AUTOIMMUNE, CHOLESTATIC AND BILIARY DISEASE Loss of Tolerance in C57BL/6 Mice to the Autoantigen E2 Subunit of Pyruvate Dehydrogenase by a Xenobiotic with Ensuing Biliary Ductular Disease
AUTOIMMUNE, CHOLESTATIC AND BILIARY DISEASE Loss of Tolerance in C57BL/6 Mice to the Autoantigen E2 Subunit of Pyruvate Dehydrogenase by a Xenobiotic with Ensuing Biliary Ductular Disease
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发表时间：
2008
期刊：
影响因子：
2.9
通讯作者：
K. Wakabayashi;Zhe‐Xiong Lian;P. Leung;Y. Moritoki;K. Tsuneyama;Mark J. Kurth;Kit S. Lam;Katsunori Yoshida;Guo‐Xiang-X. Yang;T. Hibi;A. Ansari;W. Ridgway;R. Coppel;Ian R. Mackay;M. Gershwin
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作者：
K. Wakabayashi;Zhe‐Xiong Lian;P. Leung;Y. Moritoki;K. Tsuneyama;Mark J. Kurth;Kit S. Lam;Katsunori Yoshida;Guo‐Xiang-X. Yang;T. Hibi;A. Ansari;W. Ridgway;R. Coppel;Ian R. Mackay;M. Gershwin
在确定几种人类自身免疫性疾病的效应机制方面取得了重要进展。然而，对于大多数人类自身免疫性疾病，诱导阶段不太明确，病因学线索很少。我们的实验室一直致力于确定原发性胆汁性肝硬化（PBC）中自身抗体识别和表位修饰的分子基础。我们的工作已经证明，线粒体抗体，疾病的标志，是针对丙酮酸脱氢酶的一个非常保守的网站，丙酮酸脱氢酶的E2亚基（PDC-E2）。我们还证明了几种化学外源性物质，选择的基础上定量结构活性关系分析和严格的表位分析，当耦合到赖氨酸残基，通常结合的硫辛酸辅因子PDC-E2，反应以及或更好地PBC血清比天然自身抗原。在本研究中，我们免疫C57 BL/6小鼠与这样的异生物质，2-辛炔酸，偶联牛血清白蛋白，我们跟踪小鼠24周。研究动物的组织学病变的外观以及PDC-E2抗体的外观，肿瘤坏死因子和干扰素的血清水平，以及脾和肝淋巴细胞表型通过流式细胞术。用2-辛炔酸免疫的小鼠表现出自身免疫性胆管炎、典型的线粒体自身抗体、肝淋巴样细胞数量增加、CD 8肝浸润细胞（特别是共表达CD 44的CD 8 T细胞）增加，以及最终血清肿瘤坏死因子和干扰素升高。结论：这些数据提供了一个有说服力的论点，有利于人类PBC的环境起源。（《肝脏病学》2008年;48：531-540。）
There have been important advances in defining effector mechanisms for several human autoimmune diseases. However, for most human autoimmune diseases, the induction stage is less well defined and there are very few clues on etiology. Our laboratory has focused on defining the molecular basis of autoantibody recognition and epitope modification in primary biliary cirrhosis (PBC). Our work has demonstrated that antibodies to mitochondria, the hallmark of disease, are directed against a very conserved site of pyruvate dehydrogenase, the E2 subunit of pyruvate dehydrogenase (PDC-E2). We have also demonstrated that several chemical xenobiotics, chosen based on quantitative structural activity relationship analysis and rigorous epitope analysis, when coupled to the lysine residue that normally binds the lipoic acid cofactor of PDC-E2, reacts as well or better to PBC sera than native autoantigen. In the present studies, we immunized C57BL/6 mice with one such xenobiotic, 2-octynoic acid, coupled to bovine serum albumin and we followed the mice for 24 weeks. Animals were studied for appearance of histologic lesions as well as appearance of antibodies to PDC-E2, serum levels of tumor necrosis factor– and interferon, and splenic and liver lymphoid phenotyping by flow cytometry. Mice immunized with 2-octynoic acid manifest autoimmune cholangitis, typical mitochondrial autoantibodies, increased liver lymphoid cell numbers, an increase in CD8 liver infiltrating cells, particularly CD8 T cells that coexpress CD44, and finally an elevation of serum tumor necrosis factor– and interferon. Conclusion: these data provide a persuasive argument in favor of an environmental origin for human PBC. (HEPATOLOGY 2008;48:531-540.)