循环和肝脏BDCA1 +，BDCA2 +和BDCA3 +树突状细胞在慢性HBV感染患

StephenW

Front Immunol. 2019 Feb 4;10:112. doi: 10.3389/fimmu.2019.00112. eCollection 2019.
Circulating and Hepatic BDCA1+, BDCA2+, and BDCA3+ Dendritic Cells Are Differentially Subverted in Patients With Chronic HBV Infection.
Ouaguia L1,2, Leroy V3,4,5, Dufeu-Duchesne T1,4, Durantel D6, Decaens T3,4,5, Hubert M6, Valladeau-Guilemond J6, Bendriss-Vermare N6, Chaperot L1,2, Aspord C1,2.
Author information

1
    Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases, Inserm U 1209, CNRS UMR 5309, Université Grenoble Alpes, Grenoble, France.
2
    Etablissement Français du Sang Auvergne-Rhône-Alpes, R&D Laboratory, Grenoble, France.
3
    Université Grenoble Alpes, Grenoble, France.
4
    CHU Grenoble Alpes, Hepato-gastroenterology Unit, Grenoble, France.
5
    Institute for Advanced Biosciences, Research Center Inserm U1209/CNRS 5309/UGA, Analytic Immunology of Chronic Pathologies, La Tronche, France.
6
    Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France.

Abstract

Background and aims: Chronic hepatitis B virus (HBV) infection is a major health burden potentially evolving toward cirrhosis and hepatocellular carcinoma. HBV physiopathology is strongly related to the host immunity, yet the mechanisms of viral evasion from immune-surveillance are still misunderstood. The immune response elicited at early stages of viral infection is believed to be important for subsequent disease outcome. Dendritic cells (DCs) are crucial immune sentinels which orchestrate antiviral immunity, which offer opportunity to pathogens to subvert them to escape immunity. Despite the pivotal role of DCs in orientating antiviral responses and determining the outcome of infection, their precise involvement in HBV pathogenesis is not fully explored. Methods: One hundred thirty chronically HBV infected patients and 85 healthy donors were enrolled in the study for blood collection, together with 29 chronically HBV infected patients and 33 non-viral infected patients that were included for liver biopsy collection. In a pioneer way, we investigated the phenotypic and functional features of both circulating and intrahepatic BDCA1+ cDC2, BDCA2+ pDCs, and BDCA3+ cDC1 simultaneously in patients with chronic HBV infection by designing a unique multi-parametric flow cytometry approach. Results: We showed modulations of the frequencies and basal activation status of blood and liver DCs associated with impaired expressions of specific immune checkpoints and TLR molecules on circulating DC subsets. Furthermore, we highlighted an impaired maturation of circulating and hepatic pDCs and cDCs following stimulation with specific TLR agonists in chronic HBV patients, associated with drastic dysfunctions in the capacity of circulating DC subsets to produce IL-12p70, TNFα, IFNα, IFNλ1, and IFNλ2 while intrahepatic DCs remained fully functional. Most of these modulations correlated with HBsAg and HBV DNA levels. Conclusion: We highlight potent alterations in the distribution, phenotype and function of all DC subsets in blood together with modulations of intrahepatic DCs, revealing that HBV may hijack the immune system by subverting DCs. Our findings provide innovative insights into the immuno-pathogenesis of HBV and the mechanisms of virus escape from immune control. Such understanding is promising for developing new therapeutic strategies restoring an efficient immune control of the virus.
KEYWORDS:

Type I and Type III interferons; antiviral immune responses; cDC1/BDCA3; cDC2/BDCA1; chronic hepatitis B patients; hepatitis B virus; pDCs/BDCA2; viral immune evasion

PMID:
    30778353
PMCID:
    PMC6369167
DOI:
    10.3389/fimmu.2019.00112

StephenW

前免疫。 2019年2月4日; 10：112。 doi：10.3389 / fimmu.2019.00112。 eCollection 2019。
循环和肝脏BDCA1 +，BDCA2 +和BDCA3 +树突状细胞在慢性HBV感染患者中差异性地被破坏。
Ouaguia L1,2，Leroy V3,4,5，Dufeu-Duchesne T1,4，Durantel D6，Decaens T3,4,5，Hubert M6，Valladeau-Guilemond J6，Bendriss-Vermare N6，Chaperot L1,2，Aspord C1， 2。
作者信息

1
    慢性病高级生物科学，免疫生物学和免疫疗法研究所，Inserm U 1209，CNRS UMR 5309，UniversitéGrenobleAlpes，Grenoble，France。
2
    EtablissementFrançaisduSang Auvergne-Rhône-Alpes，法国格勒诺布尔研发实验室。
3
    法国格勒诺布尔大学格勒诺布尔阿尔卑斯大学。
4
    CHU Grenoble Alpes，法国格勒诺布尔肝脏胃肠病科。
五
    高级生物科学研究中心，Inserm U1209 / CNRS 5309 / UGA研究中心，慢性病理学分析免疫学，法国La Tronche。
6
    Univ Lyon，UniversitéClaudeBernard Lyon 1，INSERM 1052，CNRS 5286，CentreLéonBérard，Centre de RechercheenCancérologiedeLyon，Lyon，France。

抽象

背景和目的：慢性乙型肝炎病毒（HBV）感染是可能发展为肝硬化和肝细胞癌的主要健康负担。 HBV病理生理学与宿主免疫力密切相关，但免疫监视中病毒逃避的机制仍然被误解。在病毒感染的早期阶段引发的免疫应答被认为对随后的疾病结果很重要。树突状细胞（DC）是关键的免疫哨兵，它们协调抗病毒免疫，这为病原体提供了破坏它们以逃避免疫力的机会。尽管DC在定位抗病毒反应和确定感染结果方面发挥着关键作用，但尚未充分探索它们在HBV发病机制中的确切参与。方法：130名慢性HBV感染患者和85名健康捐献者参加了血液采集研究，同时收集了29名慢性HBV感染患者和33名非病毒感染患者，这些患者被收集用于肝脏活检。我们以先锋的方式，通过设计独特的多参数流式细胞术方法，同时研究了慢性HBV感染患者的循环和肝内BDCA1 + cDC2，BDCA2 + pDC和BDCA3 + cDC1的表型和功能特征。结果：我们显示血液和肝脏DC的频率和基础激活状态的调节与特定免疫检查点和TLR分子在循环DC子集上的受损表达相关。此外，我们强调了慢性HBV患者特异性TLR激动剂刺激后循环和肝脏pDC和cDC的成熟受损，与循环DC亚群产生IL-12p70，TNFα，IFNα，IFNλ1和IFNλ2的能力急剧功能障碍相关。而肝内DC仍保持完全功能。大多数这些调节与HBsAg和HBV DNA水平相关。结论：我们强调血液中所有DC亚群的分布，表型和功能的有效改变以及肝内DC的调节，揭示HBV可能通过颠覆DC来劫持免疫系统。我们的研究结果为HBV的免疫发病机制和病毒逃避免疫控制的机制提供了创新见解。这种理解有望用于开发恢复病毒的有效免疫控制的新治疗策略。
关键词：

I型和III型干扰素;抗病毒免疫反应; CDC1 / BDCA3; CDC2 / BDCA1;慢性乙型肝炎患者;乙型肝炎病毒;的pDC / BDCA2;病毒性免疫逃避

结论：
    30778353
PMCID：
    PMC6369167
DOI：
    10.3389 / fimmu.2019.00112

StephenW

https://www.frontiersin.org/arti ... mmu.2019.00112/full