Center for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Victoria, Australia.
Cell Immunol. 2013 Mar;282(1):21-7. doi: 10.1016/j.cellimm.2013.04.007. Epub 2013 Apr 25.
Autoimmunity to the neutrophil enzyme myeloperoxidase (MPO) is an important cause of rapidly progressive glomerulonephritis, but the relative roles of MPO-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA) and autoreactive effector MPO-specific CD4(+) T cells are unclear. We confirmed that passive transfer of murine MPO-ANCA to agammaglobulinemic μMT mice immunized with OVA induces glomerular injury with capillary wall thickening, fibrinoid necrosis, mesangial cell proliferation, and periglomerular cell infiltration. Preimmunization of μMT mice with MPO induced MPO-specific CD4(+) T cells and significantly enhanced renal injury after MPO-ANCA transfer. CD4(+) T cell depletion prevented this augmentation of injury, confirming the importance of effector T cells in the development of MPO-ANCA associated glomerulonephritis. Therefore, MPO-ANCA can induce glomerulonephritis through both direct humoral mechanisms (recruitment of neutrophils and deposition of MPO) and indirectly by initiating MPO deposition in glomeruli, thereby directing effector CD4(+) T cell mediated injury. To confirm and support this data, we transferred T cells from MPO-immunized Mpo(-/-)μMT mice into Rag1(-/-) mice (control mice received ovalbumin specific T cells) and triggered injury by passive MPO-ANCA. Renal injury was significantly greater in mice transferred with T cells from MPO-immunized mice. These current studies demonstrate that MPO-ANCA induces injury via both humoral and cell mediated immune mechanisms.
自身免疫性中性粒细胞酶髓过氧化物酶 (MPO) 是快速进行性肾小球肾炎的重要原因，但 MPO 特异性抗中性粒细胞胞质抗体 (MPO-ANCA) 和自身反应性效应 MPO 特异性 CD4(+) T 细胞的相对作用尚不清楚。我们证实，将小鼠 MPO-ANCA 被动转移到用 OVA 免疫的无丙种球蛋白血症 μMT 小鼠中，可诱导肾小球损伤，表现为毛细血管壁增厚、纤维蛋白样坏死、系膜细胞增殖和肾小球周围细胞浸润。μMT 小鼠预先用 MPO 免疫可诱导 MPO 特异性 CD4(+) T 细胞，并在 MPO-ANCA 转移后显著增强肾脏损伤。CD4(+) T 细胞耗竭可防止这种损伤增强，证实了效应 T 细胞在 MPO-ANCA 相关肾小球肾炎发展中的重要性。因此，MPO-ANCA 可通过直接体液机制（招募中性粒细胞和 MPO 沉积）和间接通过在肾小球中引发 MPO 沉积，从而指导效应 CD4(+) T 细胞介导的损伤，来诱导肾小球肾炎。为了证实和支持这些数据，我们将来自 MPO 免疫的 Mpo(-/-)μMT 小鼠的 T 细胞转移到 Rag1(-/-)小鼠中（对照小鼠接受卵清蛋白特异性 T 细胞），并通过被动 MPO-ANCA 触发损伤。从 MPO 免疫的小鼠转移的 T 细胞的小鼠中，肾脏损伤明显更大。这些当前的研究表明，MPO-ANCA 通过体液和细胞介导的免疫机制诱导损伤。
