Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization
Induction of primary biliary cirrhosis in guinea pigs following chemical xenobiotic immunization
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DOI：
10.4049/jimmunol.179.4.2651
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Gershwin, M. Eric
中科院分区：
文献类型：
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作者：
Leung, Patrick S. C.;Park, Ogyi;Gershwin, M. Eric
虽然在解剖自身免疫的效应机制方面已经取得了重大进展，但主要的绊脚石仍然是定义疾病前的病因学事件。原发性胆汁性肝硬化（PBC）说明了这一范例，因为它的高度遗传性，其女性优势，其非常具体和明确的免疫反应和目标破坏。在PBC中，主要的自身抗原属于E2组分的2-氧代-酸脱氢酶家族的位于前列腺的酶，共享一个脂酰化肽序列，这是免疫显性的目标。我们以前的工作已经证明，合成模拟的硫辛酸分子，如6-溴己糖，表现出高度的反应性与PBC血清提示。我们用与BSA偶联的6-溴己糖免疫豚鼠组。在这项研究中，我们提供的血清学和免疫组化证据表明，这种免疫豚鼠不仅发展抗线粒体自身抗体反应类似于人类PBC，但也发展自身免疫性胆管炎后18个月。异种生物免疫豚鼠是PBC的第一个诱导模型，并提出了对其他人类自身免疫性疾病的病因具有影响的病因学。这些数据还反映了这样的可能性，在PBC中，多谱系抗线粒体反应是一种致病机制，并且耐受性的丧失和随后的胆道病变的发展取决于宿主线粒体Ag的修饰或由于分子模拟而引起的类似的分解。
Although significant advances have been made in dissecting the effector mechanisms in autoimmunity, the major stumbling block remains defining the etiological events that precede disease. Primary biliary cirrhosis (PBC) illustrates this paradigm because of its high degree of heritability, its female predominance, and its extraordinarily specific and defined immune response and target destruction. In PBC, the major autoantigens belong to E2 components of the 2-oxo-acid dehydrogenase family of mitochondrially located enzymes that share a lipoylated peptide sequence that is the immunodominant target. Our previous work has demonstrated that synthetic mimics of the lipoate molecule such as 6-bromohexoanate demonstrate a high degree of reactivity with PBC sera prompted. us to immunize groups of guinea pigs with 6-bromohexoanate conjugated to BSA. In this study, we provide serologic and immunohistochemical evidence that such immunized guinea pigs not only develop antimitochondrial autoantibody responses similar to human PBC, but also develop autoimmune cholangitis after 18 mo. Xenobiotic-immunized guinea pigs are the first induced model of PBC and suggest an etiology that has implications for the causation of other human autoimmune diseases. The data also reflect the likelihood that, in PBC, the multilineage antimitochondrial response is a pathogenic mechanism and that loss of tolerance and subsequent development of biliary lesions depends on either modification of the host mitochondrial Ag or a similar breakdown due to molecular mimicry.