Yamagiwa Satoshi, Kamimura Hiroteru, Takamura Masaaki, Genda Takuya, Ichida Takafumi, Nomoto Minoru, Aoyagi Yutaka
1. Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi-dori, Chuo-ku, Niigata 951-8510, Japan;
2. Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, 1129 Nagaoka, Izunokuni 410-2295, Japan.
Int J Med Sci. 2014 Jun 8;11(9):850-6. doi: 10.7150/ijms.8633. eCollection 2014.
Autoimmune hepatitis (AIH) can arise de novo after liver transplantation (LT) for non-autoimmune liver diseases. Considering the identical features of de novo AIH after LT and classical AIH, as well as the importance of anti-human leukocyte antigen (HLA) antibodies in graft rejection, we investigated the presence of circulating anti-HLA class II antibodies in the sera of 35 patients with AIH, 30 patients with primary biliary cirrhosis (PBC), and 30 healthy donors using fluorescent dye-impregnated beads bound to HLA molecules. We then investigated the allele specificity of the antibodies and identified the HLA alleles in each patient using DNA-based HLA typing. We also examined HLA class II expression in liver samples using immunohistochemistry. Anti-HLA class II antibodies were detected significantly more frequently in the patients with AIH (88.1%) than in the patients with PBC (33.3%) or in the healthy donors (13.3%) (both P <0.01). We confirmed that the anti-HLA class II antibodies in the AIH patients showed specificity for several HLA class II alleles, including self HLA class II alleles. Moreover, positive reactivity with anti-self HLA class II antibodies was associated with higher serum transaminase levels. In conclusion, we demonstrated, for the first time, that antibodies against self HLA class II alleles were detectable in patients with AIH. Our results suggest that an antibody-mediated immune response against HLA class II molecules on hepatocytes may be involved in the pathogenesis or acceleration of liver injury in AIH.
自身免疫性肝炎（AIH）可在因非自身免疫性肝病进行肝移植（LT）后新发。鉴于LT后新发AIH与经典AIH具有相同特征，以及抗人白细胞抗原（HLA）抗体在移植物排斥反应中的重要性，我们使用与HLA分子结合的荧光染料浸渍微珠，调查了35例AIH患者、30例原发性胆汁性肝硬化（PBC）患者和30名健康供者血清中循环抗HLA II类抗体的存在情况。然后我们研究了抗体的等位基因特异性，并使用基于DNA的HLA分型确定了每位患者的HLA等位基因。我们还使用免疫组织化学检查了肝组织样本中HLA II类分子的表达。AIH患者中抗HLA II类抗体的检出率显著高于PBC患者（33.3%）或健康供者（13.3%）（P均<0.01）。我们证实，AIH患者中的抗HLA II类抗体对几种HLA II类等位基因具有特异性，包括自身HLA II类等位基因。此外，与抗自身HLA II类抗体的阳性反应性与较高的血清转氨酶水平相关。总之，我们首次证明，AIH患者中可检测到针对自身HLA II类等位基因的抗体。我们的结果表明，针对肝细胞上HLA II类分子的抗体介导的免疫反应可能参与AIH肝损伤的发病机制或加速肝损伤。
