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不可逆转地联系在一起，在诱导和/或预防感染（包括牙周病）中都起着主要作用。toll样受体（Toll-like receptor, TLRs）是一类模式识别受体（pattern- recognition receptor, PRRs），能够检测微生物的保守分子产物，是启动对微生物抗原的先天和适应性免疫应答的关键。我们提出，先天免疫系统对其与毒力抗原相互作用的免疫调节是开发治疗的基础，旨在操纵效应免疫反应，以获得宿主的优势和保护。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都是独一无二的，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，我们已经发现了来自卟啉单胞菌的血凝素/黏附素毒力抗原kp - harep和HagB的适应性免疫反应的差异，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na - ve T细胞的精细特性，因此在先天和适应性反应中至关重要。此外，我们的研究将追求对随之而来的适应性免疫反应的理解。因此，本研究的目的是：(1)确定tlr在Kgp-HArep和HagB刺激的先天和适应性反应中的作用；(2)确定先天和效应细胞对Kgp- HArep和HagB的反应是否需要脂筏，以及诱导特定效应反应或使用特定TLR如何影响信号分子进入脂筏的特定募集和浓度；(3)确定CD25+CD4+ Treg细胞在Kgp-HArep和HagB免疫应答和牙龈假单胞菌感染中的作用。预计这些研究将导致对宿主细胞遇到毒力抗原HArep和HagB时发生的细胞事件的理解，并将提供1)深入了解它们在发病机制/免疫中的作用，2)为开发疫苗或治疗方法提供相关信息，这些疫苗或治疗方法将特异性地保护或改善牙龈卟啉单胞菌感染。牙龈卟啉单胞菌是牙周病的主要病原。这种炎症性疾病广泛存在，并且与心血管疾病等严重全身性疾病存在关联。由于牙龈卟啉卟啉抗原在宿主反应中的免疫调节特性尚不清楚，因此了解宿主细胞对牙龈卟啉卟啉主要抗原的反应，包括激活的信号通路，以便开发新的治疗方法和疫苗，从而改善或控制牙周病，就变得至关重要。

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.