Major Histocompatibility Complex Class I–Related Chains A and B (Mic A/B): A Novel Role in Nonalcoholic Steatohepatitis

Kahraman, Alişan; Schlattjan, Martin; Kocabayoglu, Peri; Yildiz-Meziletoglu, Sule; Schlensak, Matthias; Fingas, Christian D.; Wedemeyer, Inga; Marquitan, Guido; Gieseler, Robert K.; Baba, Hideo A.; Gerken, Guido; Canbay, Ali

doi:10.1002/hep.23253

Cited by 106 publications

(85 citation statements)

References 49 publications

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“…may affect the progression of liver injury. 46 Taken together, we present the first data indicating that NKp46 High NK cells represent a specific ''bifunctional'' NK-cell subset that may be involved both in the control of viral replication and inhibition of liver fibrosis in hepatitis C. Moreover, our data clearly support an important role of the NKp46 receptor in HCV infection.…”

Section: Nk Cells (Supportingsupporting

confidence: 66%

Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

et al. 2012

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Natural killer (NK) cells play a role in the early control and natural course of hepatitis C virus (HCV) infection. NK cell function is regulated by a multitude of receptors, including activating NKp46 receptor. However, reports on NKp46 in hepatitis C are controversial. Therefore, we investigated the hepatic recruitment and function of NKp46(1) NK cells, considering differential surface expression of NKp46 resulting in NKp46 High and NKp46 Dim subsets. Intra-and extrahepatic NK-cell subsets from HCV-infected patients were characterized by flow cytometry. Cytotoxic activity and interferon-gamma (IFN-c) secretion were studied using K-562, P815, and primary hepatic stellate cells as targets. Anti-HCV activity of NK-cell subsets was studied using the replicon system. Density of NKp46 surface expression clearly segregated NKp46 Dim and NKp46 High subsets, which differed significantly with respect to the coexpression of maturation markers and NK-cell receptors. More important, NKp46 High NK cells showed a higher cytolytic activity and stronger IFN-c secretion than NKp46 Dim NK cells. Accordingly, NKp46 High NK cells efficiently blocked HCV replication in vitro. Blocking experiments confirmed an important role for the NKp46 receptor. Furthermore, we found an intrahepatic accumulation of NKp46 High NK cells. Of note, high cytolytic activity of NKp46 High NK cells was also confirmed in the intrahepatic NK-cell population, and the frequency of intrahepatic NKp46 High NK cells was inversely correlated with HCV-RNA levels and fibrosis stage. Conclusions: NKp46 High expression defines a specific NK-cell subset that may be involved in both the suppression of HCV replication and HCV-associated liver damage underpinning the role of NK cells in the immunopathogenesis of HCV. (HEPATOLOGY 2012;56:1201-1213 See Editorial on Page 1197 I nfection with the hepatitis C virus (HCV) often results in chronic liver disease. Elimination of HCV infection requires the coordinated function of the innate and the adaptive immune system. Natural killer (NK) cells constitute a major component of the intrahepatic lymphocyte pool. In contrast to the peripheral blood, which contains approximately 5%-10% NK cells, intrahepatic lymphocytes comprise approximately 30% NK cells, and the percentage of intrahepatic NK cells may increase >50% in liver diseases. 1 Immunogenetic analyses indicate that NK cells may influence the outcome of acute HCV infection as well as immunopathogenesis in chronic hepatitis C (CHC). 2 Accordingly, in vitro studies suggest that NK cells are able to recognize and kill HCV-infected hepatocytes in vivo. 3 However, published data on phenotype and function of NK cells in HCV infection are controversial. [4][5][6][7][8][9][10][11][12][13]

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Section: Nk Cells (Supportingsupporting

confidence: 66%

Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

et al. 2012

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“…Therefore, measurement of MICA/B serum levels may be utilized as a novel marker to assess liver injury in NASH in a non-invasive fashion. Importantly, our data indicated that MICA/B are expressed on hepatocytes in patients with NASH and their expression may play an important role in their susceptibility to NK cells during hepatic inflammation as mediated by fatty infiltration of the liver (22).…”

Section: Discussionmentioning

confidence: 71%

Vitamin D ameliorates stress ligand expression elicited by free fatty acids in the hepatic stellate cell line LX-2

Seydel¹,

Beilfuss²,

Kahraman³

et al. 2011

Turk J Gastroenterol

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“…3). Similarly, hepatocytes upregulate NK cell NKG2D ligands in a murine model of HBV infection, rendering the hepatocytes susceptible to increased lysis (52), and NKG2D-mediated hepatocyte killing has been described for nonalcoholic steatohepatitis (53). NK cell upregulation of TRAIL, FAS, and other granzymes and perforins has been shown to be in- volved in both hepatocellular damage and HCV clearance (54)(55)(56).…”

Section: Discussionmentioning

confidence: 96%

Acute Liver Damage Associated with Innate Immune Activation in a Small Nonhuman Primate Model of Hepacivirus Infection

Manickam

Rajakumar

Wachtman

et al. 2016

J Virol

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Despite its importance in shaping adaptive immune responses, viral clearance, and immune-based inflammation, tissue-specific innate immunity remains poorly characterized for hepatitis C virus (HCV) infection due to the lack of access to acutely infected tissues. In this study, we evaluated the impact of natural killer (NK) cells and myeloid (mDCs) and plasmacytoid (pDCs) dendritic cells on control of virus replication and virus-induced pathology caused by another, more rapidly resolving hepacivirus, GB virus B (GBV-B), in infections of common marmosets. High plasma and liver viral loads and robust hepatitis characterized acute GBV-B infection, and while viremia was generally cleared by 2 to 3 months postinfection, hepatitis and liver fibrosis persisted after clearance. Coinciding with peak viral loads and liver pathology, the levels of NK cells, mDCs, and pDCs in the liver increased up to 3-fold. Although no obvious numerical changes in peripheral innate cells occurred, circulating NK cells exhibited increased perforin and Ki67 expression levels and increased surface expression of CXCR3. These data suggested that increased NK cell arming and proliferation as well as tissue trafficking may be associated with influx into the liver during acute infection. Indeed, NK cell frequencies in the liver positively correlated with plasma (R ‫؍‬ 0.698; P ‫؍‬ 0.015) and liver (R ‫؍‬ 0.567; P ‫؍‬ 0.057) viral loads. Finally, soluble factors associated with NK cells and DCs, including gamma interferon (IFN-␥) and RANTES, were increased in acute infection and also were associated with viral loads and hepatitis. Collectively, the findings showed that mobilization of local and circulating innate immune responses was linked to acute virus-induced hepatitis, and potentially to resolution of GBV-B infection, and our results may provide insight into similar mechanisms in HCV infection. IMPORTANCEHepatitis C virus (HCV) infection has created a global health crisis, and despite new effective antivirals, it is still a leading cause of liver disease and death worldwide. Recent evidence suggests that innate immunity may be a potential therapeutic target for HCV, but it may also be a correlate of increased disease. Due to a lack of access to human tissues with acute HCV infection, in this study we evaluated the role of innate immunity in resolving infection with a hepacivirus, GBV-B, in common marmosets. Collectively, our data suggest that NK cell and DC mobilization in acute hepacivirus infection can dampen virus replication but also regulate acute and chronic liver damage. How these two opposing effects on the host may be modulated in future therapeutic and vaccine approaches warrants further study. H epatitis C virus (HCV) infection has become a global health epidemic, with the virus infecting more than 170 million people worldwide (1) and resulting in 350,000 HCV-related liver disease deaths each year (2). HCV infection results in the following two disparate manifestations: (i) an acute, self-resolving infection and (ii) a chron...

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Major Histocompatibility Complex Class I–Related Chains A and B (Mic A/B): A Novel Role in Nonalcoholic Steatohepatitis

Cited by 106 publications

References 49 publications

Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis

Vitamin D ameliorates stress ligand expression elicited by free fatty acids in the hepatic stellate cell line LX-2

Acute Liver Damage Associated with Innate Immune Activation in a Small Nonhuman Primate Model of Hepacivirus Infection

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