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.

丙酮酸脱氢酶E_2亚基(PDC-E_2)是抗胆道抗体识别的主要自身抗原，常见于原发性胆汁性肝硬变(PBC)患者的小叶间胆管，近年来有报道发现PDC-E_2在PBC的小叶间胆管中异常表达。在这项国际合作项目中，使用与PDC-E2的内部硫辛酸结构域反应的单抗和免疫组织化学包括激光共聚焦显微镜、原位杂交和胆汁免疫印迹来检测这些现象。发现该抗原异常表达于受损小叶间胆管的管腔一侧、线粒体外，而在其他疾病的胆管上呈灶性或弱表达。在PBC的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可检测到该抗原的mRNA。在PBC患者胆汁中经常检测到与PDC-E_2交叉反应的物质(S)，其相对分子质量约为74kD。此外，正在探索一种新的PBC模式。在这只动物(小鼠)中，非化脓性胆管炎和免疫异常都是自发发生的。这些结果提示，PDC-E_2在胆汁中异常表达，并进入小叶间胆管，这些物质在胆汁中异常出现，并进入小叶间胆管，但这些物质的来源及如何被胆管上皮细胞异常吸收尚不清楚。PDC-E_2在胆管上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。