Effects of HDV infection and pegylated interferon α treatment on the natural killer cell compartment in chronically infected individuals.
OBJECTIVE
Although hepatitis delta is considered an immune-mediated disease, adaptive immune responses to hepatitis delta virus (HDV) are hardly detectable. Thus, the role of other immune responses, including those mediated by natural killer (NK) cells, must be considered in HDV pathogenesis and in treatments with immune-stimulating agents such as interferon (IFN)α. However, the phenotype and function of NK cells in chronic HDV infection, or in HDV-infected individuals undergoing IFNα treatment, have not been extensively studied.


METHODS
We performed an extensive analysis of NK cells in chronically HDV-infected patients before and during treatment with IFNα, and compared the results with those for patients with HBV mono-infection as well as healthy controls.


RESULTS
In untreated HDV-infected patients, a higher than normal frequency of NK cells was observed in peripheral blood with unaltered phenotypic NK cell differentiation status. In contrast, long-term IFNα treatment of HDV-infected patients caused a significant change in NK cell differentiation status, with selective loss of terminally differentiated NK cells and, in parallel, a relative enrichment in immature NK cell subsets. Treatment was associated with marked functional impairment of the NK cells, which was independent of the changes in NK cell differentiation status. Furthermore, treatment polarised NK cell IFN signalling from STAT4 towards STAT1 dependency. Strikingly, a high frequency of CD56(dim) NK cells at baseline was positively associated with IFNα treatment outcome in the patients.


CONCLUSIONS
We describe in detail how HDV infection, and IFNα treatment of this infection, affects the NK cell compartment and what consequences this has for the functional capacity of NK cells.
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Sebastian
S
Lunemann
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
David F G
DF
Malone
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Jan
J
Grabowski
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Kerstin
K
Port
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Vivien
V
Béziat
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Birgit
B
Bremer
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden Institute for Cancer Research, Oslo University Hospital, Oslo, Norway Institute for Cancer Research, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Karl-Johan
KJ
Malmberg
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Michael P
MP
Manns
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Johan K
JK
Sandberg
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Markus
M
Cornberg
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.
Hans-Gustaf
HG
Ljunggren
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
Heiner
H
Wedemeyer
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden Liver Immunology Laboratory, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
Niklas K
NK
Björkström
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D005260:Female; D005434:Flow Cytometry; D019701:Hepatitis D, Chronic / Q000188:drug therapy* / Q000276:immunology; D003698:Hepatitis Delta Virus / Q000187:drug effects; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000502:physiology; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D055815:Young Adult
D000998:Antiviral Agents; D016898:Interferon-alpha
Hepatitis D; Immunology; Interferon-Alpha