Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis.
Quantitative and functional analysis of PDC-E2-specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis.
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DOI：
10.1172/jci14698
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发表时间：
2002-05
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影响因子：
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通讯作者：
H. Kita;Shuji Matsumura;Xiao‐Song He;A. Ansari;Zhe‐Xiong Lian;J. Van de Water;R. Coppel;Marshall M. Kaplan;M. Gershwin
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文献类型：
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作者：
H. Kita;Shuji Matsumura;Xiao‐Song He;A. Ansari;Zhe‐Xiong Lian;J. Van de Water;R. Coppel;Marshall M. Kaplan;M. Gershwin
虽然原发性胆汁性肝硬化（PBC）中器官特异性组织损伤的病理机制仍然是一个谜，但已表明病理是由浸润肝内胆管的自身反应性T细胞介导的。以前，我们已经证明，有100倍富集的频率的CD 4（+）自身反应性T细胞在肝脏中，是特异性的丙酮酸脱氢酶复合物（PDC-E2）的E2组分编码的肽。我们最近还鉴定了PDC-E2的第一个MHC I类限制性表位，即氨基酸159-167，这是一个与MHC II类限制性CD 4（+）细胞和自身抗体识别的表位非常相似的区域。这些PDC-E2（159-167）特异性CD 8（+）细胞毒性T淋巴细胞（CTL）的效应子功能尚不清楚。我们已经利用四聚体技术并在本文中报道，与PBC中的血液相比，肝脏中PDC-E2（159-167）特异性CTL的频率增加了10倍。此外，早期PBC患者血液中CTLs前体频率明显较高。令人感兴趣的事实是，在用肽刺激后，PDC-E2（159-167）四聚体阳性细胞的应答在IFN-γ合成方面是异质的。我们相信，这些数据首次记录了PBC肝脏中自身抗原特异性CD 8（+）T细胞的富集，表明CD 8（+）T细胞在PBC的免疫发病机制中发挥着重要作用。
While the pathologic mechanisms responsible for organ-specific tissue damage in primary biliary cirrhosis (PBC) remain an enigma, it has been suggested that the pathology is mediated by autoreactive T cells infiltrating the intrahepatic bile ducts. Previously, we have documented that there is 100-fold enrichment in the frequency of CD4(+) autoreactive T cells in the liver that are specific for peptides encoded by the E2 components of the pyruvate dehydrogenase complexes (PDC-E2). We have also recently characterized the first MHC class I-restricted epitope for PDC-E2, namely amino acid 159-167, a region very similar to the epitope recognized by MHC class II-restricted CD4(+) cells and by autoantibodies. The effector functions of these PDC-E2(159-167)-specific CD8(+) cytotoxic T lymphocytes (CTLs) are not well understood. We have taken advantage of tetramer technology and report herein that there is tenfold increase in the frequency of PDC-E2(159-167)-specific CTLs in the liver as compared with the blood in PBC. In addition, the precursor frequency of the CTLs in blood was significantly higher in early-stage PBC. Of interest was the fact that, upon stimulation with the peptide, the response of PDC-E2(159-167) tetramer-positive cells is heterogeneous with respect to IFN-gamma synthesis. These data, we believe for the first time, document the enrichment of autoantigen-specific CD8(+) T cells in the PBC liver, suggesting that CD8(+) T cells play a significant role in the immunopathogenesis of PBC.