Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Front Immunol. 2019 Jun 12;10:1334. doi: 10.3389/fimmu.2019.01334. eCollection 2019.
ANCA associated vasculitis (AAV) is characterized by systemic necrotizing vasculitis with the presence of ANCA. Although BPI-ANCA is one of the atypical ANCAs and is occasionally seen in patients with vasculitis, the pathogenicity of BPI-ANCA remains unclear. This study was performed to examine the pathogenic role of BPI-ANCA against neutrophils. A 76-year-old Japanese man showed BPI-ANCA positive systemic vasculitis with a medical history of infection. BPI-ANCA IgGs were eluted from the patient serum using an immunoadsorbent column. experiment, healthy donor neutrophils were treated with BPI-AAV IgGs, MPO-AAV IgGs, healthy control IgGs under TNFα stimulation. After 3 h incubation, neutrophil extracellular trap (NET) was assessed by immunofluorescent imaging. To determine the pathogenicity of BPI-ANCA, TNFα-primed neutrophils were incubated with monoclonal BPI-ANCA in the presence or absence of recombinant BPI. BPI-AAV IgGs-treated neutrophils showed NET formation with histone citrullination. Interestingly, the monoclonal BPI-ANCA did not induce NET, but the immune complexes (ICs) of recombinant BPI and BPI-ANCA induced TNFα-dependent NET formation with hypercitrullination. Furthermore, TNFα increased the expression of BPIs in neutrophils and the BPIs were translocated to cell surface. BPI-ANCA could affect neutrophils leading to NET formation and may play a role in the development of systemic vasculitis as pathogenic autoantibody.
抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）的特征是存在 ANCA 的系统性坏死性血管炎。虽然 BPI-ANCA 是一种非典型的 ANCAs，偶尔可见于血管炎患者，但 BPI-ANCA 的致病性尚不清楚。本研究旨在探讨 BPI-ANCA 对中性粒细胞的致病作用。
一名 76 岁的日本男性出现 BPI-ANCA 阳性系统性血管炎，有感染病史。使用免疫吸附柱从患者血清中洗脱 BPI-ANCA IgG。在实验中，在 TNFα 刺激下，用 BPI-AAV IgG、MPO-AAV IgG、健康对照 IgG 处理健康供体中性粒细胞。孵育 3 小时后，通过免疫荧光成像评估中性粒细胞细胞外陷阱（NET）。为了确定 BPI-ANCA 的致病性，在存在或不存在重组 BPI 的情况下，用单克隆 BPI-ANCA 孵育 TNFα 预刺激的中性粒细胞。BPI-AAV IgG 处理的中性粒细胞显示具有组蛋白瓜氨酸化的 NET 形成。有趣的是，单克隆 BPI-ANCA 不会诱导 NET，但重组 BPI 和 BPI-ANCA 的免疫复合物（ICs）诱导 TNFα 依赖性 NET 形成，伴有过度瓜氨酸化。此外，TNFα 增加了中性粒细胞中 BPIs 的表达，并且 BPIs 易位到细胞表面。BPI-ANCA 可能影响中性粒细胞导致 NET 形成，并可能作为致病性自身抗体在系统性血管炎的发展中发挥作用。
