Protection against gastrointestinal nematode infection by sialic acid linkaged mucin

我们项目的目标是更好地了解对胃肠道线虫感染的保护机制。我们采用具有代表性的胃肠道线虫感染实验模型之一巴西尼波圆线虫感染小鼠模型。在本研究中，我们首先尝试交换大鼠和小鼠系统中分别显示的保护机制信息。1930年开始对大鼠的排毒机制进行了研究，并提出了两个步骤。然后我们检验了大鼠的两步理论是否也适用于小鼠。结果表明，第一步，免疫介导的蠕虫损伤，并不是小鼠从小肠排出成虫所必需的，第二步，非特异性粘膜反应，是至关重要的（Ishiwata et al. 2002）。此外，我们认为第二步是stat6依赖性杯状细胞在小鼠中的反应。两种小鼠模型都表明CD4+细胞对排毒很重要。最近在小鼠系统中发现，IL-13/IL-4受体/Stat6通路对成虫巴西蠓的驱逐是必需的。接下来，我们通过凝集素组织化学检测小鼠杯状细胞粘蛋白的特征性变化。结果表明，杯状细胞黏液蛋白中的唾液酸链与成虫的排出有关（Ishiwata等人提交）。此外，唾液基转移酶（sialyltransferase）的表达在蠕虫排出时或外源IL-13处理下上调，诱导成虫排出。综上所述，我们认为小鼠对巴西巴西虫感染的保护机制为：CD4+细胞释放IL-13 -> IL-13结合杯状细胞上的IL-4受体->激活Stat6 ->上调唾液基转移酶表达->唾液添加与粘蛋白连锁->成虫排出。

The goal of our project is to get a better understanding on the protective mechanisms against gastrointestinal nematode infection. We employ Nippostrongylus brasiliensis-infected murine model that is one of the representative experimental models of gastrointestinal nematode infection. In this study, we firstly tried to interchange the information on protective mechanisms shown separately from rats- and mice-system. Expulsion mechanism in rats has been studied since 1930 and proposed to have two steps. Then we examined the two step theory in rats is also applicable in mice. Results suggested that first step, immune-mediated damage to the worms, is not essential for mice to expel adult N. brasiliensis from small intestine and that second step, non-specific mucosal responses, is critical (Ishiwata et al. 2002). Further, we suggested that the second step was Stat6-dependent goblet cell-response in mice. Both murine models have implied that CD4+ cells are important for the expulsion. Mice system recently showed the requirement of the IL-13/IL-4 receptor/Stat6 pathway for the adult N. brasiliensis expulsion. We next examined characteristic change in mice goblet cell mucins by lectin histochemistry. Results showed that sialic acid linkage in goblet cell mucin was associated with adult N. brasiliensis expulsion (Ishiwata et al. submitted). Furthermore, the expression of the enzyme, sialyltransferase, was upregulated at the time of worm expulsion or under exogenous IL-13 treatment which induces adult worm expulsion in scid mice. In summary, we suggested a protective mechanism against N. brasiliensis infection in mice as followed : CD4+ cells release IL-13 -> IL-13 binds to IL-4 receptor on goblet cells -> Stat6 activation -> up-regulation of the sialyltransferase expression -> sialic add linkage to mucin -> adult worm expulsion.