University of Pennsylvania, Philadelphia, PA, USA.
Am J Nephrol. 2009;30(5):474-80. doi: 10.1159/000242476. Epub 2009 Sep 28.
BACKGROUND/AIMS: Patients with anti-glomerular basement membrane diseases produce pathogenic autoantibodies (autoAb) that deposit in the kidney and initiate severe inflammation. Restricted antigenic specificity of the autoAb against 2 regions (with related sequences) within alpha3(IV)NC1, along with shared idiotypes (i.e. structural determinants), among pathogenic human autoAb suggested that common genetic elements encode the autoAb. The aim of this study was to determine whether the idiotypic relatedness of the autoAb was due to the fact that unique and similar genes were used to encode them, divergent genes were used to produce Ab with similar Ag-binding properties and conformation, or if other mechanisms were operative.
The encoding V gene sequences of pathogenic human anti-alpha3(IV)NC1 Ab, derived following immunization of XenoMice which produce human but not murine IgG, with alpha3(IV)NC1 were determined. Predicted conformations of autoAb-alpha3(IV)NC1 interactions were derived using the Ab sequences and molecularmodels of the alpha3(IV)NC1 structure.
The pathogenic Ab were encoded by multiple, common V(H) and V(L) gene families indicating that they were not encoded by a unique subset of genes and that normal individuals have the capacity to produce them. However, modeling of the Ag-Ab interactions suggested that although the contact regions varied for individual Ab, the optimized energy constraints facilitate interaction of both Ab-binding regions with pathogenically relevant epitopes on alpha3(IV)NC1.
The results suggest that the repetitive nature and relatedness of the alpha3(IV)NC1 antigenic epitopes facilitate cross-linking of pathogenic Ab, in vivo, by allowing both IgG Fab to bind to the basement membrane. This most likely accounts for the high-affinity Ab binding we and others observed among human anti-alpha3(IV)NC1 Ab. Based on these observations, we postulate that this interaction provides for the stability of the Ab interaction, resulting in a high-affinity interaction that serves as an ideal scaffold for optimal FcR engagement and complement activation, thereby accelerating inflammation and contributing to the rapidly progressive nature of this disease.
背景/目的：患有抗肾小球基底膜疾病的患者会产生致病性自身抗体 (autoAb)，这些抗体在肾脏中沉积并引发严重的炎症。致病性人类自身抗体针对 α3(IV)NC1 内的 2 个区域（具有相关序列）具有有限的抗原特异性，以及共享的独特型（即结构决定簇），这表明共同的遗传元件编码自身抗体。本研究的目的是确定自身抗体的独特型相关性是否是由于以下原因：独特且相似的基因用于编码它们，不同的基因用于产生具有相似抗原结合特性和构象的抗体，或者是否存在其他机制在起作用。
使用 XenoMice （可产生人类而非鼠类 IgG）免疫α3(IV)NC1 后，确定了致病性人类抗 α3(IV)NC1 Ab 的编码 V 基因序列。使用 Ab 序列和 α3(IV)NC1 结构的分子模型，推导了自身抗体-α3(IV)NC1 相互作用的预测构象。
致病性 Ab 由多个常见的 V(H)和 V(L)基因家族编码，这表明它们不是由独特的基因子集编码的，并且正常个体有能力产生它们。然而，对 Ag-Ab 相互作用的建模表明，尽管单个 Ab 的接触区域不同，但优化的能量约束有利于 Ab 结合区域与 α3(IV)NC1 上的致病性相关表位相互作用。
这些结果表明，α3(IV)NC1 抗原表位的重复性和相关性通过允许 IgG Fab 与基底膜结合，促进了致病性 Ab 的体内交联。这很可能解释了我们和其他人观察到的人类抗 α3(IV)NC1 Ab 之间的高亲和力 Ab 结合。基于这些观察，我们假设这种相互作用提供了 Ab 相互作用的稳定性，导致高亲和力相互作用，作为最佳 FcR 结合和补体激活的理想支架，从而加速炎症并导致这种疾病的快速进展性质。
