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.

牙周病细菌的免疫调节已与炎症牙周疾病的发病机理。一个新颖的班级微生物衍生的T细胞有丝分裂剂，称为超抗原（SAG），具有最近被描述了。下垂是独特的，因为它们激活和扩展 T细胞以抗原独立的方式大量的子集，而这些可以通过区分区分的试剂来识别子集 T细胞抗原可变结构域的不同亚型（家族）受体（TCRVBETA。SAG被认为会在A中引起免疫功能障碍大规模T细胞激活的疾病数量，导致：L）阐述绝大多数的某些细胞因子，以及其他细胞因子的抑郁，从而破坏正常免疫调节稳态和介导组织损伤； 2）多克隆B细胞激活， 3）静态自动反应性T细胞的激活和扩展，4）使定向免疫反应的效率降低。在初步研究，我们已经证明了：牙龈疟原虫和 A.肌肉菌的体外具有下垂性能，大多数具有2）牙周患者，某些子集的代表过多牙龈T细胞，标志着其TCR VBETA区域表达，这是 T细胞体内下垂刺激的标志之一。在某些人中患者，几个TCR VBETA家族占所有牙龈T的近50％细胞表明SAG构成T细胞激活的主要途径和扩展。 T细胞子集的这种偏斜特别令人震惊在活化的T细胞中，表明这些T细胞的体内刺激（最有可能通过SAG）。因此，我们假设一些推定的牙周病细菌会产生激活和膨胀的超抗原以抗原独立的方式进行了大量T细胞。而且，超抗原扩张的T细胞存在于牙周炎部位。到研究我们的假设，我们已经开发了特定的目标：1）确定牙龈疟原虫和曲霉是否确实可以有资格作为下垂。这将通过研究关键属性来实现利用体外鼠和人类系统。 2）评估体内刺激的T细胞的存在牙周炎部位的子集，3）纯化和表征P。牙龈 - 和A.放线菌ceTemcitans相关的SAG。如果我们假设已得到证实，它对发病机理具有重要意义牙周炎，涉及最初的AG非依赖性激活和 T细胞的扩展，多克隆B细胞活化，失调的细胞因子自动反应性T和B细胞的释放和产生。此外，识别TCR分子的结构域和细菌成分与他们互动，为设计新的免疫性卫生性奠定了基础涉及这些分子更具体靶向的方法。