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SUPER ANTIGENS IN PERIODONTAL DISEASES

牙周疾病中的超级抗原

基本信息

批准号：
6164407
负责人：
HOMAYOUN H ZADEH
金额：
$ 11.08万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
1996
资助国家：
美国
起止时间：
1996-03-15 至 2002-02-28
项目状态：
已结题

项目摘要

Immunomodulation by periodontopathic bacteria has been implicated in the pathogenesis of inflammatory periodontal diseases. A novel class of microbial-derived T cell mitogens, referred to as superantigens (SAg), has recently been described. SAg are unique in that they activate and expand large subsets of T cells in an antigen-independent manner, and these subsets can be identified with reagents that discriminate between different subtypes (families) of the variable domain of T cell antigen receptor (TCR Vbeta. SAg are believed to cause immune dysfunction in a number of diseases by large-scale T cell activation, leading to: l) elaboration of overwhelmingly high levels of some cytokines, and depression of other cytokines, thereby disrupting normal immunoregulatory homeostasis and mediating tissue injury; 2) polyclonal B cell activation, 3) activation and expansion of quiescent autoreactive T cells, and 4) rendering the directed immune response less efficient. In preliminary studies, we have demonstrated that: P. gingivalis and A.actinomycetemcomitans have SAg properties in vitro and 2) in most periodontal patients, there is an overrepresentation of some subsets of gingival T cells, marked by their TCR Vbeta region expression, which is one of the hallmarks of in vivo SAg stimulation of T cells. In some patients, a few TCR Vbeta families comprised nearly 50% of all gingival T cells suggesting that SAg constitute a major pathway of T cell activation and expansion. This skewing of T cell subsets was particularly striking among activated T cells, suggesting in vivo stimulation of those T cells (most likely by SAg). Hence, we hypothesize that some of the putative periodontopathic bacteria produce superantigens that activate and expand a large number of T cells in a antigen-independent fashion. Moreover, superantigen-expanded T cells are present in periodontitis sites. To investigate our hypothesis, we have developed specific aims to: 1) determine whether P. gingivalis and A.actinomycetemcomitans can indeed qualify as SAg. This will be accomplished by investigating key properties that distinguish SAg from conventional Ag, utilizing in vitro murine and human systems. 2) Evaluate the existence of in vivo SAg-stimulated T cell subsets in periodontitis sites and 3) purify and characterize P. gingivalis- and A. actinomycetemcomitans -associated SAg. If our hypothesis is confirmed, it has important implications on the pathogenesis of periodontitis, involving initial Ag-independent activation and expansion of T cells, polyclonal B-cell activation, dysregulated cytokine release and generation of autoreactive T and B cells. Furthermore, identifying domains of the TCR molecules and the bacterial components that interact with them, lays the foundation for devising new immunoerapeutic approaches involving more specific targeting of these molecules.

牙周致病菌的免疫调节作用与牙周炎的发生有关。炎症性牙周病的发病机制。一类新的微生物来源的T细胞有丝分裂原，称为超抗原（SAg），最近被描述。SAg的独特之处在于它们激活并扩展以抗原非依赖性方式产生大量T细胞亚群，而这些子集可以用区分 T细胞抗原可变区的不同亚型（家族）受体（TCR V β. SAg被认为会导致免疫功能障碍，通过大规模T细胞活化的疾病的数量，导致：某些细胞因子水平极高，抑制其他细胞因子，从而破坏正常的免疫调节稳态和介导组织损伤; 2）多克隆B细胞活化， 3)激活和扩增静止的自身反应性T细胞，和4）使得定向免疫应答效率较低。初步研究表明：牙龈卟啉单胞菌和伴放线菌在体外具有SAg特性，2）在大多数牙周病患者，有一个过度的代表性的一些子集，牙龈T细胞，以其TCR V β区表达为标志，体内SAg刺激T细胞的标志之一。在一些患者中，少数TCR V β家族占所有牙龈T细胞的近50%，表明SAg构成T细胞活化的主要途径和扩张。这种T细胞亚群的倾斜特别引人注目在活化的T细胞中，表明这些T细胞在体内刺激 (most可能是SAG）。因此，我们假设一些假定的牙周病细菌产生超抗原，大量的T细胞以抗原非依赖的方式。此外，委员会认为，超抗原扩增的T细胞存在于牙周炎部位。到研究我们的假设，我们已经制定了具体的目标：1）确定牙龈卟啉单胞菌和伴放线菌是否确实可以有资格成为SAG。这将通过调查关键属性来实现利用体外小鼠和人类系统。2)评价体内SAg刺激的T细胞的存在牙周炎部位的亚群和3）纯化和表征P. gingivalis和A.伴放线菌相关SAg.如果我们的这一假说得到证实，对该病的发病机制有重要意义牙周炎，涉及初始Ag非依赖性激活， T细胞扩增，多克隆B细胞活化，失调的细胞因子自身反应性T和B细胞的释放和产生。此外，委员会认为，鉴定TCR分子的结构域和细菌组分，与它们相互作用，为设计新的免疫增强剂奠定基础涉及这些分子的更特异性靶向的方法。