Molecular biological and immunological analysis for the relationship between periodontal disease and atherosclerosis

据推测，牙周感染可能参与动脉粥样硬化和随后的冠心病的发生和发展。虽然这一概念已得到流行病学病例对照研究的支持，但牙周炎与动脉粥样硬化的发生和发展的生物学相关性仍不清楚。在本研究项目中，我们分析了牙周炎病变中合成的细菌抗原和炎性细胞因子对内皮细胞功能的影响，以及对细菌抗原和交叉反应性内源性抗原的体液和细胞免疫反应在动脉粥样硬化形成中的作用。牙龈卟啉单胞菌(P.gigivalis)的脂多糖和GroEL(HSP60)可上调人冠状动脉内皮细胞ICAM-1和VCAM-a的表达。IL-1b和TNF-a都与牙周炎的组织破坏有关，它们也在牙周炎患者的血清中上调了这些分子的表达浓度。尽管HSP60在原核细胞和真核细胞之间高度同源，但它具有很强的免疫原性，被认为与炎症和自身免疫性疾病有关。动脉粥样硬化患者对人类和牙龈假单胞菌的抗体水平最高，其次是牙周炎患者和健康受试者。对T细胞的克隆性分析清楚地表明，动脉粥样硬化患者的外周循环中不仅存在人HSP60-，而且存在牙龈假单胞菌GroEL反应性T细胞群。此外，这些HSP60反应性T细胞似乎存在于某些患者的动脉粥样硬化病变中。这些结果清楚地表明，牙周感染有可能影响人冠状动脉内皮细胞，并可能促进后续动脉粥样硬化的发展。

Is has been postulated that periodontal infection may be involved in the initiation and progression of atherosclerosis and subsequent coronary heart disease. Although this concept has been supported by epidemiological case control studies, biological relevance of periodontitis to initiation and progression of atherosclerosis remained unknown. In this research project we analyzed the effects of bacterial antigens and inflammatory cytokines synthesized in the periodontitis lesion on endothelial cell function and the role of humoral and cellular immune responses to bacterial antigen and cross-reactive endogenous antigen on the atherogenesis. Lipopolysaccharide (LPS) and GroEL (HSP60) from Porphyromonas gingivalis (P.gingivalis), a representative periodontopathic bacterium, up-regulated the expression of ICAM-1 and VCAM-a on human coronary arterial endothelial cells. IL-1b and TNF-a, both of which are involved in the tissue destruction seen in periodontitis, also up-regulated the expression of these molecules at concentrations seen in the sera of periodontitis patients. Despite being highly homologous between prokaryotic and eukaryotic cells, HSP60s are strongly immunogenic and are thought to implicate in inflammation as well as the autoimmune diseases. Antibody levels to both human and P.gingivalis HSP60s were the highest in atherosclerosis patients followed by periodontitis patients and healthy subjects. Clonal analysis of the T cells clearly demonstrated the presence of not only human HSP60-but also P.gingivalis GroEL-reactive T-cell populations in the peripheral circulation of atherosclerosis patients. Furthermore, these HSP60-reactive T cells seemed to be present in atherosclerotic lesions in some patients. These results clearly indicate that periodontal infection has the potential to affect human coronary arterial endothelial cells and may contribute to the development of subsequent atherosclerosis.