Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo
Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo
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DOI：
10.1182/blood-2004-01-0267
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发表时间：
2004-09-01
期刊：
影响因子：
20.3
通讯作者：
Jenne, DE
中科院分区：
文献类型：
--
作者：
Pfister, H;Ollert, M;Jenne, DE
抗中性粒细胞胞质自身抗体（ANCA）识别中性粒细胞颗粒的人蛋白酶3是韦格纳肉芽肿病的诊断标志，韦格纳肉芽肿病是一种自身免疫性系统性血管炎，好发于呼吸道和肾脏。体外实验表明ANCA可能导致组织损伤的几种机制。然而，对蛋白酶3特异性抗体在体内的致病意义知之甚少。ANCA介导的促炎作用的体内模型尚未出现，主要是因为人蛋白酶3上的ANCA表位不被鼠同源物共享。在这项研究中，我们在蛋白酶3/中性粒细胞弹性蛋白酶缺陷小鼠中产生了针对重组鼠蛋白酶3的ANCA，所述蛋白酶3/中性粒细胞弹性蛋白酶缺陷小鼠识别中性粒细胞表面上的鼠抗原。皮内注射肿瘤坏死因子α诱导的局部炎症在被动转移的全身性蛋白酶3-ANCA的存在下比在模拟免疫血清的存在下引发更强的皮下脂膜炎。当我们将小鼠蛋白酶3-ANCA血清转移到全身性脂多糖致敏的野生型小鼠中时，用蛋白酶3-ANCA处理的小鼠与相应的模拟免疫血清处理的动物相比没有出现显著更强的肺部或肾脏炎症体征。总之，我们的体内研究提供了蛋白酶3特异性ANCA在局部炎症部位致病作用的第一个证据。(C)2004年，美国血液学会。
Antineutrophil cytoplasmic autoantibodies (ANCAs) recognizing human proteinase 3 of neutrophil granules are a diagnostic hallmark of Wegener granulomatosis, an autoimmune systemic vasculitis with predilection for the respiratory tract and kidneys. In vitro experiments have implicated several mechanisms by which ANCAs may lead to tissue injury. However, little is known about the pathogenic significance of proteinase 3-specific antibodies in vivo. In vivo models for ANCA-mediated proinflammatory effects have not been forthcoming, primarily because ANCA epitopes on human proteinase 3 are not shared by the murine homolog. in this study we generated ANCAs against recombinant murine proteinase 3 in proteinase 3/neutrophil elastase-deficient mice that recognized the murine antigen on the surface of neutrophils. Local inflammation induced by intradermal injection of tumor necrosis factor alpha triggered a stronger subcutaneous panniculitis in the presence of passively transferred systemic proteinase 3-ANCAs than in the presence of mock immune serum. When we transferred mouse proteinase 3-ANCA serum to systemically lipopolysaccharide-primed wild-type mice, mice treated with proteinase 3-ANCAs did not develop significantly stronger signs of inflammation of the lungs or kidneys than the respective mock immune serum-treated animals. In conclusion, our in vivo study provides the first evidence for a pathogenic effect of proteinase 3-specific ANCAs at local sites of inflammation. (C) 2004 by The American Society of Hematology.