Bacterial peptidylarginine deiminase, a link between gums and joint disease

描述（由申请人提供）：牙龈卟啉单胞菌是慢性牙周炎的主要病原体，慢性牙周炎是一种涉及支持牙齿的组织进行性破坏的疾病过程。最近，据报道，该生物体产生一种独特的细菌酶，牙龈卟啉单胞菌肽基精氨酸脱亚胺酶（PPAD），其具有将蛋白质中的精氨酸残基转化为瓜氨酸的能力。瓜氨酸蛋白改变蛋白质结构和功能，因此，PPA可能参与宿主免疫逃避信号网络的失调。此外，越来越多的证据揭示了抗瓜氨酸化蛋白的自身免疫在类风湿性关节炎（RA）发展中的作用。由于吸烟者肺部的炎症状况导致对瓜氨酸化表位的免疫耐受性的破坏，牙周炎部位长期暴露于瓜氨酸化蛋白也可能使易感个体易于产生自身抗体并引发RA。因此，PPAD可能代表牙周炎和类风湿性关节炎之间的机制联系-已知在流行病学水平上彼此显著相关的疾病。 我们假设，在慢性炎症环境和细菌源性“危险信号”刺激的免疫系统中，PPAD对牙周/牙龈组织中细菌和宿主蛋白的瓜氨酸化导致对瓜氨酸化蛋白和肽的免疫耐受性的最初破坏。此外，PPAD可以通过修饰先天免疫的重要效应分子，包括C3 a和C5 a过敏毒素和缓激肽，来操纵炎症牙周组织中的免疫应答。这些肽的生物活性取决于C-末端精氨酸，其也是PPAD的优先靶点。因此，本研究计划将探讨PPAD作为牙龈卟啉单胞菌的毒力因子以及牙周炎和RA之间的机制联系这一重要而创新的概念，具体目标如下：（i）在体内和离体检查PPAD在RA发病机制中的作用;（ii）各种形式的PPAD的功能和结构研究;及（iii）研究PPAD的免疫调节作用与牙周病发病机制的关系。因此，拟议的研究将阐明PPAD对牙龈卟啉单胞菌感染驱动的慢性炎症的贡献，并阐明牙周病和类风湿性关节炎之间可能的联系。这些知识将为牙周炎的治疗和易感人群类风湿性关节炎的预防创造新的视角。

DESCRIPTION (provided by applicant): Porphyromonas gingivalis is a leading pathogen in chronic periodontitis, a disease process involving progressive destruction of tissues that support the teeth. Recently, the organism has been reported to produce a unique bacterial enzyme, P. gingivalis peptidylarginine deiminase (PPAD), which has the ability to convert arginine residues in proteins to citrulline. Protein citrullination alters protein structure and function, hence, PPA may be involved in dysregulation of the host's signaling network for immune evasion. Further, accumulating evidence has revealed the role of autoimmunity against citrullinated proteins in the development of rheumatoid arthritis (RA). As inflammatory conditions in the lungs of cigarette smokers contributes to the breakdown of immune tolerance to citrullinated epitopes, chronic exposure to citrullinated proteins at periodontitis sites may also predispose susceptible individuals to the development of autoantibodies and initiation of RA. Thus, PPAD may represent the mechanistic link between periodontitis and rheumatoid arthritis - diseases that are known to be significantly associated to each other at the epidemiological level. We hypothesize that citrullination of bacterial and host proteins in periodontal/gingival tissues by PPAD, within the chronic inflammatory environment and immune system stimulation by bacteria- derived "danger signals", leads to the initial break of immune tolerance to citrullinated proteins and peptides. In addition PPAD may manipulate immune responses in inflamed periodontal tissues by modifying important effector molecules of the innate immunity, including C3a and C5a anaphylatoxins and bradykinin. Biological activity of these peptides depends on the C-terminal arginine, which is also a preferential target for PPAD. Hence, this research proposal will investigate the important and innovative concept that PPAD as a virulence factor of P. gingivalis and mechanistic link between periodontitis and RA with the following specific aims: (i) in vivo and ex vivo examination of PPAD's role in the pathogenesis of RA; (ii) functional and structural studies of various forms of PPAD; and (iii) investigate the immunomodulatory effect of PPAD that is relevant to the pathogenesis of periodontal disease. Thus, the proposed research will illuminate the PPAD's contribution to chronic inflammation driven by P. gingivalis infection and shed light on the possible link between periodontal disease and rheumatoid arthritis. This knowledge will create new perspectives in the treatment of periodontitis and prevention of rheumatoid arthritis in susceptible individuals.