PMID- 30778353 OWN - NLM STAT- MEDLINE DCOM- 20191231 LR - 20211204 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 10 DP - 2019 TI - Circulating and Hepatic BDCA1+, BDCA2+, and BDCA3+ Dendritic Cells Are Differentially Subverted in Patients With Chronic HBV Infection. PG - 112 LID - 10.3389/fimmu.2019.00112 [doi] LID - 112 AB - 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, TNFalpha, IFNalpha, IFNlambda1, and IFNlambda2 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. FAU - Ouaguia, Laurissa AU - Ouaguia L AD - Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases, Inserm U 1209, CNRS UMR 5309, Universite Grenoble Alpes, Grenoble, France. AD - Etablissement Francais du Sang Auvergne-Rhone-Alpes, R&D Laboratory, Grenoble, France. FAU - Leroy, Vincent AU - Leroy V AD - Universite Grenoble Alpes, Grenoble, France. AD - CHU Grenoble Alpes, Hepato-gastroenterology Unit, Grenoble, France. AD - Institute for Advanced Biosciences, Research Center Inserm U1209/CNRS 5309/UGA, Analytic Immunology of Chronic Pathologies, La Tronche, France. FAU - Dufeu-Duchesne, Tania AU - Dufeu-Duchesne T AD - Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases, Inserm U 1209, CNRS UMR 5309, Universite Grenoble Alpes, Grenoble, France. AD - CHU Grenoble Alpes, Hepato-gastroenterology Unit, Grenoble, France. FAU - Durantel, David AU - Durantel D AD - Univ Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Leon Berard, Centre de Recherche en Cancerologie de Lyon, Lyon, France. FAU - Decaens, Thomas AU - Decaens T AD - Universite Grenoble Alpes, Grenoble, France. AD - CHU Grenoble Alpes, Hepato-gastroenterology Unit, Grenoble, France. AD - Institute for Advanced Biosciences, Research Center Inserm U1209/CNRS 5309/UGA, Analytic Immunology of Chronic Pathologies, La Tronche, France. FAU - Hubert, Margaux AU - Hubert M AD - Univ Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Leon Berard, Centre de Recherche en Cancerologie de Lyon, Lyon, France. FAU - Valladeau-Guilemond, Jenny AU - Valladeau-Guilemond J AD - Univ Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Leon Berard, Centre de Recherche en Cancerologie de Lyon, Lyon, France. FAU - Bendriss-Vermare, Nathalie AU - Bendriss-Vermare N AD - Univ Lyon, Universite Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Leon Berard, Centre de Recherche en Cancerologie de Lyon, Lyon, France. FAU - Chaperot, Laurence AU - Chaperot L AD - Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases, Inserm U 1209, CNRS UMR 5309, Universite Grenoble Alpes, Grenoble, France. AD - Etablissement Francais du Sang Auvergne-Rhone-Alpes, R&D Laboratory, Grenoble, France. FAU - Aspord, Caroline AU - Aspord C AD - Institute for Advanced Biosciences, Immunobiology and Immunotherapy in Chronic Diseases, Inserm U 1209, CNRS UMR 5309, Universite Grenoble Alpes, Grenoble, France. AD - Etablissement Francais du Sang Auvergne-Rhone-Alpes, R&D Laboratory, Grenoble, France. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190204 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Antigens, CD1) RN - 0 (Antigens, Surface) RN - 0 (CD1C protein, human) RN - 0 (CLEC4C protein, human) RN - 0 (DNA, Viral) RN - 0 (Glycoproteins) RN - 0 (Hepatitis B Surface Antigens) RN - 0 (Interferon Type I) RN - 0 (Lectins, C-Type) RN - 0 (Membrane Glycoproteins) RN - 0 (Receptors, Immunologic) RN - 0 (THBD protein, human) RN - 0 (Thrombomodulin) RN - 0 (Toll-Like Receptors) RN - 82115-62-6 (Interferon-gamma) SB - IM MH - Adolescent MH - Adult MH - Aged MH - Antigens, CD1/*metabolism MH - Antigens, Surface/*metabolism MH - Biopsy MH - DNA, Viral/metabolism MH - Dendritic Cells/*metabolism MH - Female MH - Glycoproteins/*metabolism MH - Hepatitis B Surface Antigens/metabolism MH - Hepatitis B virus/*immunology MH - Hepatitis B, Chronic/*blood/*pathology MH - Humans MH - Interferon Type I/metabolism MH - Interferon-gamma/metabolism MH - Lectins, C-Type/*metabolism MH - Liver/*pathology MH - Male MH - Membrane Glycoproteins/*metabolism MH - Middle Aged MH - Receptors, Immunologic/*metabolism MH - Thrombomodulin MH - Toll-Like Receptors/agonists/metabolism MH - Young Adult PMC - PMC6369167 OTO - NOTNLM OT - Type I and Type III interferons OT - antiviral immune responses OT - cDC1/BDCA3 OT - cDC2/BDCA1 OT - chronic hepatitis B patients OT - hepatitis B virus OT - pDCs/BDCA2 OT - viral immune evasion EDAT- 2019/02/20 06:00 MHDA- 2020/01/01 06:00 PMCR- 2019/01/01 CRDT- 2019/02/20 06:00 PHST- 2018/11/14 00:00 [received] PHST- 2019/01/15 00:00 [accepted] PHST- 2019/02/20 06:00 [entrez] PHST- 2019/02/20 06:00 [pubmed] PHST- 2020/01/01 06:00 [medline] PHST- 2019/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2019.00112 [doi] PST - epublish SO - Front Immunol. 2019 Feb 4;10:112. doi: 10.3389/fimmu.2019.00112. eCollection 2019.