Increased Goodpasture antigen-binding protein expression induces type IV collagen disorganization and deposit of immunoglobulin A in glomerular basement membrane
Increased Goodpasture antigen-binding protein expression induces type IV collagen disorganization and deposit of immunoglobulin A in glomerular basement membrane
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DOI：
10.2353/ajpath.2007.070205
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发表时间：
2007-11-01
影响因子：
6
通讯作者：
Saus, Juan
中科院分区：
文献类型：
--
作者：
Revert, Fernando;Merino, Ramon;Saus, Juan
Good及ure抗原结合蛋白(GPBP)是一种结合和磷酸化基底膜胶原的蛋白，其表达增加与免疫复合物介导的发病机制有关。然而，最近的报道对这一生物学功能提出了质疑，并提出GPBP作为胞浆神经酰胺转运体(CERTL)。因此，GPBP在体内的作用尚不清楚。新西兰白(NZW)小鼠被认为是健康的动物，尽管它们具有免疫复合体介导的肾小球肾炎的遗传易感性。在这里，我们发现NZW小鼠出现了年龄依赖性的狼疮倾向自身免疫反应和免疫复合体介导的肾小球肾炎，其特征是GPBP升高，肾小球基底膜(GBM)胶原结构紊乱和扩张，以及破坏的GBM上IgA沉积。转基因过表达人GPBP(HGPBP)在非狼疮易感小鼠体内引发了类似的肾小球异常，包括在没有明显自身免疫反应的情况下，毛细血管基底膜上沉积了IgA。我们提供的体内证据表明，GPBP调节GBM的胶原组织，其高表达导致IgA在GBM上的解离和随后的积聚。最后，我们描述了一种以前未知的致病机制，它可能与人类初级免疫复合体介导的肾小球肾炎有关。
increased expression of Goodpasture antigen-binding protein (GPBP), a protein that binds and phosphorylates basement membrane collagen, has been associated with immune complex-mediated pathogenesis. However, recent reports have questioned this biological function and proposed that GPBP serves as a cytosolic ceramide transporter (CERTL). Thus, the role of GPBP in vivo remains unknown. New Zealand White (NZW) mice are considered healthy animals although they convey a genetic predisposition for immune complex-mediated glomerulonephritis. Here we show that NZW mice developed age-dependent lupus-prone autoimmune response and immune complex-mediated glomerulonephritis characterized by elevated GPBP, glomerular basement membrane (GBM) collagen disorganization and expansion, and deposits of IgA on disrupted GBM. Transgenic overexpression of human GPBP (hGPBP) in non-lupusprone mice triggered similar glomerular abnormalities including deposits of IgA on a capillary GBM that underwent dissociation, in the absence of an evident autoimmune response. We provide in vivo evidence that GPBP regulates GBM collagen organization and its elevated expression causes dissociation and subsequent accumulation of IgA on the GBM. Finally, we describe a previously unrecognized pathogenic mechanism that may be relevant in human primary immune complex-mediated glomerulonephritis.