Identification of a clinically relevant immunodominant region of collagen IV in Goodpasture disease
Identification of a clinically relevant immunodominant region of collagen IV in Goodpasture disease
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DOI：
10.1046/j.1523-1755.1999.055003936.x
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发表时间：
1999-03-01
影响因子：
19.6
通讯作者：
Wieslander, J
中科院分区：
文献类型：
--
作者：
Hellmark, T;Segelmark, M;Wieslander, J
背景Goodpasture病的特征性特征是对肺泡和肾小球基底膜中IV型胶原[α 3（IV）NC 1] α 3链的非胶原结构域发生自身抗体反应。这些抗体与快速进行性肾小球肾炎的发展相关，伴或不伴肺出血，而对异源三聚体IV型胶原蛋白的其他α链特异性的自身抗体可能不会引起疾病。在这项研究中，我们调查了α 3（IV）NC 1自身免疫识别的精细特异性差异是否与临床结果相关。为了定位抗体与IV型胶原的结合，产生嵌合胶原构建体，其中α 3（IV）NC 1结构域的部分被同源非反应性α 1（IV）的相应序列取代。不同的重组胶原嵌合体允许分析77例有良好记录的患者血清中的抗体特异性。一个结构，窝藏的α 3（IV）NC 1的氨基末端的第三个被所有血清识别，表明它代表了在Goodpasture病的B细胞反应的主要目标。70%的样本也识别出了分子的其他部分。然而，只有对α 3（TV）NC 1的N-末端的反应性与预后相关，即，随访6个月后的肾存活率。这些结果表明，抗体识别这个特定的域对于Goodpasture疾病的发病机制至关重要，从而为开发更好的诊断和治疗程序开辟了新的途径。
Background. The characteristic feature of Goodpasture disease is the occurrence of an autoantibody response to the noncollagenous domain of the alpha 3 chain of type IV collagen [alpha 3(IV)NC1] in the alveolar and glomerular basement membrane. These antibodies are associated with the development of a rapidly progressive glomerulonephritis, with or without lung hemorrhage, whereas autoantibodies specific for the other alpha chains of the heterotrimeric type IV collagen probably do not cause disease. In this study, we have investigated whether differences in fine specificity of autoimmune recognition of the alpha 3(IV)NC1 correlate with clinical outcome.Methods. For mapping of antibody binding to type IV collagen, chimeric collagen constructs were generated in which parts of the alpha 3(IV)NC1 domain were replaced by the corresponding sequences of homologous nonreactive alpha 1(IV). The different recombinant collagen chimeras allowed the analysis of antibody specificities in 77 sera from well-documented patients.Results. One construct that harbors the aminoterminal third of the alpha 3(IV)NC1 was recognized by all sera, indicating that it represents the dominant target of the B-cell response in Goodpasture disease. Seventy percent of the samples recognized other parts of the molecule as well. However, only reactivity to the N-terminus of the alpha 3(TV)NC1 correlated with prognosis, that is, kidney survival after six months of follow-up.Conclusion. The results indicate the crucial importance of antibody recognition of this particular domain for the pathogenesis of Goodpasture disease, thereby opening new avenues for the development of better diagnostic and therapeutic procedures.