Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system.
Anti-proteinase 3 anti-neutrophil cytoplasm autoantibodies recapitulate systemic vasculitis in mice with a humanized immune system.
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DOI：
10.1371/journal.pone.0028626
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Duffield JS
中科院分区：
文献类型：
--
作者：
Little MA;Al-Ani B;Ren S;Al-Nuaimi H;Leite M Jr;Alpers CE;Savage CO;Duffield JS
人类抗蛋白酶-3 （PR3）抗体在系统性血管炎和多血管炎肉芽肿病（GPA，韦格纳肉芽肿病）发生中的直接致病性缺乏证据。由于鼠中性粒细胞缺乏PR3的表达，以及不同种类的fc受体对IgG的亲和力不同，这些抗体在啮齿动物中的研究进展受到阻碍。因此，我们测试了人类抗pr3抗体是否能在具有人类免疫系统的小鼠中诱导急性血管炎。嵌合小鼠是通过将人造血干细胞注射到辐照的NOD-scid-IL2Rγ−/−小鼠体内生成的。用抗pr3阳性肾、肺血管炎患者的人IgG治疗配对嵌合体小鼠；非血管性肾病患者；或者健康对照。6天后，39%的抗pr3治疗小鼠出现血尿，而对照组没有。抗pr3治疗动物肺表面出现点状出血，组织学表现为血管炎和出血。抗pr3治疗小鼠出现轻度的少免疫增殖性肾小球肾炎，伴人和小鼠白细胞浸润。3只小鼠（17%）肾小球损伤较严重。对照组未见肾小球改变。因此，来自抗pr3自身抗体患者的人IgG具有致病性。这种抗pr3抗体介导的血管炎模型可能有助于解剖微血管损伤的机制。
Evidence is lacking for direct pathogenicity of human anti-proteinase-3 (PR3) antibodies in development of systemic vasculitis and granulomatosis with polyangiitis (GPA, Wegener's granulomatosis). Progress in study of these antibodies in rodents has been hampered by lack of PR3 expression on murine neutrophils, and by different Fc-receptor affinities for IgG across species. Therefore, we tested whether human anti-PR3 antibodies can induce acute vasculitis in mice with a human immune system. Chimeric mice were generated by injecting human haematopoietic stem cells into irradiated NOD-scid-IL2Rγ−/− mice. Matched chimera mice were treated with human IgG from patients with: anti-PR3 positive renal and lung vasculitis; patients with non-vasculitic renal disease; or healthy controls. Six-days later, 39% of anti-PR3 treated mice had haematuria, compared with none of controls. There was punctate bleeding on the surface of lungs of anti-PR3 treated animals, with histological evidence of vasculitis and haemorrhage. Anti-PR3 treated mice had mild pauci-immune proliferative glomerulonephritis, with infiltration of human and mouse leukocytes. In 3 mice (17%) more severe glomerular injury was present. There were no glomerular changes in controls. Human IgG from patients with anti-PR3 autoantibodies is therefore pathogenic. This model of anti-PR3 antibody-mediated vasculitis may be useful in dissecting mechanisms of microvascular injury.
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