Mori Tsutomu, Ohira Hiromasa, Kuroda Masahito, Kato Masaki, Yamaguchi Yoshiki, Kochi Hideo
Department of Human Lifesciences, Fukushima Medical University School of Nursing, 1 Hikarigaoka, Fukushima 960-1295, Japan.
Int J Hepatol. 2012;2012:369740. doi: 10.1155/2012/369740. Epub 2012 Jun 20.
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-E1α antibodies 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-E1α antibodies arise as part of the cluster against the BCOADC complex. Multiple epitopes are present on the surface of the BCOADC-E1α molecule, and the major epitope overlaps with the active center. Sera with anti-BCOADC-E1α antibodies strongly inhibited the enzyme activity. These findings suggest that the E1α subunit as part of the native BCOADC complex is an immunogen, and that determinant spreading is involved in the pathogenesis of AMA production.
原发性胆汁性肝硬化（PBC）的特征是抗线粒体抗体（AMA）与2-氧代酸脱氢酶复合物（如支链α-酮酸脱氢酶复合物（BCOADC）和丙酮酸脱氢酶复合物（PDC））中含硫辛酰的E2亚基发生反应。E2的硫辛酰结构域包含免疫病理学所必需的主要表位。然而，不含硫辛酰的E1亚基也经常成为攻击目标。由于抗E1抗体总是与抗E2抗体同时出现，针对E1的自身免疫机制可能与针对E2的机制相关，但又有所不同。在此，我们证明分子间和分子内的决定簇扩展是针对E1的自身免疫的基础。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定位。该抗体与BCOADC复合物的反应性形成一个不同于与PDC复合物反应性的簇，并且抗BCOADC-E1α抗体作为针对BCOADC复合物的簇的一部分出现。BCOADC-E1α分子表面存在多个表位，主要表位与活性中心重叠。含有抗BCOADC-E1α抗体的血清强烈抑制酶活性。这些发现表明，作为天然BCOADC复合物一部分的E1α亚基是一种免疫原，并且决定簇扩展参与了AMA产生的发病机制。
