Kornman K S, di Giovine F S
Medical Science Systems, Inc., San Antonio, TX, USA.
Ann Periodontol. 1998 Jul;3(1):327-38. doi: 10.1902/annals.1998.3.1.327.
Periodontitis is a collection of chronic inflammatory diseases that are caused by specific bacteria. The bacteria activate inflammatory mechanisms in the periodontal tissues that destroy collagen and bone that support the teeth. Although bacteria are essential for the initiation of periodontitis, the quantity and types of bacteria have not been sufficient to explain the differences in disease severity. In recent years, it has become evident that for many common chronic diseases, there are modifying factors that do not cause the disease but rather amplify some disease mechanisms to make the clinical condition more severe. There are now data to suggest that a few factors which amplify the inflammatory process make people susceptible to an increased severity of periodontitis. Studies of untreated disease in Sri Lanka identified 3 patterns of disease progression. Studies in twins suggested that part of the clinical characteristics of periodontitis may be explained by genetic factors, but previous attempts to identify genetic markers for periodontitis have been unsuccessful Some genetic variations (polymorphisms) are commonly found in our population and represent a mechanism by which individuals may exhibit variations within the range of what is considered biologically normal. Since certain cytokines are key regulators of the inflammatory response and are important in periodontitis, we investigated the relationship between genetic variations associated with cytokine production and periodontitis severity. There are several polymorphisms in the cluster of genes that influence IL-1 biological activity. In recent clinical trials, two of these polymorphisms, when found together, have been associated with a significant increase in the risk for severe generalized periodontitis. Genetic association with periodontitis was evident only when smokers were excluded from the analysis, confirming the importance of smoking, and suggesting that both smoking and the IL- I genotype are independent factors in severe periodontitis. It is notable that 1 polymorphism associated with severe periodontitis in our study is also known to correlate with a 2- to 4-fold increase in IL-1 beta production. These findings are consistent with the current model of how genetic factors influence common chronic diseases. If we apply this model to periodontitis, it would involve the following: 1) a disease-initiating factor that would undoubtedly be specific bacteria such as Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans. and Bacteroides forsythus: and 2) modifiers of disease mechanisms that account for the clinical severity, including smoking, the IL-I genotype, certain systemic diseases, and psychosocial stress. The association of the IL-I genotype with severe periodontitis is consistent with several lines of periodontal research. Several studies have suggested there is a substantial genetic influence in periodontal disease. Although specific genetic markers have been identified in the uncommon juvenile forms of periodontitis, previous studies of specific genetic markers in adults with periodontitis have not been encouraging. Many investigators have, however, demonstrated a role for IL-1 in the initiation and progression of periodontitis. For example, IL-1 activates the degradation of the extracellular matrix and bone of the periodontal tissues, and elevated tissue or gingival fluid levels of IL-1 beta have been repeatedly associated with periodontitis. In addition, IL-1 is a strong enhancer of tissue levels of PGE2 and TNF-alpha. The association of severe periodontitis with smoking and the IL-1 genotype suggest a role for these factors in the pathogenesis of periodontitis. The finding that host modifying factors are associated with severe periodontitis suggest a biological mechanism by which some individuals, if challenged by bacterial accumulations, may have a more vigorous immunoinflammatory response, leading to more severe clinical disease. (ABSTRACT
牙周炎是由特定细菌引起的一组慢性炎症性疾病。这些细菌激活牙周组织中的炎症机制，破坏支持牙齿的胶原蛋白和骨骼。虽然细菌是引发牙周炎的必要因素，但细菌的数量和种类不足以解释疾病严重程度的差异。近年来，越来越明显的是，对于许多常见的慢性疾病，存在一些调节因素，这些因素不会引发疾病，而是会放大某些疾病机制，使临床病情更加严重。现在有数据表明，一些放大炎症过程的因素会使人们更容易患严重的牙周炎。在斯里兰卡对未经治疗的疾病进行的研究确定了3种疾病进展模式。对双胞胎的研究表明，牙周炎的部分临床特征可能由遗传因素解释，但此前识别牙周炎基因标记的尝试均未成功。一些基因变异（多态性）在我们的人群中普遍存在，代表了个体在生物学正常范围内可能表现出变异的一种机制。由于某些细胞因子是炎症反应的关键调节因子，在牙周炎中很重要，我们研究了与细胞因子产生相关的基因变异与牙周炎严重程度之间的关系。影响白细胞介素-1（IL-1）生物学活性的基因簇中有几种多态性。在最近的临床试验中，其中两种多态性同时出现时，与重度广泛型牙周炎风险显著增加有关。仅在分析中排除吸烟者时，基因与牙周炎的关联才明显，这证实了吸烟的重要性，并表明吸烟和IL-1基因型都是重度牙周炎的独立因素。值得注意的是，我们研究中与重度牙周炎相关的1种多态性也已知与IL-1β产生增加2至4倍相关。这些发现与遗传因素影响常见慢性疾病的当前模型一致。如果将此模型应用于牙周炎，将涉及以下方面：1）疾病引发因素，无疑是特定细菌，如牙龈卟啉单胞菌、伴放线放线杆菌和福赛坦氏菌；2）解释临床严重程度的疾病机制调节因素，包括吸烟、IL-1基因型、某些全身性疾病和心理社会压力。IL-1基因型与重度牙周炎的关联与多项牙周研究结果一致。几项研究表明，牙周疾病存在显著的遗传影响。虽然在罕见的青少年型牙周炎中已确定了特定的基因标记，但此前对成人牙周炎特定基因标记的研究并不乐观。然而，许多研究人员已证明IL-1在牙周炎的发生和发展中起作用。例如，IL-1激活牙周组织细胞外基质和骨骼的降解，组织或龈沟液中IL-1β水平升高一直与牙周炎相关。此外，IL-1是组织中前列腺素E2（PGE2）和肿瘤坏死因子-α（TNF-α）水平的强力增强剂。重度牙周炎与吸烟和IL-1基因型的关联表明这些因素在牙周炎发病机制中起作用。宿主调节因素与重度牙周炎相关的发现提示了一种生物学机制，即一些个体如果受到细菌堆积的挑战，可能会有更强烈的免疫炎症反应，导致更严重的临床疾病。（摘要）
