Th17 Cells Promote Autoimmune Anti-Myeloperoxidase Glomerulonephritis
Th17 Cells Promote Autoimmune Anti-Myeloperoxidase Glomerulonephritis
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DOI：
10.1681/asn.2009070763
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发表时间：
2010-06-01
影响因子：
13.6
通讯作者：
Holdsworth, Stephen R.
中科院分区：
文献类型：
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作者：
Gan, Poh-Yi;Steinmetz, Oliver M.;Holdsworth, Stephen R.
髓过氧化物酶（MPO）是抗中性粒细胞胞浆抗体相关性血管炎的主要靶抗原。尽管MPO特异性CD 4（+）Th细胞似乎参与了肾损伤，但Th 17亚群的作用尚不清楚。我们假设Th 17细胞在实验性小鼠抗MPO诱导的肾小球肾炎（GN）中直接损伤性抗MPO自身免疫。我们用MPO免疫小鼠以建立自身免疫，导致全身IL-17 A产生和MPO特异性皮肤迟发型超敏反应。我们使用肾小球基底膜抗体通过中性粒细胞诱导MPO在肾小球沉积来引发疾病。野生型小鼠出现坏死性肾小球肾炎伴肾小球白细胞内流和蛋白尿。相反，缺乏关键Th 17效应细胞因子IL-17 A的小鼠几乎完全受到保护。保护作用部分是由于中性粒细胞募集减少，导致肾小球MPO的处置减少。为了测试IL-17 A是否也驱动肾脏中的自身免疫性迟发型超敏反应，我们将MPO注射到MPO致敏小鼠的肾脏中。IL-17 A缺乏减少肾巨噬细胞的积聚和肾CCL 5 mRNA表达。总之，IL-17 A有助于自身免疫性抗MPO GN的病理生理学，表明它可能是这种疾病的可行治疗靶点。
A major target autoantigen in anti-neutrophil cytoplasmic antibody associated vasculitis is myeloperoxidase (MPO). Although MPO-specific CD4(+) Th cells seem to orchestrate renal injury, the role of the Th17 subset is unknown. We hypothesized that Th17 cells direct injurious anti-MPO autoimmunity in experimental murine anti-MPO induced glomerulonephritis (GN). We immunized mice with MPO to establish autoimmunity, resulting in systemic IL-17A production with MPO-specific dermal delayed-type hypersensitivity. We triggered disease using antibodies to the glomerular basement membrane to induce glomerular deposition of MPO by neutrophils. Wild-type mice developed necrotizing GN with an influx of glomerular leukocytes and albuminuria. In contrast, mice deficient in the key Th17 effector cytokine IL-17A were nearly completely protected. The protective effects resulted partly from reduced neutrophil recruitment, which led to less disposition of glomerular MPO. To test whether IL-17A also drives autoimmune delayed-type hypersensitivity in the kidney, we injected MPO into the kidneys of MPO-sensitized mice. IL-17A deficiency reduced accumulation of renal macrophages and renal CCL5 mRNA expression. In conclusion, IL-17A contributes to the pathophysiology of autoimmune anti-MPO GN, suggesting that it may be a viable therapeutic target for this disease.