Istituto Nazionale Genetica Molecolare (INGM), 20122 Milan, Italy.
Mol Cell Proteomics. 2012 Dec;11(12):1885-97. doi: 10.1074/mcp.M112.018713. Epub 2012 Sep 20.
Autoimmune hepatitis (AIH) is an unresolving inflammation of the liver of unknown cause. Diagnosis requires the exclusion of other conditions and the presence of characteristic features such as specific autoantibodies. Presently, these autoantibodies have relatively low sensitivity and specificity and are identified via immunostaining of cells or tissues; therefore, there is a diagnostic need for better and easy-to-assess markers. To identify new AIH-specific autoantigens, we developed a protein microarray comprising 1626 human recombinant proteins, selected in silico for being secreted or membrane associated. We screened sera from AIH patients on this microarray and compared the reactivity with that of sera from healthy donors and patients with chronic viral hepatitis C. We identified six human proteins that are specifically recognized by AIH sera. Serum reactivity to a combination of four of these autoantigens allows identification of AIH patients with high sensitivity (82%) and specificity (92%). Of the six autoantigens, the interleukin-4 (IL4) receptor fibronectin type III domain of the IL4 receptor (CD124), which is expressed on the surface of both lymphocytes and hepatocytes, showed the highest individual sensitivity and specificity for AIH. Remarkably, patients' sera inhibited STAT6 phosphorylation induced by IL4 binding to CD124, demonstrating that these autoantibodies are functional and suggesting that IL4 neutralization has a pathogenetic role in AIH.
自身免疫性肝炎（AIH）是一种原因不明的肝脏持续炎症。诊断需要排除其他疾病，并存在特征性特征，如特定的自身抗体。目前，这些自身抗体的敏感性和特异性相对较低，通过细胞或组织的免疫染色来识别；因此，需要更好和易于评估的标志物进行诊断。为了鉴定新的 AIH 特异性自身抗原，我们开发了一种包含 1626 个人类重组蛋白的蛋白质微阵列，这些蛋白是通过计算机筛选出的分泌蛋白或膜相关蛋白。我们在这个微阵列上筛选了 AIH 患者的血清，并将其反应性与健康供体和慢性丙型肝炎病毒患者的血清进行了比较。我们鉴定了六种被 AIH 血清特异性识别的人类蛋白。四种自身抗原组合的血清反应性可以识别 AIH 患者，具有高敏感性（82%）和特异性（92%）。在这六种自身抗原中，白细胞介素 4（IL4）受体的纤维连接蛋白 III 结构域的白细胞介素 4 受体（CD124），在淋巴细胞和肝细胞表面均有表达，对 AIH 的个体敏感性和特异性最高。值得注意的是，患者的血清抑制了 IL4 与 CD124 结合诱导的 STAT6 磷酸化，表明这些自身抗体是功能性的，并提示 IL4 中和在 AIH 中具有发病作用。
