The P. gingivalis Autocitrullinome Is Not a Target for ACPA in Early Rheumatoid Arthritis
The P. gingivalis Autocitrullinome Is Not a Target for ACPA in Early Rheumatoid Arthritis
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DOI：
10.1177/0022034519898144
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发表时间：
2020-01-06
影响因子：
7.6
通讯作者：
Curtis, M. A.
中科院分区：
文献类型：
--
作者：
Munoz-Atienza, E.;Flak, M. B.;Curtis, M. A.
类风湿性关节炎（RA）是一种主要影响关节的慢性炎症性疾病，其特征通常是在疾病临床前阶段存在自身免疫性抗瓜氨酸蛋白抗体（ACPA）以及关节炎关节中高瓜氨酸蛋白的积累。据报道，RA 与牙周病之间存在很强的关联，而牙龈卟啉单胞菌（牙周炎的已知驱动因素）被认为是这种关联背后的微生物联系。我们最近证明了牙龈卟啉单胞菌介导的肠道屏障破坏和炎症性关节炎期间关节炎症的加剧。在本研究中，我们研究了牙龈卟啉单胞菌在 RA 发病机制中的另一个潜在作用，其基础是通过该细菌产生的独特的牙龈卟啉单胞菌肽精氨酸脱亚胺酶 (PPAD) 的活性产生 ACPA，该细菌能够进行蛋白质瓜氨酸化。使用无法进行蛋白质瓜氨酸化的新型牙龈卟啉单胞菌 W50 PPAD 突变菌株，以及来自未接受过治疗抗风湿药物的早期关节炎患者的血清，我们评估了牙龈卟啉单胞菌蛋白质组中的自身瓜氨酸化蛋白是否可以作为 ACPA 产生启动中的交叉激活靶标。我们没有发现患者自身瓜氨酸化牙龈卟啉单胞菌蛋白特异性抗体活性的证据。此外，在小鼠模型的炎症性关节炎过程中，删除 PPAD 并不能阻止牙龈卟啉单胞菌介导的肠道屏障破坏和疾病恶化。总之，这些发现表明 PPAD 的酶活性并不是炎症性关节炎早期阶段的主要毒力机制。
Rheumatoid arthritis (RA), a chronic inflammatory disease affecting primarily the joints, is frequently characterized by the presence of autoimmune anticitrullinated protein antibodies (ACPA) during preclinical stages of disease and accumulation of hypercitrullinated proteins in arthritic joints. A strong association has been reported between RA and periodontal disease, and Porphyromonas gingivalis, a known driver of periodontitis, has been proposed as the microbial link underlying this association. We recently demonstrated P. gingivalis-mediated gut barrier breakdown and exacerbation of joint inflammation during inflammatory arthritis. In the present study, we investigated another potential role for P. gingivalis in RA etiopathogenesis, based on the generation of ACPA through the activity of a unique P. gingivalis peptidylarginine deiminase (PPAD) produced by this bacterium, which is capable of protein citrullination. Using a novel P. gingivalis W50 PPAD mutant strain, incapable of protein citrullination, and serum from disease-modifying antirheumatic drug-naive early arthritis patients, we assessed whether autocitrullinated proteins in the P. gingivalis proteome serve as cross-activation targets in the initiation of ACPA production. We found no evidence for patient antibody activity specific to autocitrullinated P. gingivalis proteins. Moreover, deletion of PPAD did not prevent P. gingivalis-mediated intestinal barrier breakdown and exacerbation of disease during inflammatory arthritis in a murine model. Together, these findings suggest that the enzymatic activity of PPAD is not a major virulence mechanism during early stages of inflammatory arthritis.