CD8+ T Cells Effect Glomerular Injury in Experimental Anti-Myeloperoxidase GN
CD8+ T Cells Effect Glomerular Injury in Experimental Anti-Myeloperoxidase GN
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DOI：
10.1681/asn.2015121356
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发表时间：
2017-01-01
影响因子：
13.6
通讯作者：
Kitching, A. Richard
中科院分区：
文献类型：
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作者：
Chang, Janet;Eggenhuizen, Peter;Kitching, A. Richard
对ANCA相关性血管炎患者的观察表明，CD 8（+）T细胞参与疾病，但没有这些细胞病理参与的实验功能证据。髓过氧化物酶（MPO）是ANCA相关性血管炎的一种明确的自身抗原。抗MPO GN实验模型的研究表明，ANCA诱导的中性粒细胞定位后，肾小球内沉积的MPO被自身反应性T细胞识别，导致损伤。我们在实验性ANCA相关血管炎中检验了CD 8（+）T细胞介导疾病的假设。疾病效应期CD 8 T细胞耗竭减弱了鼠抗MPO GN的损伤。这种保护作用与肾内IFN-γ、TNF和炎性趋化因子水平降低以及肾小球巨噬细胞减少有关。此外，我们鉴定了致病性CD 8（+）T细胞MPO表位（MP 0431 439），并发现MP 0431 439特异性CD 8 + T细胞克隆的共转移加重了Rag 1（-/-）小鼠中MPO特异性CD 4（+）细胞介导的疾病。MPO 431 - 439特异性CD 8（+）细胞的转移介导了MPO植入肾小球后的肾小球损伤。这些结果显示MPO特异性CD 8（+）T细胞的致病作用，为CD 8（+）细胞是ANCA相关血管炎的治疗靶点提供了证据，并提示MPO分子内的分子热点含有重要的CD 8、CD 4（+）和B细胞表位。
Observations in patients with ANCA-associated vasculitis suggest that CD8(+) T cells participate in disease, but there is no experimental functional evidence of pathologic involvement for these cells. Myeloperoxidase (MPO) is a well defined autoantigen in ANCA-associated vasculitis. Studies in experimental models of anti-MPO GN suggest that, after ANCA-induced neutrophil localization, deposited MPO within glomeruli is recognized by autoreactive T cells that contribute to injury. We tested the hypothesis that CD8(+) T cells mediate disease in experimental ANCA-associated vasculitis. CD8 T cell depletion in the effector phase of disease attenuated injury in murine anti-MPO GN. This protection associated with decreased levels of intrarenal IFN-gamma, TNF, and inflammatory chemokines and fewer glomerular macrophages. Moreover, we identified a pathogenic CD8(+) T cell MPO epitope (MP0431 439) and found that cotransfer of MP0431_439-specific CD8+ T cell clones exacerbated disease mediated by MPO-specific CD4(+) cells in Rag1(-/-) mice. Transfer of MPO431_439-specific CD8(+) cells without CD4(+) cells mediated glomerular injury when MPO was planted in glomeruli. These results show a pathogenic role for MPOspecific CD8(+) T cells, provide evidence that CD8(+) cells are a therapeutic target in ANCA-associated vasculitis, and suggest that a molecular hotspot within the MPO molecule contains important CD8, CD4(+), and B cell epitopes.