Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Departments of Kidney Disease and Hypertension, Osaka General Medical Center, Osaka, Japan.
BMC Nephrol. 2018 Jun 22;19(1):145. doi: 10.1186/s12882-018-0953-y.
Neutrophil extracellular traps (NETs) are web-like DNA decorated with antimicrobial proteins, such as myeloperoxidase (MPO), which are extruded from activated neutrophils. Although NETs are essential in innate immunity, an excessive formation of NETs has adverse effects, e.g., induction of anti-neutrophil cytoplasmic antibody (ANCA), to the hosts. Since ANCA can induce NET formation in the primed neutrophils, a positive feedback loop can be formed between NETs and ANCA, which is called "ANCA-NETs vicious cycle."
A 79-year-old Japanese woman developed hydralazine-induced pauci-immune necrotizing crescentic glomerulonephritis with MPO-ANCA. Although the illness improved after cessation of hydralazine, MPO-ANCA-associated vasculitis relapsed 16 months later. Remission was achieved 5 months after beginning of administration of prednisone. In order to determine the involvement of ANCA-NETs vicious cycle in this patient, we examined NET degradation and induction activities in sera obtained at the disease onset (Serum A; MPO-ANCA, 107 IU/ml), at relapse (Serum B; MPO-ANCA, 195 IU/ml), at 3 months after treatment (Serum C; MPO-ANCA, 4.5 IU/ml), and at remission (Serum D; MPO-ANCA, 2.4 IU/ml). NET degradation activity was low in the all sera. NET induction activity was high in Sera A, B, and C but not in D. Additionally, we demonstrated the presence of anti-NET antibody (ANETA) in Sera B and C but not in A or D.
The collective findings suggest NET induction potential of ANETA in the present patient and that the ANETA could contribute to the enhancement of NETs resulting in amplification of the ANCA-NETs vicious cycle.
中性粒细胞胞外诱捕网（NETs）是一种网状 DNA，上面装饰着抗微生物蛋白，如髓过氧化物酶（MPO），这些蛋白从活化的中性粒细胞中挤出。虽然 NETs 在先天免疫中是必不可少的，但 NETs 的过度形成对宿主有不利影响，例如诱导抗中性粒细胞胞质抗体（ANCA）。由于 ANCA 可以诱导预刺激的中性粒细胞形成 NET，因此 NETs 和 ANCA 之间可以形成正反馈循环，这被称为“ANCA-NETs 恶性循环”。
一名 79 岁日本女性发生肼屈嗪诱导的少免疫性坏死性新月体肾小球肾炎伴 MPO-ANCA。尽管停止肼屈嗪后病情有所改善，但 MPO-ANCA 相关血管炎在 16 个月后复发。开始使用泼尼松后 5 个月达到缓解。为了确定该患者是否涉及 ANCA-NETs 恶性循环，我们检测了发病时（血清 A；MPO-ANCA，107 IU/ml）、复发时（血清 B；MPO-ANCA，195 IU/ml）、治疗后 3 个月（血清 C；MPO-ANCA，4.5 IU/ml）和缓解时（血清 D；MPO-ANCA，2.4 IU/ml）获得的血清中的 NET 降解和诱导活性。所有血清中的 NET 降解活性均较低。血清 A、B 和 C 中的 NET 诱导活性较高，但血清 D 中没有。此外，我们在血清 B 和 C 中检测到抗 NET 抗体（ANETA），但在血清 A 和 D 中未检测到。
综合研究结果表明，本患者的 ANETA 具有 NET 诱导潜能，并且 ANETA 可能有助于增强 NETs，从而放大 ANCA-NETs 恶性循环。
