Mechanisms of Immune Modulation and Periodontal Disease

描述（由申请人提供）：先天免疫系统和适应性免疫系统紧密相连，两者在诱导和/或预防感染（包括牙周病）中发挥主要作用。对启动针对微生物抗原的先天性和适应性免疫应答至关重要的是Toll样受体（TLR）的参与，Toll样受体是检测微生物的保守分子产物的模式识别受体（PRR）家族。我们认为，先天免疫系统与毒力抗原相互作用后产生的免疫调节是开发治疗方法的基础，这些治疗方法旨在操纵效应免疫应答，以利于宿主并保护宿主。我们研究的基本假设是，每种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差异。在这方面，我们已经显示了对来自豚鼠红卟啉单胞菌的血凝素/粘附素毒力抗原Kgp-HArep和HagB的适应性免疫应答的差异，这表明它们与先天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TLR和树突状细胞上，因为这些抗原呈递细胞具有激活幼稚T细胞的精致特性，因此在先天性和适应性反应中至关重要。此外，我们的调查将追求随后的适应性免疫反应的理解。因此，该提议的目的是（1）确定TLR在对Kgp-HArep和HagB刺激的先天性和适应性应答中的作用;（2）确定对Kgp-HArep和HagB的先天性和效应细胞应答是否需要脂筏，以及特定效应应答的诱导或某种TLR的使用如何影响信号分子进入脂筏的特定募集和浓度;以及（3）确定CD 25 + CD 4 + Treg细胞在对Kgp-HArep和HagB的免疫应答中以及在牙龈卟啉单胞菌感染中的作用。预计这些研究将有助于理解宿主细胞遇到毒力抗原HArep和HagB时发生的细胞事件，并将提供1）深入了解其在发病机制/免疫中的作用和2）开发疫苗或治疗的相关信息，这些疫苗或治疗将特异性保护或改善病原体牙龈卟啉单胞菌的感染。牙龈卟啉单胞菌是牙周病的主要致病菌。这种炎症性疾病是广泛的，并且已经在这种疾病和严重的全身性疾病如心血管疾病之间建立了关联。由于牙龈卟啉单胞菌抗原在宿主应答中的免疫调节特性知之甚少，因此了解宿主细胞对牙龈卟啉单胞菌主要抗原的应答（包括激活的信号传导途径）变得至关重要，以便开发可以改善或控制牙周病的新疗法和疫苗。

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.