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首页> 外文期刊>Journal of Molecular Biology >Immunogenetic analysis reveals that epitope shifting occurs during B-cellaffinity maturation in primary biliary cirrhosis
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Immunogenetic analysis reveals that epitope shifting occurs during B-cellaffinity maturation in primary biliary cirrhosis

机译：免疫遗传学分析显示在原发性胆汁性肝硬化的B细胞亲和力成熟过程中发生表位转移

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Primary biliary cirrhosis (PBC) is a liver disease characterized by serum autoantibodies against the pyruvate dehydrogenase complex (PDC) located in the inner mitochondrial membrane. The predominant target in PDC has previously been localized to the inner lipoyl domain (ILD) of the E2 subunit. The etiology of PBC is unknown, although molecular mimicry with bacterial PDC has been proposed. Here, we have investigated the etiology of PBC and nature of the autoimmune response by analyzing the structure of a human monoclonal antibody with ILD specificity. Mutants of the monoclonal antibody, which was originally isolated from a patient with PBC, were expressed as Fab by phage display, and tested for reactivity against recombinant domains of the E2 subunit. Fab in which the V-H-encoded portions were reverted to germline lost reactivity against the ILD alone, but recognized a different epitope in a didomain construct encompassing the ILD, hinge region and E1/E3 binding domain. The complete V-H and V-L germline revertant was unreactive with the human ILD and didomain, the Escherichia coli didomain, and whole PDC. We hypothesize that the IgM on the surface of the naive B-cell first recognizes an as yet unidentified antigen, and that accumulation of somatic mutations results in an intermolecular epitope shift directed towards an epitope involving the E1/E3 binding domain. Further mutations result in the specificity being redirected to the ILD. These findings also suggest that bacterial molecular mimicry is not involved in initiating disease.
机译：原发性胆汁性肝硬化（PBC）是一种肝脏疾病，其特征在于针对线粒体内膜上的丙酮酸脱氢酶复合物（PDC）的血清自身抗体。 PDC中的主要目标先前已定位到E2亚基的内部脂酰结构域（ILD）。尽管已经提出了用细菌PDC进行分子模拟的方法，但PBC的病因尚不清楚。在这里，我们通过分析具有ILD特异性的人单克隆抗体的结构，研究了PBC的病因和自身免疫应答的性质。最初从PBC患者中分离出的单克隆抗体突变体通过噬菌体展示表达为Fab，并测试了其对E2亚基重组域的反应性。 V-H编码部分恢复为种系的Fab失去了对单独ILD的反应性，但在包含ILD，铰链区和E1 / E3结合结构域的双结构域构建体中识别出不同的表位。完整的V-H和V-L种系回复株与人ILD和双结构域，大肠杆菌双结构域和整个PDC没有反应。我们假设幼稚B细胞表面的IgM首先识别尚未鉴定的抗原，并且体细胞突变的积累导致分子间表位向包含E1 / E3结合域的表位转移。进一步的突变导致特异性被重定向至ILD。这些发现还表明细菌分子模拟不参与引发疾病。

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