Couser W G, Spargo B H, Stilmant M M, Lewis E J
Lab Invest. 1975 Jan;32(1):46-55.
Humoral immune processes mediate alterations in glomerular basement membrane (GBM) permeability by two mechanisms. One requires complement and polymorphonuclear leukocytes and the second is complement- and polymorphonuclear leukocyte-independent. The structural basis for enhanced GBM permeability induced by anti-GBM antibody is not clear. Experimental anti-GBM glomerulopathy was induced in guinea pigs by immunization with human GBM in complete Freund's adjuvant. Control animals received injections of complete Freund's adjuvant alone. Light, immunofluorescent, and electron microscopic studies were done on eight heavily proteinuric animals, four immunized nonproteinuric animals, three controls, and two normal animals. All animals that received injections of GBM had intense linear deposits of gamma2 anti-GBM antibody. Complement deposition was not demonstrable in vivo, and anti-GBM antibody deposits did not fix complement in vitro. Histologic abnormalities in proteinuric animals were confined to the GBM, which was of variable density and had a characteristic beaded thickening, with numerous areas of electron lucency most prominent in the outer aspect of GBM in peripheral portions of capillary loops. The inner margin and endothelium were normal. Ultrastructural tracer studies with ferritin demonstrated increased permeability confined to portions of GBM demonstrating ultrastructural lesions. The urine protein excreted by animals with ultrastructural GBM lesions was largely albumin. The absence of complement deposition accompanying anti-GBM antibody deposits in vivo and the unique GBM lesion in this model differ from the findings in nephritis induced by most heterologous nephrotoxic antibodies and suggest that GBM injury in this model is mediated by autologous antibody through complement-independent mechanisms. The selective proteinuria and ultrastructural lesions suggest a derangement in glomerular permeability functionally localized to the epithelial side of the GBM and could reflect an antibody-mediated abnormality in GBM biosynthesis.
体液免疫过程通过两种机制介导肾小球基底膜（GBM）通透性的改变。一种机制需要补体和多形核白细胞参与，另一种则不依赖补体和多形核白细胞。抗GBM抗体诱导GBM通透性增强的结构基础尚不清楚。通过在完全弗氏佐剂中用人GBM免疫豚鼠，诱导实验性抗GBM肾小球病。对照动物仅注射完全弗氏佐剂。对8只重度蛋白尿动物、4只免疫后无蛋白尿动物、3只对照动物和2只正常动物进行了光镜、免疫荧光和电镜研究。所有接受GBM注射的动物均有强烈的γ2抗GBM抗体线性沉积。体内未发现补体沉积，抗GBM抗体沉积物在体外也不固定补体。蛋白尿动物的组织学异常局限于GBM，GBM密度不一，有特征性的串珠样增厚，在毛细血管袢周边部分GBM外侧有许多电子透亮区最为明显。内缘和内皮正常。用铁蛋白进行的超微结构示踪研究表明，通透性增加仅限于显示超微结构病变的GBM部分。有GBM超微结构病变的动物排出的尿蛋白主要是白蛋白。该模型中抗GBM抗体沉积物缺乏补体沉积以及独特的GBM病变与大多数异源性肾毒性抗体诱导的肾炎不同，提示该模型中的GBM损伤是由自身抗体通过不依赖补体的机制介导的。选择性蛋白尿和超微结构病变提示肾小球通透性紊乱在功能上定位于GBM的上皮侧，可能反映了GBM生物合成中抗体介导的异常。
