Much evidence suggests that trained immunity is inappropriately activated in the synovial tissue in rheumatoid arthritis (RA), but the underlying mechanism remains unclear. Here, we describe how RA-specific autoantibody deposits can train human monocytes to exert the hyperactive inflammatory response, particularly via the exacerbated release of tumor necrosis factor α (TNFα). Comparative transcriptomic analysis by plate-bound human IgG (cIgG) or β-glucan indicated that metabolic shift towards glycolysis is a crucial mechanism for trained immunity. Moreover, the cIgG-trained gene signatures were enriched in synovial tissues from patients with ACPA- (anticitrullinated protein antibody-) positive arthralgia and undifferentiated arthritis, and early RA and established RA bore a great resemblance to the myeloid pathotype, suggesting a historical priming event in vivo. Additionally, the expression of the cIgG-trained signatures is higher in the female, older, and ACPA-positive populations, with a predictive role in the clinical response to infliximab. We conclude that RA-specific autoantibodies can train monocytes in the inflamed lesion as early as the asymptomatic stage, which may not merely improve understanding of disease progression but may also suggest therapeutic and/or preventive strategies for autoimmune diseases.

中文翻译：

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疾病特异性自身抗体在 RA 滑膜组织中诱导训练免疫，其基因特征与对临床治疗的反应相关

许多证据表明，类风湿性关节炎 (RA) 的滑膜组织中训练有素的免疫被不适当地激活，但其潜在机制尚不清楚。在这里，我们描述了RA特异性自身抗体沉积物可以如何培养人单核细胞施加过动性炎症反应，特别是通过肿瘤坏死因子的释放加剧α（TNF α）。通过板结合的人 IgG (cIgG) 或β 进行比较转录组分析-葡聚糖表明代谢转向糖酵解是训练免疫的关键机制。此外，cIgG 训练的基因特征在来自 ACPA-（抗瓜氨酸蛋白抗体-）阳性关节痛和未分化关节炎患者的滑膜组织中富集，早期 RA 和确诊 RA 与髓样病变非常相似，表明历史引发事件体内. 此外，cIgG 训练的特征在女性、老年人和 ACPA 阳性人群中的表达更高，对英夫利昔单抗的临床反应具有预测作用。我们得出结论，RA 特异性自身抗体早在无症状阶段就可以在炎症病变中训练单核细胞，这不仅可以提高对疾病进展的理解，还可以为自身免疫性疾病提供治疗和/或预防策略。