Perez-Perez G I, Peek R M, Legath A J, Heine P R, Graff L B
Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
J Physiol Pharmacol. 1999 Dec;50(5):833-45.
Two major markers of virulence have been described in H. pylori. The first is a secreted protein (VacA) that is toxic to human cells in tissue culture. This cytotoxin causes vacuolation of epithelial cells in vitro and induces epithelial cell damage in mice. The second is a 40-Kb pathogenicity island for which the gene cagA (cytotoxin-associated gene A) is a marker. Approximately 60% of H. pylori isolates in Western countries are cagA+. The protein encoded by cagA+ has a molecular weight of 120-140 kDa and exhibits sequence heterogeneity among strains isolated from Western and Eastern countries. Although no specific function has been identified for CagA, there is increasing evidence that cagA+ strains are associated with increased intensity of gastric inflammation and increased mucosal concentration of particular cytokines including interleukin 8. Inactivation of picB (Hp 0544) or any of several other genes in the cag island ablates the enhanced IL-8 secretion of human gastric epithelial cells in tissue culture. Furthermore, persons colonized with cagA+ strains have an increased risk of developing more severe gastric diseases such as peptic ulcer and distal (non-cardia) gastric cancer than those harboring cagA- strains. We investigated the role of cagA status in both gastroduodenal and extragastroduodenal disease with H. pylori. Among the diseases limited to the antrum and body of the stomach and the duodenum, we demonstrated a correlation between CagA seropositivity and peptic ulcer disease. We also showed correlation between distal gastric cancer rated and CagA prevalence in populations in both developed and developing countries. In addition, we found that for several Asian populations, the relationship between CagA seropositivity and gastroduodenal diseases was complex. For extragastroduodenal diseases, our results confirmed previous reports that demonstrated that CagA status did not play a role in diseases such as rheumatoid arthritis and hyperemesis gravidarum. However, we found a clear negative association between the presence of a positive response to CagA and esophageal diseases. Therefore, CagA seropositivity (and thus gastric carriage) is associated with increased risks of certain diseases (involving the lower stomach and duodenum) and decreased risks of GERD and its sequelae. This apparent paradox can best be explained by differences in the interaction of cagA+ and cagA- strains with their hosts.
幽门螺杆菌已被描述有两种主要的毒力标志物。第一种是一种分泌蛋白（VacA），它在组织培养中对人类细胞有毒性。这种细胞毒素在体外可导致上皮细胞空泡化，并在小鼠中诱导上皮细胞损伤。第二种是一个40kb的致病岛，其基因cagA（细胞毒素相关基因A）是一个标志物。在西方国家，大约60%的幽门螺杆菌分离株是cagA阳性。cagA阳性菌株编码的蛋白质分子量为120 - 140kDa，并且在从西方国家和东方国家分离的菌株之间表现出序列异质性。尽管尚未确定CagA的具体功能，但越来越多的证据表明，cagA阳性菌株与胃炎症强度增加以及包括白细胞介素8在内的特定细胞因子的黏膜浓度增加有关。picB（Hp 0544）或cag岛中的其他几个基因中的任何一个失活，都会消除组织培养中人类胃上皮细胞增强的IL - 8分泌。此外，感染cagA阳性菌株的人比携带cagA阴性菌株的人患更严重胃病如消化性溃疡和远端（非贲门）胃癌的风险增加。我们研究了cagA状态在幽门螺杆菌引起的胃十二指肠疾病和胃十二指肠外疾病中的作用。在仅限于胃窦、胃体和十二指肠的疾病中，我们证明了CagA血清阳性与消化性溃疡病之间存在相关性。我们还显示了发达国家和发展中国家人群中远端胃癌发病率与CagA流行率之间的相关性。此外，我们发现对于几个亚洲人群，CagA血清阳性与胃十二指肠疾病之间的关系很复杂。对于胃十二指肠外疾病，我们的结果证实了先前的报告，即表明CagA状态在类风湿性关节炎和妊娠剧吐等疾病中不起作用。然而，我们发现对CagA呈阳性反应与食管疾病之间存在明显的负相关。因此，CagA血清阳性（进而胃携带）与某些疾病（涉及胃下部和十二指肠）的风险增加以及胃食管反流病及其后遗症的风险降低有关。这种明显的矛盾最好通过cagA阳性和cagA阴性菌株与其宿主相互作用的差异来解释。
