bogdan
中科院分区：
文献类型：
--
作者：
Kang, Jeong Suk;Kashtan, Clifford E.;Borza, Dorin-Bogdan
抗肾小球基底膜（GBM）抗体肾炎是由对α 3 α 4 α 5（IV）胶原的NC 1结构域的自身免疫或同种免疫反应引起的。一些X连锁Alport综合征（XLAS）患者发生移植后肾炎，由肾移植物中存在但患者组织中不存在的针对胶原IV链的致病性抗GBM同种抗体介导。在这项工作中，这些患者的同种抗体靶向的表位进行了鉴定和表征。所有XLAS同种抗体识别α 5（IV）胶原蛋白的NC 1结构域中的构象表位，其使用在哺乳动物细胞中表达的嵌合α 1/α 5 NC 1结构域绘制。同种异体移植物洗脱的同种抗体主要靶向定位于α 5 NC 1残基1-45和114-168的两个构象同种异体表位。这些区域还包括循环XLAS同种抗体的主要表位，其在一些患者中另外靶向α 5 NC 1残基169-229。与靶向隔离的α 3 NC 1表位的抗GBM自身抗体不同，肾洗脱和循环的α 5 NC 1同种抗体都特异性靶向人GBM的α 3 α 4 α 5 NC 1六聚体中可接近的表位。结果确定了两个免疫显性α 5 NC 1表位作为α 3 α 4 α 5（IV）胶原蛋白的主要同种抗原位点，特别是与XLAS患者移植后肾炎的发病机制有关。这些同种抗原表位的可及性和自身抗原表位的隐蔽性之间的对比表明，不同分子形式的抗原可能在两种形式的抗GBM疾病中启动免疫病理过程。
Anti-glomerular basement membrane (GBM) antibody nephritis is caused by an autoimmune or alloimmune reaction to the NC1 domains of alpha 3 alpha 4 alpha 5(IV) collagen. Some patients with X-linked Alport syndrome (XLAS) develop post-transplant nephritis mediated by pathogenic anti-GBM alloantibodies to collagen IV chains present in the renal allograft but absent from the tissues of the patient. In this work, the epitopes targeted by alloantibodies from these patients were identified and characterized. All XLAS alloantibodies recognized conformational epitopes in the NC1 domain of alpha 5(IV) collagen, which were mapped using chimeric alpha 1/alpha 5NC1 domains expressed in mammalian cells. Allograft-eluted alloantibodies mainly targeted two conformational alloepitopes mapping to alpha 5NC1 residues 1-45 and 114-168. These regions also encompassed the major epitopes of circulating XLAS alloantibodies, which in some patients additionally targeted alpha 5NC1 residues 169-229. Both kidney-eluted and circulating alloantibodies to alpha 5NC1 distinctively targeted epitopes accessible in the alpha 3 alpha 4 alpha 5NC1 hexamers of human GBM, unlike anti-GBM autoantibodies, which targeted sequestered alpha 3NC1 epitopes. The results identify two immunodominant alpha 5NC1 epitopes as major alloantigenic sites of alpha 3 alpha 4 alpha 5(IV) collagen specifically implicated in the pathogenesis of post-transplant nephritis in XLAS patients. The contrast between the accessibility of these alloepitopes and the crypticity of autoepitopes indicates that distinct molecular forms of antigen may initiate the immunopathogenic processes in the two forms of anti-GBM disease.