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Studies on pathogenesis and progression of primary biliary cirrhosis with special reference to analysis of autoimmune responses to biliary tract cytoskeleton.

研究原发性胆汁性肝硬化的发病机制和进展，特别是分析胆道细胞骨架的自身免疫反应。

基本信息

批准号：
02670318
负责人：
ODA Masaya
金额：
$ 1.54万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1990
资助国家：
日本
起止时间：
1990 至 1992
项目状态：
已结题

项目摘要

Transmission electron microscopy revealed that intermediate filaments (IF) are diffusely present in the cytoplasm of bile duct epithelium, whereas microfilaments (actin filametns : AF) are located in the subplasmalemmal region. Acoording to the indirect immunofluorescent method, anti-IF (cytokeratin : CK) antibody proved by the specific immunofluorescence for IF in PtK_2 cultured cells and anti-AF antibody proved by that for AF in _3T_3 cultured cells were detected in sera of all patients with primary biliary cirrhosis (PBC). CK derived from PtK_2 cells were divided into subclass CK1(52kD) and CK2(45kD) by SDS-PAGE.Monoclonal antibodies were produced against CK1 and CK2 respectively. By the sandwich inhibition ELISA, anti-CK1 antibody titers in sera of PBC patients were proved to be significantly higher than those in patients with other liver disease, demonstrating the highest degrees on the stage I-II of PBC showing the most prominent morphological features of chronic non-suppurative destructive cholangitis (CNSDC) by liver biopsy and the lowest degrees on the stage IV hardly showing CNSDC.By long term ursodeoxycholic acid (UDCA). anti-CK1 and anti-M2 (pyruvate dehydrogenase) antibody titers were significantly reduced in sera of symptomatic and asymptomatic PBC patients, implying that UDCA therapy may affect the autoimmune abnormalities in PBC.A decrease in anti-CK1 antibody titers by UDCA therapy would reflect an improvement in pathological state of PBC.By the indirect immunoperoxidase antibody method, it was revealed that not only HLA-DR but also intercellular adhesiom molecule (ICAM)-1 are most strongly expressed on the outer surfaces of the plasma membranes of bile duct epithelial cells. Furthermore CD4 and CD8-positive cells expressed on cell surface by lymphocyte function-associated antigen(LFA)-1 were found to be infiltrated particularly around bile ducts, making direct contant with the ICAM-1-positive bile duct epithelial cells.

透射电子显微镜显示，中间丝（IF）弥漫存在于胆管上皮细胞质中，而微丝（肌动蛋白纤维：AF）位于质膜下区域。用间接免疫荧光法检测了所有原发性胆汁性肝硬化（PBC）患者血清中抗IF（细胞角蛋白：CK）抗体和抗AF抗体，其中抗IF抗体由PtK_2培养细胞中的IF特异性免疫荧光证实，抗AF抗体由_3T_3培养细胞中的AF特异性免疫荧光证实。从PtK_2细胞中分离的CK经SDS-PAGE电泳分为CK_1（52 kD）和CK_2（45 kD）两个亚类，分别制备了CK_1和CK_2的单克隆抗体。采用夹心抑制ELISA法检测，发现原发性肝癌患者血清中抗CK 1抗体滴度明显高于其他肝脏疾病患者，肝活检显示，PBC I-II期程度最高，显示慢性非化脓性破坏性胆管炎（CNSDC）的形态学特征最突出，而IV期程度最低，几乎不显示CNSDC。UDCA）。抗CK 1和抗M2结果显示，有症状和无症状PBC患者血清中抗CK 1抗体滴度均明显降低，提示UDCA治疗可能影响PBC的自身免疫异常，UDCA治疗后抗CK 1抗体滴度的降低反映PBC病理状态的改善。结果显示，不仅HLA-DR而且细胞间粘附分子（ICAM）-1在胆管上皮细胞质膜的外表面上表达最强。淋巴细胞功能相关抗原（LFA-1）表达的CD 4、CD 8阳性细胞浸润于胆管周围，与ICAM-1阳性的胆管上皮细胞直接接触。