Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
J Viral Hepat. 2020 Aug;27(8):847-851. doi: 10.1111/jvh.13290. Epub 2020 Apr 3.
Hepatitis B virus (HBV) is a major cause of acute liver failure (ALF) worldwide. While liver damage in classic acute hepatitis B is believed to be T-cell mediated, the pathogenesis of HBV-associated ALF remains largely unknown. Access to liver specimens from well-characterized patients with HBV-associated ALF provided us with the opportunity to perform next-generation sequencing (NGS) of the entire VH repertoires of IgM and IgG from the livers of four ALF patients, a control liver donor and a patient with chronic HBV infection. We found that ALF is not associated with expansion of specific B-cell lineages. However, NGS showed that the intrahepatic VH repertoires from ALF patients were characterized by the abundant presence of antibodies in germline configuration in contrast to their marginal prevalence in controls. Moreover, NGS identified a large number of VH genes in germline configuration with identical VDJ sequences in the IgM and IgG repertoires in all four ALF patients, indicating that isotype switch from IgM to IgG had occurred without somatic hypermutation. The results of this study indicate that the presence of intrahepatic antibodies in unmutated germline configuration is a broad phenomenon in the global antibody repertoire generated from total RNA derived from whole-liver tissue that is strongly associated with ALF, suggesting a major role of T cell-independent humoral immunity in the pathogenesis of ALF.
乙型肝炎病毒 (HBV) 是全球急性肝衰竭 (ALF) 的主要病因。虽然经典急性乙型肝炎中的肝损伤被认为是 T 细胞介导的，但 HBV 相关 ALF 的发病机制仍知之甚少。获得来自具有明确特征的 HBV 相关 ALF 患者的肝组织标本，使我们有机会对来自 4 名 ALF 患者、1 名对照肝供体和 1 名慢性 HBV 感染患者肝脏中的 IgM 和 IgG 的整个 VH 库进行下一代测序 (NGS)。我们发现，ALF 与特定 B 细胞谱系的扩增无关。然而，NGS 显示，与对照组相比，ALF 患者的肝内 VH 库的特征是大量以原始构型存在的抗体。此外，NGS 在所有 4 名 ALF 患者的 IgM 和 IgG 库中鉴定出大量以原始构型存在的 VH 基因，其 VDJ 序列相同，表明 IgM 向 IgG 的同种型转换发生而没有体细胞超突变。这项研究的结果表明，未突变的原始构型中的肝内抗体的存在是从整个肝组织的总 RNA 产生的全球抗体库中的一个广泛现象，与 ALF 强烈相关，提示 T 细胞非依赖性体液免疫在 ALF 的发病机制中起主要作用。
