Apotopes and the biliary specificity of primary biliary cirrhosis.
Apotopes and the biliary specificity of primary biliary cirrhosis.
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DOI：
10.1002/hep.22736
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发表时间：
2009-03
期刊：
影响因子：
13.5
通讯作者：
Gershwin, M. Eric
中科院分区：
文献类型：
--
作者：
Lleo, Ana;Selmi, Carlo;Invernizzi, Pietro;Podda, Mauro;Coppel, Ross L.;Maclay, Ian R.;Gores, Gregory J.;Ansari, Aftab A.;de Water, Judy Van;Gershwin, M. Eric
原发性胆汁性肝硬化（PBC）的特征是抗线粒体抗体（AMA），针对丙酮酸脱氢酶复合物（PDC-E2）的E2组分。尽管几乎所有有核细胞中都存在线粒体，但PBC的破坏仅限于小的肝内胆管。这种组织特异性的原因仍然未知，尽管胆管上皮细胞（BEC）在凋亡后独特地保留了PDC-E2表位。值得注意的是，PBC在同种异体移植的肝脏中复发，表明BEC的一般而不是宿主PBC特异性易感性。我们使用培养的人肝内BEC（HIBEC）和其他良好表征的细胞系，包括HeLa，CaCo-2细胞，和非转化的人角质形成细胞和支气管上皮细胞（BrEpC），以确定诱导凋亡过程中PDC-E2的完整性和特异性定位。所有细胞系，在凋亡之前和之后，用PBC患者（n=30）、其他自身免疫性肝脏和风湿性疾病患者（n=20）和健康个体（n= 20）的血清、抗PDC-E2的小鼠单克隆抗体和具有伊加同种型的AMA进行测试。发现PDC-E2在HIBEC的凋亡泡内定位为未修饰的，但在所研究的各种其他细胞谱系的泡内不定位。含有AMA的血清在不需要透化的情况下与凋亡BEC上的PDC-E2反应的事实表明，自身抗原在凋亡期间可接近免疫系统。总之，我们的数据表明，PBC中自身免疫损伤的组织（胆管细胞）特异性是HIBEC在凋亡过程中的独特特征的结果，并且可以通过暴露于凋亡泡内的完整免疫反应性PDC-E2的免疫系统来解释。
Primary biliary cirrhosis (PBC) is characterized by antimitochondrial antibodies (AMA), directed to the E2 component of the pyruvate dehydrogenase complex (PDC-E2). Notwithstanding the presence of mitochondria in virtually all nucleated cells, the destruction in PBC is limited to small intrahepatic bile ducts. The reasons for this tissue specificity remain unknown, although biliary epithelial cells (BEC) uniquely preserve the PDC-E2 epitope following apoptosis. Notably, PBC recurs in an allogeneic transplanted liver, suggesting generic rather than host-PBC-specific susceptibility of BEC. We used cultured human intrahepatic BEC (HIBEC) and other well-characterized cell lines, including, HeLa, CaCo-2 cells, and non transformed human keratinocytes and bronchial epithelial cells (BrEpC), to determine the integrity and specific localization of PDC-E2 during induced apoptosis. All cell lines, both before and after apoptosis, were tested with sera from patients with PBC (n=30), other autoimmune liver and rheumatic diseases (n=20), and healthy individuals (n=20), a mouse monoclonal antibody against PDC-E2, and AMA with an IgA isotype. PDC-E2 was found to localize unmodified within apoptotic blebs of HIBEC, but not within blebs of various other cell lineages studied. The fact that AMA- containing sera reacted with PDC-E2 on apoptotic BEC without a requirement for permeabilization suggests that the autoantigen is accessible to the immune system during apoptosis. In conclusion, our data indicate that the tissue (cholangiocyte) specificity of the autoimmune injury in PBC is a consequence of the unique characteristics of HIBEC during apoptosis and can be explained by exposure to the immune system of intact immunoreactive PDC-E2 within apoptotic blebs.
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影响因子：
13.5
作者：
Miyakawa, H;Tanaka, A;Gershwin, ME
通讯作者：
Gershwin, ME
影响因子：
15.9
作者：
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Buyon, Jill P.
影响因子：
24.5
作者：
CHAPMAN, RWG;ARBORGH, BAM;SHERLOCK, S
通讯作者：
SHERLOCK, S
影响因子：
13.5
作者：
Invernizzi, P;Crosignani, A;Podda, M
通讯作者：
Podda, M
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影响因子：
15.3
作者：
Irie, Junichiro;Wu, Yuehong;Wicker, Linda S;Rainbow, Daniel;Nalesnik, Michael A;Hirsch, Raphael;Peterson, Laurence B;Leung, Patrick S C;Cheng, Chunmei;Mackay, Ian R;Gershwin, M Eric;Ridgway, William M
通讯作者：
Ridgway, William M