Department of Nephrology, No. 181 Hospital of Guilin, Guangxi Key Laboratory of Metabolic Diseases Research, Guilin Key Laboratory of Kidney Diseases Research, Guilin, Guangxi 541002, P.R. China.
Clinical Medical Research Center, Second Clinical Medical College, Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong 518020, P.R. China.
Int J Mol Med. 2019 Jan;43(1):243-255. doi: 10.3892/ijmm.2018.3946. Epub 2018 Oct 22.
Acute‑on‑chronic liver failure (ACLF) is a newly‑defined serious syndrome with major features of acute decompensation (AD) of hepatic cirrhosis, liver failure and failure of multiple other organs. To date, the mechanism underlying the development and progression of ACLF remains to be fully elucidated. It has been noted that ACLF is associated with immune dysregulation. However, studies have mainly focused on T‑cell responses. The present study aimed to determine the composition and alterations of B‑cell receptor (BCR) heavy chain repertoires associated with ACLF using next generation sequencing (NGS). A total of six patients with hepatitis B virus (HBV)‑related ACLF and six healthy control subjects were prospectively enrolled in the present study. The B‑cell immunoglobulin heavy chain (IGH) repertoires in peripheral blood mononuclear cells (PBMCs) obtained from the patients with HBV‑related ACLF and the control subjects were analyzed using NGS, coupled with multiplex polymerase chain reaction, were Illumina sequenced, and were further characterized using the international ImMunoGeneTics database. The distribution of the BCR complementarity‑determining region 3 (CDR3) variable (V), diversity (D) and joining (J) and V‑J gene segments were found to be comparable between the ACLF and control groups. Of note, the degree of clonal expansion in the ACLF group was significantly higher than that in the control group (P<0.05). Furthermore, a t‑test of the distribution ratio of the V, D, J and V‑J combinations in patients with ACLF and control subjects revealed differentially expressed genes. In total, six genes were upregulated and 19 genes were downregulated in response to ACLF. The difference between these two groups was statistically significant (P<0.05). The approach used in the present study was feasible and effective for analyzing peripheral B‑cell repertoires in HBV‑related ACLF. These results provide direct evidence that the BCR repertoire is important in immune responses, autoimmunity and alloreactivity, and that there is a link between the BCR repertoire and HBV‑ACLF. Therefore, ACLF‑specific BCR CDR3 sequences hold promise for therapeutic benefit to HBV‑ACLF in the future.
急性慢性肝衰竭（ACLF）是一种新定义的严重综合征，其主要特征为肝硬化的急性失代偿（AD）、肝功能衰竭和多个其他器官衰竭。迄今为止，ACLF 的发展和进展的机制仍未完全阐明。据报道，ACLF 与免疫失调有关。然而，研究主要集中在 T 细胞反应上。本研究旨在使用下一代测序（NGS）确定与 ACLF 相关的 B 细胞受体（BCR）重链库的组成和变化。共前瞻性纳入 6 例乙型肝炎病毒（HBV）相关 ACLF 患者和 6 例健康对照者。使用 NGS 分析来自 HBV 相关 ACLF 患者和对照组的外周血单个核细胞（PBMC）中的 B 细胞免疫球蛋白重链（IGH）库，通过多重聚合酶链反应进行分析，然后对 Illumina 进行测序，并使用国际免疫遗传学数据库进行进一步表征。发现 ACLF 组和对照组之间 BCR 互补决定区 3（CDR3）可变（V）、多样性（D）和连接（J）以及 V-J 基因片段的分布相似。值得注意的是，ACLF 组的克隆扩增程度明显高于对照组（P<0.05）。此外，对 ACLF 患者和对照组 V、D、J 和 V-J 组合分布比例的 t 检验显示差异表达基因。总共有 6 个基因上调，19 个基因下调与 ACLF 相关。两组之间的差异具有统计学意义（P<0.05）。本研究中使用的方法可有效分析 HBV 相关 ACLF 患者的外周 B 细胞库。这些结果提供了直接证据，表明 BCR 库在免疫反应、自身免疫和同种异体反应中很重要，并且 BCR 库与 HBV-ACLF 之间存在联系。因此，ACLF 特异性 BCR CDR3 序列有望在未来为 HBV-ACLF 带来治疗益处。
