Porphyromonas gingivalis may play an important role in the pathogenesis of periodontitis-associated rheumatoid arthritis
Porphyromonas gingivalis may play an important role in the pathogenesis of periodontitis-associated rheumatoid arthritis
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牙龈卟啉单胞菌可能在牙周炎相关类风湿性关节炎的发病机制中发挥重要作用
DOI：
10.1016/j.mehy.2008.12.040
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发表时间：
2009-06-01
影响因子：
4.7
通讯作者：
Cheng, Xiangrong
中科院分区：
文献类型：
--
作者：
Liao, Feng;Li, Zubing;Cheng, Xiangrong
类风湿性关节炎（RA）是一种常见的全身性自身免疫性疾病，可导致关节结构的破坏和残疾。尽管RA的病因尚不清楚，但近年来的研究发现RA与牙周炎（periodontitis，PD）之间存在密切的关系，抗环瓜氨酸肽（anti-cycliccitrulinatedpeptide，anti-CCP）自身抗体和瓜氨酸肽参与了RA自身耐受的破坏和自身免疫的发生。瓜氨酸化肽是通过肽基精氨酸脱亚胺酶（PAD）对蛋白质结合的精氨酸进行翻译后修饰（瓜氨酸）而产生的。牙龈卟啉单胞菌（P. gingivalis）是PD的主要病原体，也是已知唯一表达PAD酶的细菌，据报道与RA显著相关。抗牙龈卟啉单胞菌抗体滴度在RA患者中显著增加，牙龈卟啉单胞菌抗体滴度与RA特异性抗CCP抗体同种型显著相关。最近的研究表明，RA特异性抗CCP自身抗体的主要滑膜靶点是纤维蛋白的α-和β-链的脱亚胺形式。同时，也证实了由牙龈卟啉单胞菌产生的细菌PAD具有将牙周病损中发现的纤维蛋白中的精氨酸脱亚胺化的能力。此外，已经证明瓜氨酸的HLA结合肽导致肽-MHC亲和力增加100倍，并导致HLA DRB 1 0401转基因小鼠中的CD 4（+）T细胞活化。因此，我们推测牙龈卟啉单胞菌可能在牙周炎相关性RA的发病机制中起着至关重要的作用。在口腔中定殖的牙龈炎持续产生PAD酶，其导致RA自身抗原的瓜氨酸化，例如滑膜关节中的纤维蛋白。这些PAD产生的抗原与主要组织相容性复合体（MHC）分子一起由抗原呈递细胞（APC）呈递，最终导致抗CCP抗体的产生。抗CCP抗体与瓜氨酸化蛋白形成免疫复合物，瓜氨酸化蛋白可通过其Fc受体与炎性细胞结合。这些免疫复合物和炎性细胞的作用由涉及补体激活的复杂级联介导。这些机制导致炎症介质的释放和关节破坏，最终导致RA的发作。这一假设表明，口腔细菌感染可能在肽瓜氨酸化中发挥作用，而肽瓜氨酸化可能与RA自我耐受性的丧失和自身免疫性的发展有关。(C)2009爱思唯尔有限公司保留所有权利。
Rheumatoid arthritis (RA) is a common, systemic autoimmune disease which leads to destruction of the joint architecture and consequent disability. Although the aetiology of RA remains unknown, accumulating studies have established a strong association between RA and periodontitis (PD).Recently, anti-cyclic citrullinated peptide (anti-CCP) autoantibody and citrullinated peptide have been realized to be involved in the breaking of self-tolerance and development of autoimmune in RA. The citrullinated peptide is generated by post-translational modification (citrullination) of protein-bound arginine by peptidylarginine deiminase (PAD). Porphyromonas gingivalis (P. gingivalis), the major aetiological agent of PD and the only bacterium known to express a PAD enzyme, has been reported to be significantly associated with RA. The antibody titers to P. gingivalis are significantly increased in patients with RA and P. gingivalis antibody titers are significantly correlated with anti-CCP antibody isotypes that are specific to RA. Recent study indicates that the major synovial targets of the RA-specific anti-CCP autoantibodies are deiminated forms of the alpha- and beta- chains of fibrin. Meanwhile, it is also confirmed that bacterial PAD produced by A gingivalis has the capacity of deiminating arginine in fibrin found in the periodontal lesion. Whatsmore, it has been demonstrated that citrullination of HLA binding peptide causes a 100-fold increase in peptide-MHC affinity and leads to the activation CD4(+)T cells in HLA DRB1 0401 transgenic mice. Therefore, we postulate that P. gingivalis may play a crucial role in the pathogenesis of periodontitis-associated RA. A gingivalis, which colonizes in the oral cavity, produces PAD enzyme continuously that leads to the citrullination of RA autoantigen such as fibrin in synovium joint. These PAD engendered antigens, presented in association with major histocompatibility complex (MHC) molecules by antigen-presenting cells (APC), ultimately lead to production of the anti-CCP antibody. The anti-CCP antibodies form immune complexes with citrullinated proteins, which can be bound by inflammatory cells via their Fc receptors. The roles of these immune complexes and inflammatory cells are mediated by a complex cascade involving complement activation. These mechanisms result in a release of mediators of inflammation and joint destruction ultimately leading to the onset of RA. This hypothesis reveals that oral bacterial infection may play a role in peptide citrullination which might be involved in loss of self-tolerance and development of autoimmune in RA. (C) 2009 Elsevier Ltd. All rights reserved.