Experimentally-induced anti-myeloperoxidase vasculitis does not require properdin, MASP-2 or bone marrow-derived C5.
Experimentally-induced anti-myeloperoxidase vasculitis does not require properdin, MASP-2 or bone marrow-derived C5.
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DOI：
10.1002/path.4754
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发表时间：
2016-09
期刊：
影响因子：
--
通讯作者：
Robson MG
中科院分区：
文献类型：
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作者：
Freeley SJ;Popat RJ;Parmar K;Kolev M;Hunt BJ;Stover CM;Schwaeble W;Kemper C;Robson MG
抗中性粒细胞胞浆抗体血管炎是一种以肾小球肾炎和肺出血为主要临床表现的系统性自身免疫性疾病。该名称反映了髓过氧化物酶和蛋白酶-3自身抗体的存在，其结合中性粒细胞和单核细胞。这些自身抗体致病性的证据是通过观察到向小鼠注射抗髓过氧化物酶抗体可引起免疫力不足的局灶节段性坏死性肾小球肾炎提供的，这在组织学上与患者肾活检中观察到的变化相似。先前在该模型中的研究涉及补体激活的替代途径和过敏毒素C5 a。尽管取得了这一进展，启动补体激活的因素尚未确定。此外，骨髓来源和循环C5的相对重要性尚不清楚。考虑到最近确定的白细胞内补体的作用，这是令人感兴趣的。我们在小鼠中诱导抗髓过氧化物酶血管炎，并通过证明C3缺陷小鼠的保护作用证实了补体激活的作用。我们发现MASP-2和备解素缺陷小鼠均未受到保护，表明旁路途径激活不需要备解素或凝集素途径。我们在骨髓嵌合体小鼠中诱导疾病，发现疾病需要循环而不是骨髓来源的C5。因此，我们已经排除了备解素和凝集素途径作为补体激活的启动子，这意味着未来的工作应该针对病变组织内的其他潜在因素。此外，鉴于我们发现循环而非骨髓来源的C5介导疾病，减少肝脏C5分泌的疗法可被视为靶向C5和C5 a的替代疗法。© 2016作者。病理学杂志由John Wiley & Sons Ltd代表大不列颠和爱尔兰病理学会出版。
Anti‐neutrophil cytoplasmic antibody vasculitis is a systemic autoimmune disease with glomerulonephritis and pulmonary haemorrhage as major clinical manifestations. The name reflects the presence of autoantibodies to myeloperoxidase and proteinase‐3, which bind to both neutrophils and monocytes. Evidence of the pathogenicity of these autoantibodies is provided by the observation that injection of anti‐myeloperoxidase antibodies into mice causes a pauci‐immune focal segmental necrotizing glomerulonephritis which is histologically similar to the changes seen on renal biopsy in patients. Previous studies in this model have implicated the alternative pathway of complement activation and the anaphylatoxin C5a. Despite this progress, the factors that initiate complement activation have not been defined. In addition, the relative importance of bone marrow‐derived and circulating C5 is not known. This is of interest given the recently identified roles for complement within leukocytes. We induced anti‐myeloperoxidase vasculitis in mice and confirmed a role for complement activation by demonstrating protection in C3‐deficient mice. We showed that neither MASP‐2‐ nor properdin‐deficient mice were protected, suggesting that alternative pathway activation does not require properdin or the lectin pathway. We induced disease in bone marrow chimaeric mice and found that circulating and not bone marrow‐derived C5 was required for disease. We have therefore excluded properdin and the lectin pathway as initiators of complement activation and this means that future work should be directed at other potential factors within diseased tissue. In addition, in view of our finding that circulating and not bone marrow‐derived C5 mediates disease, therapies that decrease hepatic C5 secretion may be considered as an alternative to those that target C5 and C5a. © 2016 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.