Hoshino Akiyoshi, Nagao Tomokazu, Nagi-Miura Noriko, Ohno Naohito, Yasuhara Masato, Yamamoto Kenji, Nakayama Toshinori, Suzuki Kazuo
International Clinical Research Center, Research Institute, International Medical Center of Japan, Tokyo, Japan.
J Autoimmun. 2008 Aug;31(1):79-89. doi: 10.1016/j.jaut.2008.03.006.
The elevation of serum anti-neutrophil cytoplasmic autoantibodies (ANCA) is significantly associated with the progression of some patients with systemic vasculitis. Especially, myeloperoxidase-specific ANCA (MPO-ANCA) play a pivotal role in the progression of systemic vasculitis including crescentic glomerulonephritis. Here we demonstrated that MPO-ANCA-activated neutrophils allow the local environment to differentiate Th(17) cells through IL-6, IL-17A, and IL-23 production. We found a variety of elevated serum cytokines, especially IL-17A, in ANCA-mediated systemic vasculitis mice. Furthermore, activated peritoneal neutrophils in vitro also produced IL-17A and IL-23 in response to MPO-ANCA. Co-stimulation of fungal mannoprotein and complements significantly enhanced the MPO-ANCA-mediated IL-17A expression, but F(ab)'(2) fragments of MPO-ANCA diminished the cytokine response. These results suggest that the activated neutrophils produce IL-17A and IL-23 in response to MPO-ANCA via their Fc-region and classical complement pathway, which initiate the first steps of chronic autoimmune inflammation by allowing the local environment to develop Th(17)-mediated autoimmunity.
血清抗中性粒细胞胞浆自身抗体（ANCA）水平升高与部分系统性血管炎患者的病情进展显著相关。尤其是，髓过氧化物酶特异性ANCA（MPO-ANCA）在包括新月形肾小球肾炎在内的系统性血管炎进展中起关键作用。在此我们证明，MPO-ANCA激活的中性粒细胞通过产生白细胞介素-6（IL-6）、白细胞介素-17A（IL-17A）和白细胞介素-23（IL-23）使局部环境分化出辅助性T细胞17（Th17）。我们在ANCA介导的系统性血管炎小鼠中发现多种血清细胞因子水平升高，尤其是IL-17A。此外，体外激活的腹腔中性粒细胞对MPO-ANCA也产生IL-17A和IL-23。真菌甘露糖蛋白与补体的共同刺激显著增强了MPO-ANCA介导的IL-17A表达，但MPO-ANCA的F(ab)'(2)片段减弱了细胞因子反应。这些结果表明，激活的中性粒细胞通过其Fc区域和经典补体途径对MPO-ANCA产生IL-17A和IL-23，通过使局部环境发展为Th(17)介导的自身免疫引发慢性自身免疫炎症的第一步。
