Division of Clinical Nephrology and Rheumatology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 9518510, Japan.
Health Administration Center, Niigata University, Niigata 9502181, Japan.
J Immunol. 2021 Apr 15;206(8):1729-1739. doi: 10.4049/jimmunol.2000260. Epub 2021 Mar 31.
Antiribosomal P protein (anti-P) autoantibodies commonly develop in patients with systemic lupus erythematosus. We have previously established hybridoma clones producing anti-P mAbs. In this study, we explored the pathogenesis of behavioral disorders induced by anti-P Abs using these mAbs. New Zealand Black × New Zealand White F1, New Zealand White, C57BL/6, and BALB/c mice were treated with 1 mg of anti-P Abs once every 2 wk. The behavioral disorder was evaluated by the tail suspension test, forced swim test, and open field test. Following administration of anti-P Abs, New Zealand Black × New Zealand White F1 and C57BL/6 mice developed depressive behavior and showed increased anxiety with elevated serum TNF-α and IL-6 levels. Anti-P Abs were not deposited in the affected brain tissue; instead, this mood disorder was associated with lower serum and brain tryptophan concentrations. Tryptophan supplementation recovered serum tryptophan levels and prevented the behavioral disorder. TNF-α and IL-6 were essential for the decreased serum tryptophan and disease development, which were ameliorated by treatment with anti-TNF-α neutralizing Abs or dexamethasone. Peritoneal macrophages from C57BL/6 mice produced TNF-α, IL-6, and IDO-1 via interaction with anti-P Abs through activating FcγRs, which were required for disease development. IVIg, which has an immunosuppressive effect partly through the regulation of FcγR expression, also prevented the decrease in serum tryptophan and disease development. Furthermore, serum tryptophan concentrations were decreased in the sera of systemic lupus erythematosus patients with anti-P Abs, and lower tryptophan levels correlated with disease activity. Our study revealed some of the molecular mechanisms of mood disorder induced by anti-P Abs.
抗核糖体 P 蛋白 (anti-P) 自身抗体通常在系统性红斑狼疮患者中产生。我们之前已经建立了产生抗-P mAb 的杂交瘤克隆。在这项研究中，我们使用这些 mAb 探讨了抗-P Abs 诱导的行为障碍的发病机制。用 1mg 抗-P Abs 每隔 2 周处理一次新西兰黑×新西兰白 F1、新西兰白、C57BL/6 和 BALB/c 小鼠。通过悬尾试验、强迫游泳试验和旷场试验评估行为障碍。给予抗-P Abs 后，新西兰黑×新西兰白 F1 和 C57BL/6 小鼠出现抑郁行为，血清 TNF-α 和 IL-6 水平升高，焦虑增加。抗-P Abs 未沉积在受影响的脑组织中；相反，这种情绪障碍与血清和大脑色氨酸浓度降低有关。色氨酸补充恢复了血清色氨酸水平并预防了行为障碍。TNF-α 和 IL-6 对于降低血清色氨酸和疾病发展是必需的，用抗 TNF-α 中和 Abs 或地塞米松治疗可改善这种情况。通过与抗-P Abs 相互作用，通过激活 FcγR，C57BL/6 小鼠的腹腔巨噬细胞产生 TNF-α、IL-6 和 IDO-1，这是疾病发展所必需的。IVIg 通过调节 FcγR 表达具有免疫抑制作用，也可防止血清色氨酸降低和疾病发展。此外，抗-P Abs 系统性红斑狼疮患者的血清中色氨酸浓度降低，较低的色氨酸水平与疾病活动度相关。我们的研究揭示了抗-P Abs 诱导的情绪障碍的一些分子机制。
