Bezerra Jorge A, Tiao Greg, Ryckman Frederick C, Alonso Maria, Sabla Gregg E, Shneider Benjamin, Sokol Ronald J, Aronow Bruce J
Division of Pediatric Gastroenterology, Children's Hospital Medical Center and University of Cincinnati, Cincinnati, OH 45229, USA.
Lancet. 2002 Nov 23;360(9346):1653-9. doi: 10.1016/S0140-6736(02)11603-5.
Biliary atresia is the commonest cause of pathological jaundice in infants and the leading indication for liver transplantation in children worldwide. The cause and pathogenesis remain largely unknown. Because of clinical heterogeneity and experimental difficulties in addressing molecular mechanisms underlying multifactorial disorders in human beings, we searched for genomic signatures of biliary atresia in affected infants.
We generated pools of biotinylated cRNA from livers of 14 infants with biliary atresia and six with neonatal intrahepatic cholestasis (diseased controls) and hybridised the cRNA against oligonucleotide-based gene chips. Immunohistochemistry and reverse transcriptase (RT)-PCR were used to assess the specificity of the findings and functional commitment of lymphocytes in affected livers.
Data filtering, to identify genes that are differentially expressed, and cluster analysis revealed a predominant and coordinated activation of immunity/inflammation genes within the livers of infants with biliary atresia. Most of the genes showed differential lymphocyte function, with activation of osteopontin, a regulator of cell-mediated (T-helper 1 [Th-1]) immunity in T-helper lymphocytes, and suppression of immunoglobulin genes in early stages of disease. These findings were associated with production of interferon gamma in 65% of infants with biliary atresia and no diseased control. However, histologically similar inflammatory infiltrates were present in livers of both groups, implying differential activation states of similar cell types.
Livers of infants with biliary atresia have a coordinated activation of genes involved in lymphocyte differentiation. Among these genes, the overexpression of osteopontin and interferon gamma points to a potential role of Th-1-like cytokines in disease pathogenesis.
胆道闭锁是婴儿病理性黄疸最常见的病因，也是全球儿童肝移植的主要指征。其病因和发病机制在很大程度上仍不清楚。由于临床异质性以及研究人类多因素疾病分子机制存在实验困难，我们在患病婴儿中寻找胆道闭锁的基因组特征。
我们从14例胆道闭锁婴儿和6例新生儿肝内胆汁淤积（疾病对照）婴儿的肝脏中提取生物素化cRNA池，并将cRNA与基于寡核苷酸的基因芯片杂交。采用免疫组织化学和逆转录（RT）-PCR评估研究结果的特异性以及患病肝脏中淋巴细胞的功能状态。
通过数据筛选以识别差异表达基因，并进行聚类分析，结果显示胆道闭锁婴儿肝脏中免疫/炎症基因存在显著且协同的激活。大多数基因表现出淋巴细胞功能差异，其中骨桥蛋白激活，骨桥蛋白是辅助性T淋巴细胞中细胞介导（辅助性T细胞1[Th-1]）免疫的调节因子，疾病早期免疫球蛋白基因受到抑制。这些发现与65%的胆道闭锁婴儿产生γ干扰素相关，而疾病对照婴儿未出现此情况。然而，两组肝脏在组织学上存在相似的炎性浸润，这意味着相似细胞类型的激活状态不同。
胆道闭锁婴儿的肝脏中参与淋巴细胞分化的基因存在协同激活。在这些基因中，骨桥蛋白和γ干扰素的过表达表明Th-1样细胞因子在疾病发病机制中可能发挥作用。
