a Department of Neurology , Affiliated Hospital of Xuzhou Medical University , Xuzhou , Jiangsu , China.
b Department of Rehabilitation , Affiliated Hospital of Xuzhou Medical University , Xuzhou , Jiangsu , China.
Autoimmunity. 2018 May;51(3):126-134. doi: 10.1080/08916934.2018.1454913. Epub 2018 Mar 23.
Previous studies have shown that interferon regulatory factor-4 (IRF4) and IRF8 play critical but distinct roles in the differentiation of B cells into plasma cells (PCs). In the present study, we aimed to measure the expression levels of IRF4 and IRF8 in B cells from patients with myasthenia gravis (MG) and to investigate whether the expression of IRF4 and IRF8 associates with pathogenesis of MG. A total of 35 anti-acetylcholine receptor (AChR) antibody (Ab)-positive patients with MG [20 generalized MG (GMG) and 15 ocular MG (OMG) and 25 healthy donors were recruited in this study. The quantitative myasthenia gravis score (QMGS) was used to evaluate the clinical severity. Real-time PCR and Western blot were used to measure the levels of IRF4 and IRF8 expressed in peripheral blood B cells. Peripheral blood CD138 PCs were assayed by flow cytometry. Our data demonstrated that the mRNA/protein levels of IRF4 and IRF8 were significantly higher and lower, respectively, in patients with OMG/GMG groups compared with healthy controls. In addition, IRF4 expression was significantly higher and IRF8 expression was significantly lower in GMG group than in OMG group. Pearson's correlation analysis revealed that IRF8 expression was negatively correlated with clinical severity, PCs frequency and anti-AChR Ab levels, while IRF4 expression and IRF4/IRF8 ratio was positively correlated with these parameters in two MG subgroups. Finally, glucocorticoid treatment can relieve the imbalance of IRF4/IRF8 in peripheral blood B cells, and this restoration is accompanied by reduced PCs frequency and clinical symptoms. These evidences suggest that IRF4 and IRF8 are important in the counter-balancing mechanisms controlling differentiation of PCs in MG. The disruption of the balanced IRF4/IFR8 ratio in B cells may play important roles in the pathogenesis of MG and offer a promising therapeutic target for the development of novel immunotherapy for MG patients.
先前的研究表明，干扰素调节因子-4（IRF4）和 IRF8 在 B 细胞向浆细胞（PC）分化中发挥关键但不同的作用。在本研究中，我们旨在测量重症肌无力（MG）患者 B 细胞中 IRF4 和 IRF8 的表达水平，并探讨 IRF4 和 IRF8 的表达是否与 MG 的发病机制有关。共招募了 35 名抗乙酰胆碱受体（AChR）抗体阳性的 MG 患者[20 名全身性 MG（GMG）和 15 名眼肌型 MG（OMG）和 25 名健康对照者]。定量重症肌无力评分（QMGS）用于评估临床严重程度。实时 PCR 和 Western blot 用于测量外周血 B 细胞中 IRF4 和 IRF8 的表达水平。通过流式细胞术检测外周血 CD138 PC。我们的数据表明，与健康对照组相比，OMG/GMG 组患者的 IRF4 和 IRF8 的 mRNA/蛋白水平均显著升高和降低。此外，GMG 组的 IRF4 表达显著升高，IRF8 表达显著降低。Pearson 相关分析显示，IRF8 表达与临床严重程度、PC 频率和抗 AChR Ab 水平呈负相关，而在两个 MG 亚组中，IRF4 表达和 IRF4/IRF8 比值与这些参数呈正相关。最后，糖皮质激素治疗可减轻外周血 B 细胞中 IRF4/IRF8 的失衡，这种恢复伴随着 PC 频率和临床症状的减少。这些证据表明，IRF4 和 IRF8 在控制 MG 中 PC 分化的平衡机制中起重要作用。B 细胞中平衡的 IRF4/IFR8 比值的破坏可能在 MG 的发病机制中起重要作用，并为开发针对 MG 患者的新型免疫疗法提供有希望的治疗靶点。
