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与炎症性牙周病的发病机制。新颖的一类微生物衍生的 T 细胞有丝分裂原，称为超级抗原 (SAg)，具有最近有描述。 SAg 的独特之处在于它们激活和扩展以不依赖于抗原的方式产生大量 T 细胞亚群，并且这些可以使用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（TCR Vbeta.SAg）被认为会导致免疫功能障碍大规模 T 细胞激活导致多种疾病，导致： l) 某些细胞因子的水平极高，并且抑制其他细胞因子，从而破坏正常的免疫调节体内平衡和介导组织损伤； 2) 多克隆B细胞激活， 3) 静态自身反应性 T 细胞的激活和扩增，以及 4) 导致定向免疫反应效率降低。在初步研究，我们已经证明： P. gingivalis 和 A.actinomycetemcomitans 在体外具有 SAg 特性，2) 在大多数情况下牙周患者中，某些亚型的比例过高牙龈 T 细胞，以 TCR Vbeta 区域表达为标志， SAg 体内刺激 T 细胞的标志之一。在一些患者中，少数 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 细胞亚群的这种倾斜尤其引人注目在活化的 T 细胞中，表明这些 T 细胞受到体内刺激（很可能是 SAg）。因此，我们假设一些假定的牙周病细菌产生激活和扩张的超抗原以不依赖于抗原的方式产生大量 T 细胞。而且，超抗原扩增的 T 细胞存在于牙周炎部位。到为了调查我们的假设，我们制定了具体目标：1) 确定 P. gingivalis 和 A.actinomycetemcomitans 是否确实可以符合 SAg 资格。这将通过调查关键属性来完成区分 SAg 和传统 Ag，利用体外小鼠和人类系统。 2) 评估体内 SAg 刺激的 T 细胞的存在牙周炎部位的子集和 3) 纯化和表征 P. gingivalis-和A. actinomycetemcomitans-相关的SAg。如果我们的假设得到证实，对发病机制具有重要意义牙周炎的发生，涉及初始的不依赖于 Ag 的激活和 T 细胞扩增、多克隆 B 细胞激活、细胞因子失调自身反应性 T 细胞和 B 细胞的释放和生成。此外，识别 TCR 分子的结构域和细菌成分与它们相互作用，为设计新的免疫治疗奠定了基础涉及对这些分子进行更具体靶向的方法。