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，这是一种疾病过程，涉及支持牙齿的组织的进行性破坏。最近，有报道称这种细菌能产生一种独特的细菌酶，即P. gingivalis peptidylarginine de亚胺酶（PPAD），它能将蛋白质中的精氨酸残基转化为瓜氨酸。蛋白质瓜氨酸化改变了蛋白质的结构和功能，因此，PPA可能参与了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关节炎（RA）发展中的作用。由于吸烟者肺部的炎症状况有助于破坏对瓜氨酸化表位的免疫耐受性，因此在牙周炎部位长期暴露于瓜氨酸化蛋白也可能使易感个体容易产生自身抗体并引发RA。因此，PPAD可能代表了牙周炎和类风湿关节炎之间的机制联系，这两种疾病在流行病学水平上彼此显著相关。我们假设PPAD导致牙周/牙龈组织中的细菌和宿主蛋白瓜氨酸化，在慢性炎症环境和细菌衍生的“危险信号”的免疫系统刺激下，导致对瓜氨酸化蛋白和肽的免疫耐受最初中断。此外，PPAD可能通过改变先天性免疫的重要效应分子，包括C3a和C5a过敏毒素和缓激肽，来操纵炎症牙周组织的免疫反应。这些肽的生物活性依赖于c端精氨酸，它也是PPAD的优先靶点。因此，本研究计划将探讨PPAD作为牙龈卟啉卟啉毒力因子以及牙周炎与RA之间的机制联系这一重要的创新概念，具体目的如下：(i)体内和离体研究PPAD在RA发病机制中的作用；（ii）各种形式PPAD的功能和结构研究；（iii）研究与牙周病发病机制相关的PPAD的免疫调节作用。因此，提出的研究将阐明PPAD对牙龈卟啉菌感染引起的慢性炎症的贡献，并阐明牙周病和类风湿关节炎之间的可能联系。这一知识将为治疗牙周炎和预防易感人群的类风湿关节炎创造新的视角。

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.