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Autoimmune-mediated mechanism of biliary injury in primary biliary cirrhosis

原发性胆汁性肝硬化中自身免疫介导的胆道损伤机制

基本信息

批准号：
07457596
负责人：
ONISHI Saburo
金额：
$ 0.32万
依托单位：
Kochi Medical School
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07457596/
关键词：
primary biliary cirrhosis immunogenetics Tap-genes alpha-enolase antibody biliary antigen

项目摘要

Primary biliary cirrhosis (PBC) is considered as an autoimmune mediated intrahepatic biliary injury. Regarding the immunopathogenesis of the disease, immunogenetical analysis and T cell responses to auto antigens (biliary protein B1-28, and pyruvate dehydrogenase E2 : PDHE2) were performed. Clinical significance of a new autoantibody against alpha enolase in PBC was also examined.1) Immunogenetics : DNA typing of HLA class I and II genes revealed that DR8 was one of susceptible genes to the development of the disease, and DRB1^<**>0803 was most frequent among 6 alleles of DR8. Heterogeneity of Tap-1, Tap-2 and DM genes which are locating close to HLA genes and function as transporter of immuno-peptides to rough ER and as stabilizer of immuno-peptide and MHC class II complexes, was also studied. Frequency of Bky2 (point mutant of Tap-2 allele type B) was significantly high in PBC,but DM genes examined was not, compared with control.2) Aotuantigen : Biliary protein B1-28 can stimulate T cells of PBC patients. Amino acid sequence analysis of the antigen showed partial homology with immuno-globulin family. Characterization of T cell clones which were established from peripheral lymphocytes of PBC patientsare under investigation, in which EBV transformed auto B cells were used as antigen presenting cells.3) A New autoantibody : alpha enolase antibody was detected with 2D western blotting. The antibody was detected in 16 of 56 PBC patients, and prognosis of the antibody positive patient was worse, compared with that of the antibody negative patients.

原发性胆汁性肝硬化（PBC）被认为是一种自身免疫介导的肝内胆道损伤。关于疾病的免疫发病机制，进行了免疫遗传学分析和T细胞对自身抗原（胆道蛋白B1-28和丙酮酸脱氢酶E2: PDHE2）的反应。研究了一种新的抗α烯醇化酶自身抗体在PBC中的临床意义。1)免疫遗传学：HLAⅰ、ⅱ类基因的DNA分型显示DR8是本病发生的易感基因之一，DR8的6个等位基因中以DRB1^<**>0803最为常见。Tap-1、Tap-2和DM基因位于HLA基因附近，是免疫肽向粗内质网的转运体，也是免疫肽和MHC II类复合物的稳定剂，研究了它们的异质性。Bky2 （Tap-2等位基因B型点突变体）在PBC中频率显著高，而DM基因在PBC中频率不高。2)胆道抗原：胆道蛋白B1-28可刺激PBC患者的T细胞。氨基酸序列分析显示抗原与免疫球蛋白家族部分同源。研究了从PBC患者外周血淋巴细胞中建立的T细胞克隆的特性，其中EBV转化的自身B细胞作为抗原提呈细胞。3)二维免疫印迹法检测到一种新的自身抗体：α烯醇化酶抗体。56例PBC患者中有16例检测到抗体，抗体阳性患者的预后较抗体阴性患者差。