BACKGROUND Wegener's Granulomatosis and Microscopic Polyangiitis are life-threatening systemic necrotizing vasculitides of unknown aetiology. The appearance of circulating antibodies to neutrophil cytoplasmic antigens (ANCA) is strongly associated with the development of the disease. A link between infection and disease has long been suspected, and the appearance of ANCA antibodies has been reported following bacterial and viral infections. The depletion of circulating B cells with monoclonal antibody therapy can induce remission, and this observation suggests a pathogenic role for B cells in this disease. As bacterial DNA is known to induce B cell proliferation and antibody production via TLR-9 stimulation, we have explored the possibility that unmethylated CpG oligodeoxynucleotide, as found in bacterial and viral DNA, may play a role in stimulating circulating autoreactive B cells to produce ANCA in patients with vasculitis. RESULTS We have confirmed that unmethylated CpG oligonucleotide is a potent stimulator of antibody production by PBMC in vitro. The stimulation of PBMC with CpG oligonucleutides resulted in the production of similar amounts of IgG in both ANCA+ patients and normal controls. In spite of this, PR3 ANCA+ patients synthesised significantly higher amount of IgG ANCA than normal controls. In MPO ANCA+ patients, there was a tendency for patients to produce higher amount of ANCA than controls, however, the difference did not reach significance. Furthermore, we were able to detect circulating MPO-reactive B cells by ELISpot assay from the peripheral blood of 2 MPO+ ANCA vasculitis patients. Together, this indicates that circulating anti-neutrophil autoreactive B cells are present in ANCA+ vasculitis patients, and they are capable of producing antibodies in response to CpG stimulation. Of note, CpG also induced the production of the relevant autoantibodies in patients with other types of autoimmune diseases. CONCLUSION Circulating ANCA autoreactive B cells are present in patients with ANCA+ vasculitis. The production of ANCA from these cells in response to unmethylated CpG stimulation lead us to propose that stimulation of these cells by immunostimulatory DNA sequences such as CpG oligodeoxynucleotide during infection may provide a link between infection and ANCA associated vasculitis. This phenomenon may also apply to other antibody mediated autoimmune diseases.

中文翻译：

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CpG 寡脱氧核苷酸刺激 ANCA 相关血管炎中抗中性粒细胞胞浆抗体的产生。


背景韦格纳肉芽肿病和显微镜下多血管炎是病因不明的危及生命的全身性坏死性血管炎。中性粒细胞胞浆抗原（ANCA）循环抗体的出现与疾病的发展密切相关。长期以来人们一直怀疑感染和疾病之间存在联系，并且有报道称细菌和病毒感染后会出现 ANCA 抗体。用单克隆抗体疗法消除循环 B 细胞可以诱导缓解，这一观察结果表明 B 细胞在这种疾病中具有致病作用。由于细菌 DNA 已知可通过 TLR-9 刺激诱导 B 细胞增殖和抗体产生，因此我们探索了细菌和病毒 DNA 中发现的未甲基化 CpG 寡脱氧核苷酸可能在刺激循环自身反应性 B 细胞产生 ANCA 方面发挥作用的可能性。血管炎患者。结果 我们已经证实，未甲基化的 CpG 寡核苷酸是体外 PBMC 产生抗体的有效刺激剂。用 CpG 寡核苷酸刺激 PBMC 导致 ANCA+ 患者和正常对照产生相似量的 IgG。尽管如此，PR3 ANCA+患者合成的 IgG ANCA 量明显高于正常对照。在 MPO ANCA+ 患者中，患者产生的 ANCA 量有高于对照组的趋势，但差异并未达到显着性。此外，我们能够通过 ELISpot 检测从 2 名 MPO+ ANCA 血管炎患者的外周血中检测到循环 MPO 反应性 B 细胞。 总之，这表明 ANCA+ 血管炎患者中存在循环抗中性粒细胞自身反应性 B 细胞，并且它们能够响应 CpG 刺激而产生抗体。值得注意的是，CpG 还诱导其他类型自身免疫性疾病患者产生相关自身抗体。结论 ANCA+ 血管炎患者中存在循环 ANCA 自身反应性 B 细胞。这些细胞响应非甲基化 CpG 刺激而产生 ANCA，这使我们提出，在感染期间通过免疫刺激性 DNA 序列（例如 CpG 寡脱氧核苷酸）刺激这些细胞可能会提供感染与 ANCA 相关血管炎之间的联系。这种现象也可能适用于其他抗体介导的自身免疫性疾病。