From the Pediatrics, Johns Hopkins Medical Institutions, Baltimore, MD.
the Genetic Medicine, Johns Hopkins Medical Institutions, Baltimore, MD.
J Pediatr Gastroenterol Nutr. 2022 Sep 1;75(3):269-275. doi: 10.1097/MPG.0000000000003538. Epub 2022 Jun 27.
To test the hypothesis that autoimmune hepatitis (AIH type I) in young subjects is due to genetic differences in proinflammatory genes responding to viral triggers in patients and controls.
Intrahepatic gene expression was compared between AIH type I (n = 24, age 9-30 years) patients (hereafter referred to as the AIH group) and controls (n = 21, age 4-25 years). RNA sequencing was performed on complementary DNA (cDNA) libraries made from total RNA extracted from formalin-fixed paraffin-embedded (FFPE) liver biopsy samples. Gene expression levels were quantified, and differentially expressed genes were functionally analyzed. Pathway analysis was performed using the databases Kyoto Encyclopedia of Genes and Genomes (KEGG) and PANTHER. The remaining sequences were mapped to the RefSeq complete set of viral genomes.
Differential gene analysis identified 181 genes that were significantly differentially expressed (136 upregulated in the AIH group). Autoimmune pathway genes such as CD19 and CD20 which are important in B cell regulation and maturation as well as, CD8 and LY9 , which are T-cell related, were upregulated in our AIH group. Genes implicated in AIH pathogenesis including CXCL10 , which is thought to be associated with AIH severity and progression, complement genes ( C1QA, C1QB , and C1QC ), and human leucocyte antigen ( HLA ) genes ( HLA-DRB1, HLA-DRA, HLA-B , and HLA-C ) were upregulated in samples from the AIH group. Specific viral etiologies were not found.
Unbiased next-generation sequencing and differential gene expression analysis of the AIH group has not only added support for the role of B cells in the pathogenesis and treatment of AIH but also has introduced potential new therapeutic targets: CXCL10 (anti- CXCL10 ) and several complement system-related genes.
验证假说，即年轻患者的自身免疫性肝炎（I 型）是由于病毒触发时，患者和对照人群中促炎基因的遗传差异所致。
比较自身免疫性肝炎（I 型）（n = 24，年龄 9-30 岁）患者（以下简称 AIH 组）和对照组（n = 21，年龄 4-25 岁）之间的肝内基因表达。从福尔马林固定石蜡包埋（FFPE）肝活检样本中提取的总 RNA 构建 cDNA 文库，然后进行 RNA 测序。定量基因表达水平，并对差异表达基因进行功能分析。使用京都基因与基因组百科全书（KEGG）和 PANTHER 数据库进行途径分析。其余序列被映射到 RefSeq 完整的病毒基因组。
差异基因分析确定了 181 个显著差异表达的基因（AIH 组中有 136 个上调）。免疫途径基因如 CD19 和 CD20，它们在 B 细胞调节和成熟中很重要，以及 CD8 和 LY9，它们与 T 细胞相关，在我们的 AIH 组中上调。与 AIH 发病机制相关的基因包括 CXCL10，它被认为与 AIH 的严重程度和进展有关，补体基因（C1QA、C1QB 和 C1QC）和人类白细胞抗原（HLA）基因（HLA-DRB1、HLA-DRA、HLA-B 和 HLA-C）在 AIH 组的样本中上调。未发现特定的病毒病因。
对 AIH 组进行无偏下一代测序和差异基因表达分析，不仅为 B 细胞在 AIH 的发病机制和治疗中的作用提供了支持，还引入了潜在的新治疗靶点：CXCL10（抗-CXCL10）和几个补体系统相关基因。
