未经治疗的慢性乙型肝炎肝内先天性免疫反应途径下调

StephenW

Intrahepatic innate immune response pathways are downregulated in untreated chronic hepatitis B
Fanny Lebossé†
, Barbara Testoni†
, Judith Fresquet
, Floriana Facchetti
, Enrico Galmozzi
, Maëlenn Fournier
, Valérie Hervieu
, Pascale Berthillon
, Françoise Berby
, Isabelle Bordes
, David Durantel
, Massimo Levrero
, Pietro Lampertico
, Fabien Zoulim'Correspondence information about the author Fabien ZoulimEmail the author Fabien Zoulim
†These authors contributed equally as joint first authors.
See Editorial, pages 884–885
Article has an altmetric score of 9
DOI: http://dx.doi.org/10.1016/j.jhep.2016.12.024 |

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Background & Aims

Hepatitis B virus (HBV) persistence and the pathobiology of chronic HBV (CHB) infections result from the interplay between viral replication and host immune responses. We aimed to comprehensively analyse the expression of intrahepatic host genes as well as serum and liver HBV markers in a large cohort of untreated CHB patients.
Methods

One-hundred and five CHB patients untreated at the time of liver biopsy (34 HBeAg[+] and 71 HBeAg[−]) were analysed for the intrahepatic expression profile of 67 genes belonging to multiple innate immunity pathways. Results were correlated to serological (quantification of HBsAg [qHBsAg] and HBV DNA) and intrahepatic viral markers (total HBV DNA, pre-genomic RNA and covalently closed circular HBV DNA).
Results

Intrahepatic gene expression profiling revealed a strong downregulation of antiviral effectors, interferon stimulated genes, Toll-like and pathogen recognition receptor pathways in CHB patients as compared to non-infected controls, which was not directly correlated to HBV replication. A subset of genes [CXCL10, GBP1, IFITM1, IFNB1, IL10, IL6, ISG15, TLR3, SOCS1, SOCS3] was more repressed in HBeAg(−) respect to HBeAg(+) patients (median of serum HBV DNA 7.9 × 103 vs. 7.9 × 107 IU/ml, respectively). Notably, HBeAg(−) patients with lower qHBsAg (<5 × 103 IU/ml) showed a relief of repression of genes belonging to multiple pathways.
Conclusions

Our results show a strong impairment of innate immune responses in the liver of CHB patients. The association of low levels of qHBsAg with gene repression, if confirmed, might prove useful for the identification of patients who would most benefit from immune-modulators and/or HBsAg targeting agents as strategies to restore immune responsiveness.
Lay summary

Chronic hepatitis B virus (HBV) infections represent a major public health problem worldwide. Over 200 million people are chronically infected and at risk of developing chronic hepatitis, liver cirrhosis and cancer. Our work aimed to understand the molecular consequences of chronic hepatitis B in the infected liver. It was conducted in a large cohort of untreated chronically infected HBV patients and analysed the expression of immunity and liver disease-related genes in the liver, with respect to markers of viral replication and persistence. Our results indicate that chronic HBV infection has a suppressive effect on immune responses, which was more pronounced with high levels of hepatitis B virus surface antigen (HBsAg). These data provide novel insight into the mechanisms of HBV persistence in the liver and suggest that approaches aimed at reducing HBsAg levels, may restore immune responsiveness against the virus.
Keywords:
HBV, Intrahepatic innate immune response, cccDNA, HBsAg

StephenW

未经治疗的慢性乙型肝炎肝内先天性免疫反应途径下调
FannyLebossé†
，Barbara Testoni†
，Judith Fresquet
，Floriana Facchetti
，Enrico Galmozzi
，MaëlennFournier
，ValérieHervieu
，Pascale Berthillon
，FrançoiseBerby
，Isabelle Bordes
戴维·杜兰特
，马西莫列夫雷罗
，Pietro Lampertico
，Fabien Zoulim'关于作者Fabien Zoulim的电子信件作者Fabien Zoulim
†这些作者作为联合第一作者一致。
见编辑部，884-885页
文章的高分为9分
DOI：http://dx.doi.org/10.1016/j.jhep.2016.12.024 |
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背景与目标

乙型肝炎病毒（HBV）持续性和慢性HBV（CHB）感染的病理生理由病毒复制和宿主免疫应答之间的相互作用产生。我们旨在全面分析大型未治疗CHB患者队列中肝内宿主基因以及血清和肝脏HBV标志物的表达。
方法

分析肝活检时未治疗的一百五十例CHB患者（34例HBeAg [+]和71例HBeAg [ - ]），分析属于多发先天免疫途径的67个基因的肝内表达谱。结果与血清学（HBsAg [qHBsAg]和HBV DNA的定量）和肝内病毒标记（总HBV DNA，前基因组RNA和共价闭合环状HBV DNA）的定量相关。
结果

与非感染对照相比，肝内基因表达谱显示CHB患者抗病毒效应物，干扰素刺激基因，Toll样和病原体识别受体通路强烈下调，与HBV复制并不直接相关。 HBeAg（+）患者的基因[CXCL10，GBP1，IFITM1，IFNB1，IL10，IL6，ISG15，TLR3，SOCS1，SOCS3]的亚型被更多的抑制（血清HBV DNA的中位数为7.9×103 vs分别为7.9×107IU / ml）。值得注意的是，具有较低qHBsAg（<5×103IU / ml）的HBeAg（ - ）患者表现出抑制属于多重途径的基因的缓解。
结论

我们的研究结果显示CHB患者肝脏先天免疫反应的强烈损伤。如果确认，低水平的qHBsAg与基因抑制的关联可能对于鉴定最有益于免疫调节剂和/或HBsAg靶向剂的患者是有用的，作为恢复免疫反应性的策略。
总结

慢性乙型肝炎病毒（HBV）感染是全世界主要的公共卫生问题。超过2亿人长期感染，有发生慢性肝炎，肝硬化和癌症的风险。我们的工作旨在了解慢性乙型肝炎在感染肝脏中的分子后果。在一大批未经治疗的长期感染的HBV患者中进行，并分析肝脏免疫和肝脏疾病相关基因在病毒复制和持续性标志方面的表达。我们的研究结果表明，慢性乙型肝炎病毒感染对免疫反应有抑制作用，而乙型肝炎病毒表面抗原（HBsAg）水平较高。这些数据提供了对HBV持久性肝脏机制的新见解，并提出旨在降低HBsAg水平的方法可能恢复对病毒的免疫应答。
关键词：
HBV，肝内先天免疫反应，cccDNA，HBsAg