Department of Internal Medicine, University Hospital Hamburg, Hamburg, Germany,
J Immunol. 2011 Sep 15;187(6):3218-29. doi: 10.4049/jimmunol.1003451. Epub 2011 Aug 15.
Subepithelial immune complex deposition in glomerular disease causes local inflammation and proteinuria by podocyte disruption. A rat model of membranous nephropathy, the passive Heymann nephritis, suggests that Abs against specific podocyte Ags cause subepithelial deposit formation and podocyte foot process disruption. In this study, we present a mouse model in which a polyclonal sheep anti-mouse podocyte Ab caused subepithelial immune complex formation. Mice developed a nephrotic syndrome with severe edema, proteinuria, hypoalbuminemia, and elevated cholesterol and triglycerides. Development of proteinuria was biphasic: an initial protein loss was followed by a second massive increase of protein loss beginning at approximately day 10. By histology, podocytes were swollen. Electron microscopy revealed 60-80% podocyte foot process effacement and subepithelial deposits, but no disruption of the glomerular basement membrane. Nephrin and synaptopodin staining was severely disrupted, and podocyte number was reduced in anti-podocyte serum-treated mice, indicating severe podocyte damage. Immunohistochemistry detected the injected anti-podocyte Ab exclusively along the glomerular filtration barrier. Immunoelectron microscopy localized the Ab to podocyte foot processes and the glomerular basement membrane. Similarly, immunohistochemistry localized mouse IgG to the subepithelial space. The third complement component (C3) was detected in a linear staining pattern along the glomerular basement membrane and in the mesangial hinge region. However, C3-deficient mice were not protected from podocyte damage, indicating a complement-independent mechanism. Twenty proteins were identified as possible Ags to the sheep anti-podocyte serum by mass spectrometry. Together, these data establish a reproducible model of immune-mediated podocyte injury in mice with subepithelial immune complex formation.
在肾小球疾病中，上皮下免疫复合物沉积通过破坏足细胞引起局部炎症和蛋白尿。膜性肾病的大鼠模型，即被动性 Heymann 肾炎，提示针对特定足细胞抗原的抗体导致上皮下沉积物形成和足细胞足突破坏。在这项研究中，我们提出了一种小鼠模型，其中多克隆绵羊抗小鼠足细胞抗体导致上皮下免疫复合物形成。小鼠发生肾病综合征，伴有严重水肿、蛋白尿、低白蛋白血症以及胆固醇和甘油三酯升高。蛋白尿的发生呈双相性：最初的蛋白丢失后，大约第 10 天开始出现第二次大量蛋白丢失。组织学检查显示足细胞肿胀。电子显微镜显示 60-80%的足细胞足突消失和上皮下沉积物，但肾小球基底膜没有破坏。nephrin 和 synaptopodin 染色严重受损，抗足细胞血清处理的小鼠中足细胞数量减少，表明足细胞严重受损。免疫组织化学检测到注射的抗足细胞抗体仅沿着肾小球滤过屏障存在。免疫电镜将抗体定位于足细胞足突和肾小球基底膜。同样，免疫组织化学将小鼠 IgG 定位于上皮下间隙。补体成分 3 (C3) 沿肾小球基底膜和系膜铰链区呈线性染色模式被检测到。然而，C3 缺陷小鼠未免受足细胞损伤的保护，表明存在补体非依赖性机制。通过质谱鉴定了 20 种可能作为绵羊抗足细胞血清的抗原。总之，这些数据在小鼠中建立了一种可重现的上皮下免疫复合物形成的免疫介导的足细胞损伤模型。
