Immunopathological and Molecular Biological Study of Primary Biliary Cirrhosis

原发性胆汁性肝硬化的免疫病理学和分子生物学研究

• 批准号: 07044239
• 负责人: NAKANUMA Yasuni
• 金额: $ 2.43万
• 依托单位: KANAZAWA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for international Scientific Research
• 财政年份: 1995
• 资助国家: 日本
• 起止时间: 1995 至 无数据
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07044239/
• 关键词: primary biliary cirrhosis; antimitochodrial antibodies; interlobular bile duct; confocal lazer microscope; pyruvate dehydrogenase; bile; ALY mouse; immunohistochemistry; Immunopathological

It has been recently reported that pyruvate dehydrogenase E2 subunit (PDC-E2), a major autoantigen recognized by antimitochodrial antibodies frequently and characteristically occurring in the patients with primary biliary cirrhosis (PBC), was abnormally expressed on the interlobular bile duct in PBC.T cells reating with this antigen were also recovered from PBC liver tissues. In this international collaborative project, these phenomena were examined using a monoclonal antibody reacting with inner lipoic domain of PDC-E2 and immunohistochemistry including confocal lazer microscope, in situ hybridization, and western blotting of bile. It was found out that this antigen was abnormally expressed on the luminal side of damaged interlobular bile ducts, outside mitochondria, while expression of this antigen on the bile ducts in other diseases was focal or weak. mRNA for this antigen was hardly detectable in the bile duct epithelial cells of PBC which were expressing this antigen, though mRNA was detectable in hepatocytes and other mesenchymal cells. Substance (s) cross-reacting with PDC-E2, about 74kD molecular weight, were detectable frequently in bile from PBC patients. In addition, a novel model of PBC is being explored. In this animal (ALY mouse), there were a spontaneous occurrence of nonsuppurative cholangitis and also immunological abnormalities. These results suggest that substances reactive with C355.1 abnormally appeared in bile and abosrbed into the interlobular bile ducts in PBC.It remains unlcear where these substances are produced and how these substances are abnormally absorbed into the bile duct epithelial cells in PBC.The fine mechanism between abnormal expression of PDC-E2 on the bile ducts and host immune system deserve further study.

最近有报道称，丙酮酸脱氢酶E2亚基（PDC-E2）是原发性胆汁性肝硬化（PBC）患者中常见的抗线粒体抗体识别的主要自身抗原，在原发性胆汁性肝硬化患者的小叶间胆管上异常表达。与该抗原反应的T细胞也从PBC肝组织中恢复。在这个国际合作项目中，使用单克隆抗体与PDC-E2的内硫辛域反应和免疫组织化学包括共聚焦激光显微镜、原位杂交和免疫印迹检测胆汁的这些现象。发现该抗原在受损小叶间胆管管腔侧线粒体外异常表达，而在其他疾病中，该抗原在胆管上的表达为局灶性或弱表达。在表达该抗原的PBC胆管上皮细胞中几乎检测不到该抗原的mRNA，但在肝细胞和其他间充质细胞中检测到mRNA。PBC患者胆汁中常检测到与PDC-E2交叉反应的物质，分子量约为74kD。此外，一种新的PBC模式正在探索中。该动物（ALY小鼠）出现自发性非化脓性胆管炎和免疫异常。提示PBC患者胆汁中存在C355.1反应性物质，并被胆管小叶间管吸收。目前尚不清楚这些物质是在哪里产生的，以及这些物质是如何被PBC的胆管上皮细胞异常吸收的。胆管上PDC-E2异常表达与宿主免疫系统之间的精细机制值得进一步研究。

项目成果

K.Tsuneyama,J.Van de Water,D.Van Thiel,R.Coppel,B.Ruebner,Y.Nakanuma Y,ER.Dickson,ME.Gershwin.: "Abnormal expression of PDC-E2 on the apical surface of biliary epithelial cells in patients with antimitochondrial antibody-negative primary biliary cirrhosis

K.Tsuneyama,J.Van de Water,D.Van Thiel,R.Coppel,B.Ruebner,Y.Nakanuma Y,ER.Dickson,ME.Gershwin.：“PDC-E2在胆管顶端表面的异常表达

Y.Nakanuma,K.Tsuneyama,N.Kono,M.Hoso,J.Van de Water,ME Gershwin: "Biliary epithelial expression of pyruvate dehydrogenase complex in primary biliary cirrhosis : An immunohistochemical and immunoelectron microscopic study" Hum Pathol. 26. 92-98 (1995)

Y.Nakanuma、K.Tsuneyama、N.Kono、M.Hoso、J.Van de Water、ME Gershwin：“原发性胆汁性肝硬化中丙酮酸脱氢酶复合物的胆道上皮表达：一项免疫组织化学和免疫电子显微镜研究”Hum Pathol。

M.Yasoshima,Y.Nakanuma,K.Tsuneyama J.Van de Water,M.E.Gershwin: "Immunohistochemical analysis of adhesion molecules in the micro-enviroment of portal tracts in relation to aberrant expression of PDC-E2 and HLA-DR on the bile ducts in primary biliary cirrh

M.Yasoshima、Y.Nakanuma、K.Tsuneyama J.Van de Water、M.E.Gershwin：“门静脉微环境中粘附分子的免疫组织化学分析与胆汁上 PDC-E2 和 HLA-DR 的异常表达相关

常山幸一、中沼安二: "抗ミトコンドリア抗体の病態生理学的意義 Annual Review消化器" 中外医学社(岡博など編), 322 (1996)

Koichi Tsuneyama、Yasuji Nakanuma：“抗线粒体抗体年度评论胃肠病学的病理生理学意义”Chugai Igakusha（Hiroshi Oka 等人编辑），322（1996）

Y.Nakanuma, K.Tsuneyama, N.Kono, M.Hoso, J.Van de Water, ME.Gershwin: "Biliary epithelial expression of pyruvate dehydrogenase complex in primary bilary cirrhosis : An Immunohistochemicaland immunoelectron microscopic study" Hum Pathol. 26. 92-98 (1995)

Y.Nakanuma、K.Tsuneyama、N.Kono、M.Hoso、J.Van de Water、ME.Gershwin：“原发性胆汁性肝硬化中丙酮酸脱氢酶复合物的胆道上皮表达：免疫组织化学和免疫电子显微镜研究”Hum Pathol。