Increased susceptibility of decay-accelerating factor deficient mice to anti-glomerular basement membrane glomerulonephritis
Increased susceptibility of decay-accelerating factor deficient mice to anti-glomerular basement membrane glomerulonephritis
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DOI：
10.4049/jimmunol.167.5.2791
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发表时间：
2001-09-01
影响因子：
4.4
通讯作者：
Song, WC
中科院分区：
文献类型：
--
作者：
Sogabe, H;Nangaku, M;Song, WC
为了防止补体介导的自体组织损伤，宿主细胞表达许多膜结合补体抑制剂。衰变加速因子（Decay-accelerating factor，CD 55）是一种GPI连接的膜补体调节因子，广泛表达于哺乳动物的肾脏等组织中。它抑制经典和旁路途径的C3转化酶。虽然β-淀粉样蛋白缺乏导致人类血液学综合征阵发性睡眠性血红蛋白尿，但β-淀粉样蛋白在自身免疫性组织损伤如免疫性肾小球肾炎中的相关性仍有待确定。在这项研究中，我们已经调查了基因敲除小鼠，缺乏GPI锚定蛋白肾毒性血清肾炎的易感性。注射亚致肾炎剂量的兔抗小鼠肾小球基底膜血清可在β-内酰胺酶基因敲除小鼠中诱导肾小球疾病，但在野生型对照组中不诱导。当在抗肾小球基底膜治疗后8天进行检查时，β 2受体敲除小鼠的患病肾小球百分比比野生型小鼠高得多（68.8 +/-25.0vs10.0 +/-3.5%; p < 0.01）。从形态学上看，β-淀粉样蛋白基因敲除小鼠的肾小球体积增加（516 +/- 68 vs 325 +/- 18 × 103 μ m/3/肾小球; p < 0.0001），细胞构成增加（47.1 +/- 8.9 vs 32.0 +/- 3.1个细胞/肾小球; p < 0.01）。尽管两组之间的血尿素氮水平没有差异，但在基因敲除小鼠中观察到蛋白尿，而在野生型小鼠中未观察到蛋白尿（1.4 +/- 0.7 vs 0.02 +/- 0.01 mg/24 h白蛋白排泄）。敲除小鼠肾脏的形态和功能异常与肾小球中补体激活增加的证据相关。这些结果支持了这样的结论，膜C3转化酶抑制剂，如C3转化酶抑制剂在体内补体介导的免疫肾小球损伤中发挥保护作用。
To prevent complement-mediated autologous tissue damage, host cells express a number of membrane-bound complement inhibitors. Decay-accelerating factor (DAF, CD55) is a GPI-linked membrane complement regulator that is widely expressed in mammalian tissues including the kidney. DAF inhibits the C3 convertase of both the classical and alternative pathways. Although DAF deficiency contributes to the human hematological syndrome paroxysmal nocturnal hemoglobinuria, the relevance of DAF in autoimmune tissue damage such as immune glomerulonephritis remains to be determined. In this study, we have investigated the susceptibility of knockout mice that are deficient in GPI-anchored DAF to nephrotoxic serum nephritis. Injection of a sub-nephritogenic dose of rabbit anti-mouse glomerular basement membrane serum induced glomerular disease in DAF knockout mice but not in wild-type controls. When examined at 8 days after anti-glomerular basement membrane treatment, DAF knockout mice had a much higher percentage of diseased glomeruli than wild-type mice (68.8 +/- 25.0 vs 10.0 +/- 3.5%; p < 0.01). Morphologically, DAF knockout mice displayed increased glomerular volume (516 +/- 68 vs 325 +/- 18 X 10(3) mum(3) per glomerulus; p < 0.0001) and cellularity (47.1 +/- 8.9 vs 32.0 +/- 3.1 cells per glomerulus; p < 0.01). Although the blood urea nitrogen level showed no difference between the two groups, proteinuria was observed in the knockout mice but not in the wild-type mice (1.4 +/- 0.7 vs 0.02 +/- 0.01 mg/24 h albumin excretion). The morphological and functional abnormalities in the knockout mouse kidney were associated with evidence of increased complement activation in the glomeruli. These results support the conclusion that membrane C3 convertase inhibitors like DAF play a protective role in complement-mediated immune glomerular damage in vivo.