Objective Sialic-acid-binding immunoglobulin-like lectin-7 (Siglec-7) is a natural killer (NK) cell inhibitory receptor associated with NK phenotypic and functional abnormalities in HIV-1 infection. We investigated the significance of NK-expressed and serum soluble Siglec-7 in relation to NK functional ability and parameters of liver necroinflammation and fibrosis in chronic HCV infection.
Design NK-expressed and serum Siglec-7 were evaluated in 130 and 166 HCV-infected individuals by flow cytometry and ELISA, respectively. NK cell degranulation and cytokine secretion were determined by flow cytometry. 65 patients with chronic HBV infection, 84 with chronic biliary disorders and 168 healthy donors served as controls.
Results Expression of Siglec-7 was significantly decreased on NK cells from HCV-infected and HBV-infected patients and, conversely, serum Siglec-7 was significantly increased in these patients compared with controls. The frequency of Siglec-7pos NK cells was significantly higher at baseline in sustained virological responders to pegylated interferon-α/ribavirin treatment than in non-responders. Activating receptor expression was significantly higher in Siglec-7pos NK cells and was associated with increased degranulation and cytokine secretion compared with Siglec-7neg cells. In chronic HCV infection, there was an inverse correlation between Siglec-7 expression and serum aminotransferases, γ-glutamyl transpeptidase, liver stiffness, aspartate aminotransferase to platelet ratio index and fibrosis-4 scores, and a positive correlation between serum Siglec-7 and the same clinical parameters, including histological staging.
Conclusions These findings identify Siglec-7neg NK cells as a dysfunctional subpopulation associated with severe liver disease in chronic HCV infection.
- LIVER IMMUNOLOGY
- HEPATITIS B
- HEPATITIS C
- CELLULAR IMMUNOLOGY
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Contributors SV performed experiments, contributed to the study design, data analysis, wrote the first draft and revised the manuscript. DM performed experiments and revised the manuscript. AL and SL recruited patients and revised the manuscript. BO and SM performed experiments and revised the manuscript. CT performed statistical analyses and contributed to the study design and manuscript revision. MS and DP provided healthy controls and contributed to the study design and manuscript revision. GF and CF recruited patients, performed liver biopsies and transient elastography. AA provided prospectively followed treated patients with chronic hepatitis C, contributed to the study design, data analysis and manuscript revision. PL and FF provided prospectively followed treated patients with chronic hepatitis B and contributed to manuscript revision. FB and PI recruited subjects with chronic biliary disorders contributed to data analysis and manuscript revision. MUM conceived and supervised the study, obtained funding, recruited subjects, wrote the manuscript and was responsible for the final version.
Funding This work was supported by research funds of the Italian Ministry of Health (Ricerca Corrente, Fondazione IRCCS Policlinico San Matteo) and by a grant from the Italian Ministry of Education, University and Research MiUR (Fondi di Investimento per la Ricerca di Base, FIRB, Protocollo: RBAP10TPXK).
Competing interests None declared.
Patient consent Obtained.
Ethics approval The study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by our institutional ethical committee.
Provenance and peer review Not commissioned; externally peer reviewed.