title: Cytotoxic T lymphocytes and natural killer cells display impaired cytotoxic functions and reduced activation in patients with alcoholic hepatitis.
abstract: The dynamics and role of cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, and NKT cells in the life-threatening inflammatory disease alcoholic hepatitis is largely unknown. These cells directly kill infected and damaged cells through, e.g., degranulation and interferon-γ (IFNγ) production, but cause tissue damage if overactivated. They also assist tissue repair via IL-22 production. We, therefore, aimed to investigate the frequency, functionality, and activation state of such cells in alcoholic hepatitis. We analyzed blood samples from 24 severe alcoholic hepatitis patients followed for 30 days after diagnosis. Ten healthy abstinent volunteers and 10 stable abstinent alcoholic cirrhosis patients were controls. Using flow cytometry we assessed cell frequencies, NK cell degranulation capacity following K562 cell stimulation, activation by natural killer group 2 D (NKG2D) expression, and IL-22 and IFNγ production. In alcoholic hepatitis we found a decreased frequency of CTLs compared with healthy controls (P < 0.001) and a similar trend for NK cells (P = 0.089). The NK cell degranulation capacity was reduced by 25% compared with healthy controls (P = 0.02) and by 50% compared with cirrhosis patients (P = 0.04). Accordingly, the NKG2D receptor expression was markedly decreased on NK cells, CTLs, and NKT cells (P < 0.05, all). The frequencies of IL-22-producing CTLs and NK cells were doubled compared with healthy controls (P < 0.05, all) but not different from cirrhosis patients. This exploratory study for the first time showed impaired cellular cytotoxicity and activation in alcoholic hepatitis. This is unlikely to cause hepatocyte death but may contribute toward the severe immune incompetence. The results warrant detailed and mechanistic studies.
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; and sidsel.stoy@post.au.dk.
authors.forename: Sidsel
authors.initials: S
authors.lastname: Støy
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; and.
authors.forename: Anders
authors.initials: A
authors.lastname: Dige
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; and.
authors.forename: Thomas Damgaard
authors.initials: TD
authors.lastname: Sandahl
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; and.
authors.forename: Tea Lund
authors.initials: TL
authors.lastname: Laursen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Christian
authors.initials: C
authors.lastname: Buus
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus, Denmark.
authors.forename: Marianne
authors.initials: M
authors.lastname: Hokland
authors.affiliation: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; and.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Vilstrup
mesh_terms: D000328:Adult; D019002:CD56 Antigen / Q000378:metabolism; D016022:Case-Control Studies; D015550:Cell Degranulation; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D005260:Female; D006519:Hepatitis, Alcoholic / Q000097:blood / Q000175:diagnosis / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D008231:Lymphopenia / Q000097:blood / Q000276:immunology; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D012720:Severity of Illness Index; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D013997:Time Factors; D000097043:Interleukin-22
chemical_list: D019002:CD56 Antigen; D007371:Interferon-gamma; D007378:Interleukins; D055655:NK Cell Lectin-Like Receptor Subfamily K; D000097043:Interleukin-22; C573415:IFNG protein, human; C527085:KLRK1 protein, human; C522918:NCAM1 protein, human
keywords: alcoholic hepatitis; cytotoxic T lymphocytes; degranulation; natural killer cells; natural killer group 2 D