Mechanisms of Immune Modulation and Periodontal Disease

描述(申请人提供)：先天免疫系统和获得性免疫系统不可挽回地联系在一起，在包括牙周病在内的感染的诱导和/或预防中发挥主要作用。启动对微生物抗原的先天和获得性免疫反应的关键是Toll样受体(TLRs)的参与，Toll样受体(TLRs)是一类模式识别受体(PRRs)，检测微生物保守的分子产物。我们认为，天然免疫系统对其与毒力抗原相互作用所施加的免疫调节是开发旨在操纵效应者免疫反应的疗法的基础，以利于宿主的优势和保护。我们研究的基本假设是，每个微生物抗原在与宿主的初始相互作用中是独特的，从而导致受体识别、信号通路激活和细胞反应的不同。在这方面，我们已经显示了不同的获得性免疫反应的血凝素/粘附素毒力抗原KGP-HArep和HagB来源于牙龈卟啉单胞菌，这表明它们与天然免疫系统的相互作用不同。我们计划将我们的研究重点放在TLRs和树突状细胞上，因为这些抗原提呈细胞具有激活NA？VE T细胞的精妙特性，因此在先天和适应性反应中起关键作用。此外，我们的调查将寻求对随之而来的适应性免疫反应的理解。因此，这项建议的目的是(1)确定TLRs在对KGP-HArep和HagB刺激的固有和适应性反应中的作用；(2)确定对KGP-HArep和HagB的固有反应和效应细胞是否需要脂筏，以及特定效应反应的诱导或特定TLR的使用如何影响信号分子在脂筏中的特定招募和浓度；以及(3)确定CD25 CD4 Treg细胞在对KGP-HArep和HagB的免疫反应中以及在牙龈假单胞菌感染中的作用。预计这些研究将有助于了解宿主细胞遇到毒力抗原HArep和HagB时发生的细胞事件，并将1)深入了解它们在发病/免疫中的作用，2)为开发专门保护或改善牙龈卟啉单胞菌感染的疫苗或治疗方法提供相关信息。牙龈卟啉单胞菌是引起牙周病的主要病原菌。这种炎症性疾病很普遍，而且这种疾病与心血管疾病等严重的全身疾病之间存在关联。由于目前对牙龈假单胞菌抗原在宿主免疫应答中的免疫调节作用知之甚少，因此了解宿主细胞对牙周炎主要抗原的免疫应答，包括激活的信号通路，以开发新的治疗方法和疫苗，从而改善或控制牙周病变得至关重要。

DESCRIPTION (provided by applicant): The innate and adaptive immune systems are irrevocably linked and both play primary roles in the induction and/or prevention of infections, including periodontal disease. Critical to the initiation of innate and adaptive immune responses to microbial antigens is the participation of Toll-like receptors (TLRs), a family of pattern- recognition receptors (PRRs) that detect conserved molecular products of microorganisms. We propose that the immune regulation exerted by the innate immune system upon its interaction with virulence antigens is the basis for the development of therapies geared to manipulate the effector immune response to the advantage and protection of the host. The fundamental hypothesis of our studies is that each microbial antigen is unique in its initial interaction with the host, thus resulting in differences in receptor recognition, activation of signaling pathways and cellular responses. In this regard, we have shown differences in the adaptive immune responses to the hemagglutinin/adhesin virulence antigens Kgp-HArep and HagB derived from Porphyromonas ginigivalis, which suggest that their interactions with the innate immune system differ. We plan to focus our investigations on the TLRs and on dendritic cells since these antigen-presenting cells have the exquisite property of activating na¿ve T cells and thus are critically involved in innate and adaptive responses. In addition, our investigations will pursue an understanding of the ensuing adaptive immune response. Therefore, the aims of this proposal are (1) to determine the role of TLRs in the innate and adaptive response to Kgp-HArep and HagB stimulation; (2) to determine if innate and effector cell responses to Kgp- HArep and HagB require lipid rafts and how the induction of a specific effector response or the use of a certain TLR affects the particular recruitment and concentration of signaling molecules into lipid rafts; and (3) to determine the role of CD25+CD4+ Treg cells in immune responses to Kgp-HArep and HagB and in P. gingivalis infection. It is anticipated that these studies will lead to an understanding of the cellular events that occur when host cells encounter the virulence antigens HArep and HagB, and will provide 1) insight into their role in pathogenesis/immunity and 2) relavant information for the development of vaccines or therapies that will specifically protect or ameliorate infections by the pathogen Porphyromonas gingivalis. Porphyromonas gingivalis is a major etiologic agent of periodontal disease. This inflammatory disease is widespread and associations have been made between this disease and serious systemic conditions such as cardiovascular diseases. Since the immunoregulatory properties of P. gingivalis antigens in host responses are poorly understood, it becomes critical to understand the host cellular responses, including the signaling pathways activated, to major antigens of P. gingivalis, in order to develop novel therapies and vaccines by which periodontal disease can be ameliorated or controlled.