Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice.
Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice.
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DOI：
10.1172/jci15918
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发表时间：
2002-10
期刊：
影响因子：
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通讯作者：
Hong Xiao;P. Heeringa;P. Hu;Zhi Liu;Minglang Zhao;Y. Aratani;N. Maeda;R. Falk;J. Jennette
中科院分区：
文献类型：
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作者：
Hong Xiao;P. Heeringa;P. Hu;Zhi Liu;Minglang Zhao;Y. Aratani;N. Maeda;R. Falk;J. Jennette
抗中性粒细胞胞浆自身抗体（ANCAs）在大约80%的少免疫坏死性和新月性肾小球肾炎和系统性小血管炎（如显微镜下的多血管炎和韦格纳肉芽肿病）患者的血液循环中被发现。ANCAs最常见的抗原靶点是髓过氧化物酶（MPO），它存在于中性粒细胞和单核细胞中。我们报告了明确的实验动物证据，证明anca是致病性的。用小鼠MPO免疫MPO敲除（-/-）小鼠。将这些小鼠或对照小鼠的脾细胞静脉注射到缺乏功能性B淋巴细胞和T淋巴细胞的重组酶激活基因2缺陷（Rag2(-/-)）小鼠中。所有接受脾细胞治疗的小鼠均出现轻度至中度肾小球免疫沉积，但只有接受1 × 10(8)或5 × 10(7)抗mpo脾细胞治疗的小鼠出现严重坏死性和新月形肾小球肾炎、肉芽肿性炎症和系统性坏死性血管炎，包括坏死性动脉炎和出血性肺毛细血管炎。为了检测抗体单独的致病性，将纯化的抗mpo IgG或对照IgG静脉注射Rag2（-/-）小鼠和野生型小鼠。注射抗mpo IgG而不注射对照IgG的小鼠出现局灶性坏死性和新月形肾小球肾炎，肾小球Ig沉积缺乏。因此，在Rag2（-/-）小鼠和野生型C57BL/6J小鼠中，抗mpo IgG单独能够在缺乏功能性T淋巴细胞或B淋巴细胞的情况下引起缺乏免疫的肾小球坏死和新月形成。该动物模型有力地支持了ANCA IgG在人肾小球肾炎和血管炎中的直接致病作用。
Antineutrophil cytoplasmic autoantibodies (ANCAs) are identified in the circulation of approximately 80% of patients with pauci-immune necrotizing and crescentic glomerulonephritis and systemic small vessel vasculitis, such as microscopic polyangiitis and Wegener granulomatosis. The most common antigen target for ANCAs is myeloperoxidase (MPO), which is found in neutrophils and monocytes. We report definitive experimental animal evidence that ANCAs are pathogenic. MPO knockout (Mpo(-/-)) mice were immunized with mouse MPO. Splenocytes from these mice or from control mice were injected intravenously into recombinase-activating gene-2-deficient (Rag2(-/-)) mice, which lack functioning B lymphocytes and T lymphocytes. All mice that received splenocytes developed mild to moderate glomerular immune deposits, but only mice that received 1 x 10(8) or 5 x 10(7) anti-MPO splenocytes developed severe necrotizing and crescentic glomerulonephritis, granulomatous inflammation, and systemic necrotizing vasculitis, including necrotizing arteritis and hemorrhagic pulmonary capillaritis. To test the pathogenic potential of antibodies alone, purified anti-MPO IgG or control IgG was injected intravenously into Rag2(-/-) mice and wild-type mice. Mice that received anti-MPO IgG but not mice that received control IgG developed focal necrotizing and crescentic glomerulonephritis with a paucity of glomerular Ig deposition. Thus, anti-MPO IgG alone was able to cause pauci-immune glomerular necrosis and crescent formation in the absence of functional T or B lymphocytes in Rag2(-/-) mice and in the presence of an intact immune system in wild-type C57BL/6J mice. This animal model offers strong support for a direct pathogenic role for ANCA IgG in human glomerulonephritis and vasculitis.