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首页> 外文期刊>International Journal of Hepatology >Characterization of Autoantibodies against the E1αSubunit of Branched-Chain 2-Oxoacid Dehydrogenase in Patients with Primary Biliary Cirrhosis
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Characterization of Autoantibodies against the E1αSubunit of Branched-Chain 2-Oxoacid Dehydrogenase in Patients with Primary Biliary Cirrhosis

机译：原发性胆汁性肝硬化患者抗支链2-氧酸脱氢酶E1α亚基自身抗体的表征

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摘要

Primary biliary cirrhosis (PBC) is characterized by antimitochondrial antibodies (AMAs) that react with the lipoyl-containing E2 subunits of 2-oxoacid dehydrogenase complexes such as BCOADC and PDC. The lipoyl domains of E2 contain the major epitopes essential for immunopathology. However, the non-lipoyl-containing E1 subunits are also frequently targeted. Since anti-E1 antibodies always appear in combination with anti-E2 antibodies, the mechanisms underlying the autoimmunity against E1 may be linked to, but distinct from, those against E2. Here, we demonstrate that intermolecular and intramolecular determinant spreading underlies the autoimmunity against E1. We performed characterizations and epitope mapping for anti-BCOADC-E1αantibodies from both the intermolecular and intramolecular points of view. The antibody reactivities form a cluster against the BCOADC complex that is distinct from that against the PDC complex, and the anti-BCOADC-E1αantibodies arise as part of the cluster against the BCOADC complex. Multiple epitopes are present on the surface of the BCOADC-E1αmolecule, and the major epitope overlaps with the active center. Sera with anti-BCOADC-E1αantibodies strongly inhibited the enzyme activity. These findings suggest that the E1αsubunit as part of the native BCOADC complex is an immunogen, and that determinant spreading is involved in the pathogenesis of AMA production.
机译：原发性胆汁性肝硬化（PBC）的特征是抗线粒体抗体（AMAs）与2-含氧酸脱氢酶复合物（如BCOADC和PDC）的含脂酰的E2亚基反应。 E2的脂酰结构域包含免疫病理学必不可少的主要表位。然而，非脂基基团的E1亚基也经常被靶向。由于抗E1抗体总是与抗E2抗体组合出现，因此针对E1的自身免疫的潜在机制可能与针对E2的机制相关，但又有所不同。在这里，我们证明分子间和分子内行列式传播是抗E1自身免疫的基础。我们从分子间和分子内的角度对抗BCOADC-E1α抗体进行了表征和表位作图。抗体反应性形成了针对BCOADC复合物的簇，该簇与针对PDC复合物的簇不同，抗BCOADC-E1α抗体作为针对BCOADC复合物的簇的一部分出现。 BCOADC-E1α分子的表面上存在多个表位，并且主要表位与活性中心重叠。带有抗BCOADC-E1α抗体的血清强烈抑制了酶的活性。这些发现表明，作为天然BCOADC复合体一部分的E1α亚基是一种免疫原，并且决定性传播与AMA产生的发病机制有关。

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