类风湿关节炎（RA）的发病与抗瓜氨酸化蛋白抗体（ACPA）的产生密切相关，而牙龈卟啉单胞菌（Pg）是已知唯一能分泌肽酰精氨酸脱亚氨酶（PAD）使蛋白瓜氨酸化的细菌。我们发表于JAMA Network Open的论文提示牙周炎及其致病菌Pg是诱发RA的危险因素，但Pg对RA的致病机制尚不明了。抗菌肽LL37有多个可能被瓜氨酸化的精氨酸残基，并在牙周炎和RA患者体内有较高表达。我们推测：PgPAD能使LL37瓜氨酸化，继而驱动RA相关自身抗体的应答。为此，本项目拟通过Pg体外实验验证PAD对LL37的瓜氨酸化作用及功能性影响；通过口腔临床样本检测，比较RA患者和健康人龈下PgPAD基因表达、酶活性、蛋白组瓜氨酸化情况以及唾液中ACPA水平，探究PgPAD瓜氨酸化LL37或其他蛋白与RA的关系。相关成果将进一步揭示RA的发病机制，为RA早期诊断以及今后将牙周治疗应用于RA的临床干预提供理论指导。

It is generally accepted that rheumatoid arthritis (RA) is associated with an increase of anti-citrullinated protein antibodies (ACPA), which are derived through citrullination by peptidylarginine deiminase enzyme (PAD). Periodontal pathogen Porphyromonas gingivalis (Pg) can produce PAD, which is unique among microorganisms of the human resident microbiota. We recently reported an increased prevalence of periodontitis and Pg in individuals at-risk of developing RA, suggesting that Pg may act as an important risk factors in RA initiation. However, the role of Pg in the etiology of RA is still not clear. Host defence peptides, such as LL37 and the α- and β-defensins, are antimicrobial and immunomodulatory innate defence molecules, vital to the defence of many sites in the body. LL37, in particular, has emerged as important in preventing the development of periodontitis and was detected at higher levels in the synovial samples of RA patients. Therefore, we aim to test the hypothesis that LL37 is subject to citrullination by PgPAD and citrullination of LL37 may contribute to the etiology of RA through increased generation of ACPA in susceptible individuals. The PAD deficient Pg mutant will be used to test the in vitro citrullination of LL37 and its effect. ACPA levels in the saliva, together with the PAD gene expression, enzyme activity and the citrullinome in the gingival crevicular fluid will be examined and compared between RA patients and healthy controls. The data generated from this study would be helpful to further understanding the etiology of RA. This study will also lay the groundwork for finding novel methods for early diagnosis and prevention of the RA development. Periodontal treatment may be considered as an adjunct to immunotherapy in RA patients in future.