Immunodominant Stress Proteins of Porphyromonas gingivalis

描述（由申请人提供）：伴侣蛋白或热休克蛋白存在于从细菌到人类的所有细胞中，是自然界中最高度保守和免疫优势的分子之一。最初被认为是促进蛋白质的三维组装，但越来越清楚的是，这些分子具有涉及对各种微生物的免疫反应的功能。此外，研究表明，对应激蛋白的保护性反应可能参与IBD、军团菌、耶尔森菌、衣原体和幽门螺杆菌感染以及动脉硬化等疾病的控制。这项工作的长期目标是阐明伴侣参与牙周炎和牙周炎相关全身性疾病的机制，并为这些疾病的药物治疗制定策略。我们已经证明，在一组牙龈炎受试者中，发现牙周病原体牙龈卟啉单胞菌HSP90同源物（HtpG）抗体水平升高与口腔健康状况改善有关。在我们目前的资助中，我们已经证明HtpG具有诱导免疫调节活性的能力，类似于与慢性传染病相关的其他细菌的伴侣蛋白。在牙周炎中，牙龈假单胞菌HtpG招募抗体产生细胞到病变处，并上调白细胞和血管细胞上的趋化因子受体，促进组织的持续破坏。HtpG存在于循环和CVD动脉粥样硬化中，可诱导泡沫细胞形成，这是动脉粥样硬化斑块形成的重要步骤。HtpG抗体下调白细胞和静脉细胞中IL-8的产生，并可能减轻牙周炎的炎症作用。该应用将1)表征牙龈假单胞菌HtpG在体外独特的受体介导的免疫调节活性；2)通过显微解剖、基因组/蛋白质组学方法证明牙周炎和血管组织在体内具有相同的活性；3)将血清抗体与驱动这一过程的分子的存在联系起来。这样的示范将为牙周炎和牙周炎相关全身性疾病的新治疗和诊断模式铺平道路。

DESCRIPTION (provided by applicant): Chaperones or heat shock proteins are found in all cells from bacteria to man and are among the most highly conserved and immunodominant molecules in nature. Originally thought to facilitate the three dimensional assembly of proteins it has become increasingly clear that these molecules have functions involving the immune response to a variety of microorganisms. In addition it has been shown that protective response to stress proteins may be involved in control of diseases like IBD, Legionella, Yersinia, Chlamydia and H. pylori infections and arteriosclerosis. The long-term goals of this work is to deliniate the mechanisms of chaperone involvement in periodontitis and periodontitis-related systemic disease and to develop strategies for medicinal treatment for those diseases. We have shown that elevated levels of antibodies to the HSP90 homolog (HtpG) of the periodontal pathogen P. gingivalis were found associated with better oral health in a group of gingivitis subjects. During our current grant we have demonstrated HtpG has the ability to induce immunomodulatory activity similar to chaperones from other bacteria associated with chronic infectious diseases. In periodontitis P. gingivalis HtpG recruits antibody producing cells to the lesion and upregulates chemokine receptors on both leukocytes and vascular cells contributing to the continuning tissue destruction. HtpG is found in circulation and CVD atheromas and can induce foam cell formation, an important step in atherosclerotic plaque formation. Antibodies to HtpG downregulate IL-8 production in both leukocytes and vein cells and may mitigate the inflammatory effects in periodontitis. This application will 1) chacterize the distinct receptor-mediated immunomodulatory activities of P. gingivalis HtpG in vitro; 2) demonstrate the same activity in vivo in periodontitis and vascular tissue by microdisection, genomic/proteomic approaches; 3) correlate serum antibodies to the presence of the molecules that drive this process. Such a demonstration will prepare the way for novel therapeutic and diagnostic modalities for both periodontitis and periodontitisrelated systemic diseases. PROJECT NARATIVE: Molecules that produce a particular class of proteins proteins in cells called chaperones can become involved in disease processes under some circumstances. Understanding the way this happens can lead to treatments for chronic diseases that are the result of long-lasting, unresolved periodontitis.