戊型肝炎病毒感染对肠道黏膜免疫的影响
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摘要
为了进一步揭示戊型肝炎病毒(HEV)与肠道黏膜免疫屏障的相互作用,本研究应用新西兰大白兔及长爪沙鼠作为HEV的感染的动物模型,目标锁定HEV相关抗原在肠道组织中的定位及其对肠道黏膜免疫的影响,采用组织病理学、组织细胞化学、免疫组织化学、PCR等方法,全面系统地观察兔及沙鼠感染HEV后,肠道结构,肠道黏膜免疫相关细胞的数量及黏膜免疫相关因子表达,揭示了HEV侵入过程中肠道免疫细胞间及局部黏膜免疫功能之间的关系,进而阐明黏膜免疫相关细胞和分子在HEV感染中的功能作用。试验结果如下：
1、兔源HEV感染家兔试验兔源HEV腹腔感染兔后,呈现不同的感染类型,感染后血清、粪便均可检测到]HEV RNA,血清中可检测到HEV ORF2抗原,同时肝脏也表现出与人HEV感染相似的病理变化；HEV感染兔全身组织器官HEV RNA及ORF2抗原检测结果显示,兔源HEV RNA及ORF2抗原可在感染兔不同组织器官(肝脏、脾脏、肺脏、淋巴结、十二指肠、空肠、回肠、圆小囊、蚓突)中分布,并且当粪便内存在HEV RNA时,肠道及肠相关淋巴组织可呈HEV抗原阳性；免疫组织化学观察结果表明：HEV ORF2抗原阳信信号主要分布于肠道黏膜上皮细胞、肠腺上皮细胞胞浆及圆小囊及蚓突的圆顶上皮M细胞胞浆中,而HEV ORF3抗原阳信信号主要成片分布于肠道黏膜上皮细胞、肠腺上皮细胞胞浆中,呈颗粒状分布于肠道管腔面,圆顶上皮细胞胞浆顶端及淋巴滤泡内的滤泡成纤维网状细胞中。
2、猪源HEV感染沙鼠试验猪源HEV感染沙鼠后,沙鼠粪便及肠道组织在不同时间点均能检测出HEV RNA,且肠道呈HEV ORF2抗原阳性,阳性信号主要分布于肠道上皮细胞、肠腺上皮细胞胞浆中；沙鼠肠道形态与结构的观察与分析表明：HEV感染后沙鼠肠道杯状细胞数量未出明显变化。攻毒后7天及14天,攻毒组沙鼠十二指肠绒毛长度和回肠隐窝深度值显著下降(p<0.05)。而攻毒后第21及28天,沙鼠肠道绒毛长度及隐窝深度值均有回升。层粘蛋白免疫组织化学显示HEV感染后沙鼠肠道黏膜基底膜的层粘蛋白表达量没有显著变化。
HEV感染后沙鼠肠道黏膜免疫相关指标的观察结果表明：肠道派尔氏结及上皮内淋巴细胞数量均有不显著的升高,肠道总的肥大细胞数量在感染后21天及28天显著升高(p<0.05)。HEV感染后不同时间点,沙鼠肠道中IgA的表达量与对照组相比均显著升高(p<0.05)。肠道固有层树突状细胞数量在攻毒后21天及28天有所增加,尤其在攻毒后21天树突状细胞数量呈显著增加(p<0.05)。
3、活体兔肠袢结扎感染试验HEV感染活体兔结扎的回肠及圆小囊后10min即可见回肠及圆小囊黏膜上皮中有HEV ORF2抗原表达,而且感染HEV后30min HEV ORF2抗原阳性信号比感染后10min显著增强。阳性信号主要分布于肠道黏膜上皮细胞、腺上皮细胞、圆小囊圆顶上皮细胞及少量的圆小囊淋巴滤泡中的单核细胞胞浆内。HEV感染活体兔结扎的圆小囊后24h,兔圆小囊的淋巴细胞刺激指数明显升高。活体兔结扎的回肠及圆小囊经抗sIgA抗体处理后再用HEV感染,圆小囊中的HEV ORP2抗原变化不明显,而回肠黏膜上皮细胞胞浆及其表面的HEVORF2阳性信号明显增多,表明肠道黏膜组织不仅仅是HEV侵入机体的门户,而且也是HEV繁殖的重要场场所。同时表明sIgA在肠道黏膜抗HEV感染免疫中担任了得要的角色,当其表达受到抑制时,HEV就易于感染上皮细胞,并很快在细胞内增殖。
上述研究结果表明,HEV可以直接作用于肠道黏膜上皮,引起黏膜上皮细胞感染。感染HEV后,HEV RNA及其抗原在各段肠道及肠相关淋巴组织中广泛分布。HEV感染对肠道的结构有一定的损伤作用,同时能激发肠道黏膜免疫功能,使肠道内肥大细胞、树突状细胞的数量和sIgA的表达量增多。IgA在肠道黏膜抗HEV感染免疫中担任了重要的角色。
In order to reveal the interaction between Hepatitis E virus (HEV) and intestine, we used New Zealand white rabbits and gerbils to study the effect of HEV on intestinal mucosal immune and the location of HEV antigen in the gut. Histopathology, histocytochemistry, immunohistochemistry and PCR methods were used to analyze the effect of HEV on intestine structure, and quantify the intestinal mucosal immune cells and relevant factors. The results revealed the relationship between intestinal immune cells and local mucosal immune function during the process of HEV invasion.
1After the infection of rabbits with HEV through intraperitoneal injection, the rabbits showed different infection types. HEV RNA can be detected in the serum and fecea, and HEV ORF2antigen can be detected in serum. While the liver also showed similar pathological changes with human HEV. HEV RNA and ORF2antigen in rabbits were distributed in the different tissues and organs in rabbits after infection. At the same time, HEV antigen was positive in the gut and gut-associated lymphoid tissue when HEV RNA was existed in feces. HEV ORF2antigen was mainly existed in the cytoplasm of intestine epithelial cells and M cells of sacculus and appendix. While HEV ORF3antigen was largely distributed in cytoplasm intestine epithelial cells, but granularly distributed in luminal surface of the follicular associated epithelial cells and within few monocytes in lymphoid tissues.
2After infected swine HEV, the feces and intestine tissues can be detected HEV RNA positive in all gerbils at different time after inoculation. HEV ORF2antigen was positive in the intestine, and the positive signals were mainly distributed in the cytoplasm of epithelial cells and glandular epithelium. The observation of gerbils intestinal morphology showed that the structure was normal, the numbers of goblet cells was not increased significantly after HEV infection. But the length of intestinal villi, the depth of crypt was decreased at7days and14days post inoculation, while rebounded at21days and28days post inoculation. Immunohistochemistry for laminin showed that the basic membrane structure was not changed.
The data of mucosal immune showed that the number of Payer's patch and intraepithelial cells was increased but not significantly. The total number of mast cells was increased significantly at21days and28days post inoculation. The IgA expression was elevated significantly at each time post inoculation, and the numbers of dendritic cells in intestinal lamina propria increased at21and28days after infection, especially at21days.
3After inoculating ligated intestine in vivo in rabbits, HEV ORF2antigen in ileum and sacculus was positive, furthermore, the positive signal of HEV ORF2antigen was stronger at30min than10min after inoculation. The positive signals were mainly distributed in the intestine epithelial cells, sacculus dome epithelium and few monocytes at lymphoid tissue. The lymphocyte stimulation index in sacculus was increased significantly in rabbits at24h after inoculation. When pretreated with IgA antibody, the HEV ORF2antigen in sacculus was not varied obviously, but the expression of HEV antigens in ileum mucosal epithelial surface was increased a lot.
The results above showed that HEV could interact directly with intestine. The HEV RNA and HEV antigens were distributed in each segment of intestine and gut-associated lymphoid tissue. At the same time, the infection of HEV could affect the intestine structure and mucosal immune function, especially increase the expression of IgA and the amount of mast cells and dendritic cells.
1、兔源HEV感染家兔试验兔源HEV腹腔感染兔后,呈现不同的感染类型,感染后血清、粪便均可检测到]HEV RNA,血清中可检测到HEV ORF2抗原,同时肝脏也表现出与人HEV感染相似的病理变化；HEV感染兔全身组织器官HEV RNA及ORF2抗原检测结果显示,兔源HEV RNA及ORF2抗原可在感染兔不同组织器官(肝脏、脾脏、肺脏、淋巴结、十二指肠、空肠、回肠、圆小囊、蚓突)中分布,并且当粪便内存在HEV RNA时,肠道及肠相关淋巴组织可呈HEV抗原阳性；免疫组织化学观察结果表明：HEV ORF2抗原阳信信号主要分布于肠道黏膜上皮细胞、肠腺上皮细胞胞浆及圆小囊及蚓突的圆顶上皮M细胞胞浆中,而HEV ORF3抗原阳信信号主要成片分布于肠道黏膜上皮细胞、肠腺上皮细胞胞浆中,呈颗粒状分布于肠道管腔面,圆顶上皮细胞胞浆顶端及淋巴滤泡内的滤泡成纤维网状细胞中。
2、猪源HEV感染沙鼠试验猪源HEV感染沙鼠后,沙鼠粪便及肠道组织在不同时间点均能检测出HEV RNA,且肠道呈HEV ORF2抗原阳性,阳性信号主要分布于肠道上皮细胞、肠腺上皮细胞胞浆中；沙鼠肠道形态与结构的观察与分析表明：HEV感染后沙鼠肠道杯状细胞数量未出明显变化。攻毒后7天及14天,攻毒组沙鼠十二指肠绒毛长度和回肠隐窝深度值显著下降(p<0.05)。而攻毒后第21及28天,沙鼠肠道绒毛长度及隐窝深度值均有回升。层粘蛋白免疫组织化学显示HEV感染后沙鼠肠道黏膜基底膜的层粘蛋白表达量没有显著变化。
HEV感染后沙鼠肠道黏膜免疫相关指标的观察结果表明：肠道派尔氏结及上皮内淋巴细胞数量均有不显著的升高,肠道总的肥大细胞数量在感染后21天及28天显著升高(p<0.05)。HEV感染后不同时间点,沙鼠肠道中IgA的表达量与对照组相比均显著升高(p<0.05)。肠道固有层树突状细胞数量在攻毒后21天及28天有所增加,尤其在攻毒后21天树突状细胞数量呈显著增加(p<0.05)。
3、活体兔肠袢结扎感染试验HEV感染活体兔结扎的回肠及圆小囊后10min即可见回肠及圆小囊黏膜上皮中有HEV ORF2抗原表达,而且感染HEV后30min HEV ORF2抗原阳性信号比感染后10min显著增强。阳性信号主要分布于肠道黏膜上皮细胞、腺上皮细胞、圆小囊圆顶上皮细胞及少量的圆小囊淋巴滤泡中的单核细胞胞浆内。HEV感染活体兔结扎的圆小囊后24h,兔圆小囊的淋巴细胞刺激指数明显升高。活体兔结扎的回肠及圆小囊经抗sIgA抗体处理后再用HEV感染,圆小囊中的HEV ORP2抗原变化不明显,而回肠黏膜上皮细胞胞浆及其表面的HEVORF2阳性信号明显增多,表明肠道黏膜组织不仅仅是HEV侵入机体的门户,而且也是HEV繁殖的重要场场所。同时表明sIgA在肠道黏膜抗HEV感染免疫中担任了得要的角色,当其表达受到抑制时,HEV就易于感染上皮细胞,并很快在细胞内增殖。
上述研究结果表明,HEV可以直接作用于肠道黏膜上皮,引起黏膜上皮细胞感染。感染HEV后,HEV RNA及其抗原在各段肠道及肠相关淋巴组织中广泛分布。HEV感染对肠道的结构有一定的损伤作用,同时能激发肠道黏膜免疫功能,使肠道内肥大细胞、树突状细胞的数量和sIgA的表达量增多。IgA在肠道黏膜抗HEV感染免疫中担任了重要的角色。
In order to reveal the interaction between Hepatitis E virus (HEV) and intestine, we used New Zealand white rabbits and gerbils to study the effect of HEV on intestinal mucosal immune and the location of HEV antigen in the gut. Histopathology, histocytochemistry, immunohistochemistry and PCR methods were used to analyze the effect of HEV on intestine structure, and quantify the intestinal mucosal immune cells and relevant factors. The results revealed the relationship between intestinal immune cells and local mucosal immune function during the process of HEV invasion.
1After the infection of rabbits with HEV through intraperitoneal injection, the rabbits showed different infection types. HEV RNA can be detected in the serum and fecea, and HEV ORF2antigen can be detected in serum. While the liver also showed similar pathological changes with human HEV. HEV RNA and ORF2antigen in rabbits were distributed in the different tissues and organs in rabbits after infection. At the same time, HEV antigen was positive in the gut and gut-associated lymphoid tissue when HEV RNA was existed in feces. HEV ORF2antigen was mainly existed in the cytoplasm of intestine epithelial cells and M cells of sacculus and appendix. While HEV ORF3antigen was largely distributed in cytoplasm intestine epithelial cells, but granularly distributed in luminal surface of the follicular associated epithelial cells and within few monocytes in lymphoid tissues.
2After infected swine HEV, the feces and intestine tissues can be detected HEV RNA positive in all gerbils at different time after inoculation. HEV ORF2antigen was positive in the intestine, and the positive signals were mainly distributed in the cytoplasm of epithelial cells and glandular epithelium. The observation of gerbils intestinal morphology showed that the structure was normal, the numbers of goblet cells was not increased significantly after HEV infection. But the length of intestinal villi, the depth of crypt was decreased at7days and14days post inoculation, while rebounded at21days and28days post inoculation. Immunohistochemistry for laminin showed that the basic membrane structure was not changed.
The data of mucosal immune showed that the number of Payer's patch and intraepithelial cells was increased but not significantly. The total number of mast cells was increased significantly at21days and28days post inoculation. The IgA expression was elevated significantly at each time post inoculation, and the numbers of dendritic cells in intestinal lamina propria increased at21and28days after infection, especially at21days.
3After inoculating ligated intestine in vivo in rabbits, HEV ORF2antigen in ileum and sacculus was positive, furthermore, the positive signal of HEV ORF2antigen was stronger at30min than10min after inoculation. The positive signals were mainly distributed in the intestine epithelial cells, sacculus dome epithelium and few monocytes at lymphoid tissue. The lymphocyte stimulation index in sacculus was increased significantly in rabbits at24h after inoculation. When pretreated with IgA antibody, the HEV ORF2antigen in sacculus was not varied obviously, but the expression of HEV antigens in ileum mucosal epithelial surface was increased a lot.
The results above showed that HEV could interact directly with intestine. The HEV RNA and HEV antigens were distributed in each segment of intestine and gut-associated lymphoid tissue. At the same time, the infection of HEV could affect the intestine structure and mucosal immune function, especially increase the expression of IgA and the amount of mast cells and dendritic cells.
引文
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