Division of Immunology and Rheumatology, Stanford University, Stanford, CA 94305, USA.
VA Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Sci Transl Med. 2023 Feb 22;15(684):eabq8476. doi: 10.1126/scitranslmed.abq8476.
Periodontal disease is more common in individuals with rheumatoid arthritis (RA) who have detectable anti-citrullinated protein antibodies (ACPAs), implicating oral mucosal inflammation in RA pathogenesis. Here, we performed paired analysis of human and bacterial transcriptomics in longitudinal blood samples from RA patients. We found that patients with RA and periodontal disease experienced repeated oral bacteremias associated with transcriptional signatures of ISG15HLADR and CD48S100A2 monocytes, recently identified in inflamed RA synovia and blood of those with RA flares. The oral bacteria observed transiently in blood were broadly citrullinated in the mouth, and their in situ citrullinated epitopes were targeted by extensively somatically hypermutated ACPAs encoded by RA blood plasmablasts. Together, these results suggest that (i) periodontal disease results in repeated breaches of the oral mucosa that release citrullinated oral bacteria into circulation, which (ii) activate inflammatory monocyte subsets that are observed in inflamed RA synovia and blood of RA patients with flares and (iii) activate ACPA B cells, thereby promoting affinity maturation and epitope spreading to citrullinated human antigens.
牙周病在患有可检测抗瓜氨酸化蛋白抗体 (ACPAs) 的类风湿关节炎 (RA) 个体中更为常见，这表明口腔黏膜炎症与 RA 的发病机制有关。在这里，我们对来自 RA 患者的纵向血液样本进行了人类和细菌转录组的配对分析。我们发现，患有 RA 和牙周病的患者经历了与 ISG15HLADR 和 CD48S100A2 单核细胞转录特征相关的反复口腔菌血症，这些特征最近在炎症性 RA 滑膜和 RA 发作患者的血液中被发现。在血液中观察到的口腔细菌在口腔中广泛瓜氨酸化，其原位瓜氨酸化表位被 RA 血液浆细胞中广泛体细胞超突变的 ACPA 编码靶向。总之，这些结果表明：（i）牙周病导致口腔黏膜反复破裂，将瓜氨酸化的口腔细菌释放到循环中，这会激活炎症性单核细胞亚群，这些细胞在炎症性 RA 滑膜和 RA 发作患者的血液中被观察到；（ii）激活 ACPA B 细胞，从而促进亲和成熟和表位扩展到瓜氨酸化的人类抗原。
