Chronic hepatitis delta virus infection leads to functional impairment and severe loss of MAIT cells
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Chronic hepatitis delta virus infection leads to functional impairment and severe loss of MAIT cells. / Dias, Joana; Hengst, Julia; Parrot, Tiphaine; Leeansyah, Edwin; Lunemann, Sebastian; Malone, David F.G.; Hardtke, Svenja; Strauss, Otto; Zimmer, Christine L.; Berglin, Lena; Schirdewahn, Thomas; Ciesek, Sandra ; Marquardt, Nicole; von Hahn, Thomas; Manns, Michael P; Cornberg, Markus; Ljunggren, Hans-Gustaf; Wedemeyer, Heiner; Sandberg, Johan K.; Björkström, Niklas K.
in: J HEPATOL, Jahrgang 71, Nr. 2, 08.2019, S. 301-312.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Chronic hepatitis delta virus infection leads to functional impairment and severe loss of MAIT cells
AU - Dias, Joana
AU - Hengst, Julia
AU - Parrot, Tiphaine
AU - Leeansyah, Edwin
AU - Lunemann, Sebastian
AU - Malone, David F.G.
AU - Hardtke, Svenja
AU - Strauss, Otto
AU - Zimmer, Christine L.
AU - Berglin, Lena
AU - Schirdewahn, Thomas
AU - Ciesek, Sandra
AU - Marquardt, Nicole
AU - von Hahn, Thomas
AU - Manns, Michael P
AU - Cornberg, Markus
AU - Ljunggren, Hans-Gustaf
AU - Wedemeyer, Heiner
AU - Sandberg, Johan K.
AU - Björkström, Niklas K
N1 - Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2019/8
Y1 - 2019/8
N2 - BACKGROUND & AIMS: Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. Although HDV-associated liver disease is considered immune-mediated, adaptive immune responses against HDV are weak. Thus, the role of several other cell-mediated mechanisms such as those driven by mucosa-associated invariant T (MAIT) cells, a group of innate-like T cells highly enriched in the human liver, has not been extensively studied in clinical HDV infection.METHODS: MAIT cells from a sizeable cohort of patients with chronic HDV were analyzed ex vivo and in vitro after stimulation. Results were compared with MAIT cells from hepatitis B virus (HBV) monoinfected patients and healthy controls.RESULTS: Circulating MAIT cells were dramatically decreased in the peripheral blood of HDV-infected patients. Signs of decline were also observed in the liver. In contrast, only a modest decrease of circulating MAIT cells was noted in HBV monoinfection. Unsupervised high-dimensional analysis of residual circulating MAIT cells in chronic HDV infection revealed the appearance of a compound phenotype of CD38hiPD-1hiCD28loCD127loPLZFloEomesloHelioslo cells indicative of activation. Corroborating these results, MAIT cells exhibited a functionally impaired responsiveness. In parallel to MAIT cell loss, HDV-infected patients exhibited signs of monocyte activation and increased levels of proinflammatory cytokines IL-12 and IL-18. In vitro, IL-12 and IL-18 induced an activated MAIT cell phenotype similar to the one observed ex vivo in HDV-infected patients. These cytokines also promoted MAIT cell death, suggesting that they may contribute to MAIT cell activation and subsequent loss during HDV infection.CONCLUSIONS: These results suggest that chronic HDV infection engages the MAIT cell compartment causing activation, functional impairment, and subsequent progressive loss of MAIT cells as the HDV-associated liver disease progresses.LAY SUMMARY: Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. We found that in patients with HDV, a subset of innate-like T cells called mucosa-associated invariant T cells (or MAIT cells), which are normally abundant in peripheral blood and the liver, are activated, functionally impaired and severely depleted.
AB - BACKGROUND & AIMS: Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. Although HDV-associated liver disease is considered immune-mediated, adaptive immune responses against HDV are weak. Thus, the role of several other cell-mediated mechanisms such as those driven by mucosa-associated invariant T (MAIT) cells, a group of innate-like T cells highly enriched in the human liver, has not been extensively studied in clinical HDV infection.METHODS: MAIT cells from a sizeable cohort of patients with chronic HDV were analyzed ex vivo and in vitro after stimulation. Results were compared with MAIT cells from hepatitis B virus (HBV) monoinfected patients and healthy controls.RESULTS: Circulating MAIT cells were dramatically decreased in the peripheral blood of HDV-infected patients. Signs of decline were also observed in the liver. In contrast, only a modest decrease of circulating MAIT cells was noted in HBV monoinfection. Unsupervised high-dimensional analysis of residual circulating MAIT cells in chronic HDV infection revealed the appearance of a compound phenotype of CD38hiPD-1hiCD28loCD127loPLZFloEomesloHelioslo cells indicative of activation. Corroborating these results, MAIT cells exhibited a functionally impaired responsiveness. In parallel to MAIT cell loss, HDV-infected patients exhibited signs of monocyte activation and increased levels of proinflammatory cytokines IL-12 and IL-18. In vitro, IL-12 and IL-18 induced an activated MAIT cell phenotype similar to the one observed ex vivo in HDV-infected patients. These cytokines also promoted MAIT cell death, suggesting that they may contribute to MAIT cell activation and subsequent loss during HDV infection.CONCLUSIONS: These results suggest that chronic HDV infection engages the MAIT cell compartment causing activation, functional impairment, and subsequent progressive loss of MAIT cells as the HDV-associated liver disease progresses.LAY SUMMARY: Hepatitis delta virus (HDV) infection is the most severe form of viral hepatitis. We found that in patients with HDV, a subset of innate-like T cells called mucosa-associated invariant T cells (or MAIT cells), which are normally abundant in peripheral blood and the liver, are activated, functionally impaired and severely depleted.
U2 - 10.1016/j.jhep.2019.04.009
DO - 10.1016/j.jhep.2019.04.009
M3 - SCORING: Journal article
C2 - 31100314
VL - 71
SP - 301
EP - 312
JO - J HEPATOL
JF - J HEPATOL
SN - 0168-8278
IS - 2
ER -