Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland.
Department of Biomedicine, University Hospital Basel, University of Basel, Basel, Switzerland; Division of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerland.
Gastroenterology. 2018 May;154(6):1778-1790. doi: 10.1053/j.gastro.2018.01.034. Epub 2018 Mar 19.
BACKGROUND & AIMS: Most viruses are detected at early stages of cell infection and induce an innate immune response mediated by production of interferons (IFNs). IFNs induce expression of hundreds of IFN-stimulated genes (ISGs). Infection of chimpanzees with hepatitis C virus, but not hepatitis B virus (HBV), induces ISG expression in the liver. HBV might not induce an innate immune response because it is not detected by pattern recognition receptors (the stealth properties of HBV) or because HBV suppresses IFN production or signaling despite detection by pattern recognition receptors. We studied innate immune signaling in liver biopsies from patients with different stages of chronic HBV infection and uninfected individuals (controls).
We obtained liver within 10 minutes after collection from 30 patients with chronic HBV infection (hepatitis B e antigen-positive or -negative, with or without hepatitis) and 42 controls (most with fatty liver disease). The liver tissues were analyzed by histology, immunohistochemistry, quantitative reverse-transcription polymerase chain reaction, in situ hybridization, HBV RNA quantification, and HBV genotyping; some specimens were incubated with toll-like receptor (TLR) ligands (polyinosinic-polycytidylic acid) or infected with Sendai virus and then analyzed.
Liver specimens from patients with HBV infection were not expressing more IFN or ISGs than those from control patients, indicating that chronic HBV infection did not activate an innate immune response. However, liver specimens from patients with HBV infection did produce IFN and induce expression of ISGs following activation of TLR3 with poly(I:C) or Sendai virus infections, so the innate immune response is not suppressed in these tissues.
Liver tissues from patients with chronic HBV infection do not have induction of an innate immune response, but this response can be activated by other factors (TLR3 binding, Sendai virus infection) in HBV-infected liver tissue. These findings support the hypothesis that HBV is invisible to pattern recognition receptors.
大多数病毒在细胞感染的早期阶段被检测到，并通过产生干扰素（IFNs）介导先天免疫反应。IFNs 诱导数百种干扰素刺激基因（ISGs）的表达。感染 HCV 而非 HBV 的黑猩猩会诱导肝脏中 ISG 的表达。HBV 可能不会诱导先天免疫反应，因为它不能被模式识别受体（HBV 的隐匿特性）检测到，或者因为 HBV 抑制 IFN 的产生或信号转导，尽管它被模式识别受体检测到。我们研究了不同阶段慢性 HBV 感染患者和未感染个体（对照）肝活检中的先天免疫信号。
我们从 30 例慢性 HBV 感染（乙型肝炎 e 抗原阳性或阴性，有或无肝炎）和 42 例对照（大多数为脂肪肝患者）患者收集肝脏后 10 分钟内获得肝脏。通过组织学、免疫组织化学、定量逆转录聚合酶链反应、原位杂交、HBV RNA 定量和 HBV 基因分型分析肝组织；一些标本用 Toll 样受体（TLR）配体（多聚肌苷酸-多聚胞苷酸）孵育或用仙台病毒感染，然后进行分析。
HBV 感染患者的肝组织表达的 IFN 或 ISGs 并不比对照患者多，表明慢性 HBV 感染并未激活先天免疫反应。然而，用多聚（I:C）或仙台病毒感染激活 TLR3 后，HBV 感染患者的肝组织会产生 IFN 并诱导 ISG 的表达，因此该组织中的先天免疫反应并未受到抑制。
慢性 HBV 感染患者的肝组织没有诱导先天免疫反应，但该反应可以被 HBV 感染肝组织中的其他因素（TLR3 结合、仙台病毒感染）激活。这些发现支持 HBV 对模式识别受体不可见的假设。
