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Chen Y.-Y.,University of Birmingham | Jeffery H.C.,University of Birmingham | Hunter S.,University of Birmingham | Bhogal R.,University of Birmingham | And 14 more authors.

Regulatory T cells (Treg) suppress T effector cell proliferation and maintain immune homeostasis. Autoimmune liver diseases persist despite high frequencies of Treg in the liver, suggesting that the local hepatic microenvironment might affect Treg stability, survival, and function. We hypothesized that interactions between Treg and endothelial cells during recruitment and then with epithelial cells within the liver affect Treg stability, survival, and function. To model this, we explored the function of Treg after migration through human hepatic sinusoidal-endothelium (postendothelial migrated Treg [PEM Treg]) and the effect of subsequent interactions with cholangiocytes and local proinflammatory cytokines on survival and stability of Treg. Our findings suggest that the intrahepatic microenvironment is highly enriched with proinflammatory cytokines but deficient in the Treg survival cytokine interleukin (IL)-2. Migration through endothelium into a model mimicking the inflamed liver microenvironment did not affect Treg stability; however, functional capacity was reduced. Furthermore, the addition of exogenous IL-2 enhanced PEM Treg phosphorylated STAT5 signaling compared with PEMCD8. CD4 and CD8 T cells are the main source of IL-2 in the inflamed liver. Liver-infiltrating Treg reside close to bile ducts and coculture with cholangiocytes or their supernatants induced preferential apoptosis of Treg compared with CD8 effector cells. Treg from diseased livers expressed high levels of CD95, and their apoptosis was inhibited by IL-2 or blockade of CD95. Conclusion: Recruitment through endothelium does not impair Treg stability, but a proinflammatory microenvironment deficient in IL-2 leads to impaired function and increased susceptibility of Treg to epithelial cell-induced Fas-mediated apoptosis. These results provide a mechanism to explain Treg dysfunction in inflamed tissues and suggest that IL-2 supplementation, particularly if used in conjunction with Treg therapy, could restore immune homeostasis in inflammatory and autoimmune liver disease. (Hepatology 2016;64:138–150). © 2016 The Authors. HEPATOLOGY published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases. Source

Coombes J.D.,The Institute of Hepatology | Swiderska-Syn M.,Duke University | Dolle L.,Vrije Universiteit Brussel | Reid D.,University of Calgary | And 17 more authors.

Background Chronic liver injury triggers a progenitor cell repair response, and liver fibrosis occurs when repair becomes deregulated. Previously, we reported that reactivation of the hedgehog pathway promotes fibrogenic liver repair. Osteopontin (OPN) is a hedgehog-target, and a cytokine that is highly upregulated in fibrotic tissues, and regulates stem-cell fate. Thus, we hypothesised that OPN may modulate liver progenitor cell response, and thereby, modulate fibrotic outcomes. We further evaluated the impact of OPN-neutralisation on murine liver fibrosis. Methods Liver progenitors (603B and bipotential mouse oval liver) were treated with OPN-neutralising aptamers in the presence or absence of transforming growth factor (TGF)-β, to determine if (and how) OPN modulates liver progenitor function. Effects of OPN-neutralisation (using OPN-aptamers or OPN-neutralising antibodies) on liver progenitor cell response and fibrogenesis were assessed in three models of liver fibrosis (carbon tetrachloride, methionine-choline deficient diet, 3,5,-diethoxycarbonyl-1,4-dihydrocollidine diet) by quantitative real time (qRT) PCR, Sirius-Red staining, hydroxyproline assay, and semiquantitative double-immunohistochemistry. Finally, OPN expression and liver progenitor response were corroborated in liver tissues obtained from patients with chronic liver disease. Results OPN is overexpressed by liver progenitors in humans and mice. In cultured progenitors, OPN enhances viability and wound healing by modulating TGF-β signalling. In vivo, OPN-neutralisation attenuates the liver progenitor cell response, reverses epithelial-mesenchymal-transition in Sox9+ cells, and abrogates liver fibrogenesis. Conclusions OPN upregulation during liver injury is a conserved repair response, and influences liver progenitor cell function. OPN-neutralisation abrogates the liver progenitor cell response and fibrogenesis in mouse models of liver fibrosis. © 2014 BMJ Publishing Group Ltd & British Society of Gastroenterology. Source

Manka P.,University of Duisburg - Essen | Bechmann L.P.,University of Duisburg - Essen | Coombes J.D.,The Institute of Hepatology | Thodou V.,University of Duisburg - Essen | And 9 more authors.
Clinical Gastroenterology and Hepatology

In Western countries, infection with the hepatitis E virus (HEV) is considered to be rare and imported from endemic regions. However, the prevalence of HEV infection has increased among adults in central Europe. HEV infection can cause acute liver failure (ALF), but there have been only a few confirmed cases of HEV-associated ALF in Europe. We investigated the number of cases of indeterminate ALF associated with HEV infection. Methods: We performed a retrospective analysis of 80 patients diagnosed with ALF or acute hepatitis at the University Hospital Essen in Germany from November 2006 through December 2013. Clinical data were collected from the hospital databases; archived sera were tested for IgG and IgM against HEV, as well as HEV RNA. Results: Sera from 12 patients (15%) tested positive for IgG against HEV IgG; 7 of these samples did not test positive for HEV IgM or HEV RNA. Sera from 64 patients (80%) did not test positive for IgG or IgM against HEV or HEV RNA. Sera from 8 patients (10%) tested positive for HEV RNA (only 4 of these were positive for HEV IgG) and had clinical findings to support acute HEV infection. Conclusions: In a hospital in Germany, approximately 10% to 15% of patients with ALF had evidence for HEV infection. Serologic tests for IgG against HEV are insufficient to identify or exclude HEV infection; tests for HEV RNA also should be performed on patients with ALF of ambiguous etiology. © 2015 AGA Institute. Source

Coombes J.D.,The Institute of Hepatology | Coombes J.D.,Kings College London | Choi S.S.,Duke University | Choi S.S.,Durham Veteran Affairs Medical Center | And 30 more authors.
Biochimica et Biophysica Acta - Molecular Basis of Disease

Introduction: Liver fibrosis develops when hepatic stellate cells (HSC) are activated into collagen-producing myofibroblasts. In non-alcoholic steatohepatitis (NASH), the adipokine leptin is upregulated, and promotes liver fibrosis by directly activating HSC via the hedgehog pathway. We reported that hedgehog-regulated osteopontin (OPN) plays a key role in promoting liver fibrosis. Herein, we evaluated if OPN mediates leptin-profibrogenic effects in NASH. Methods: Leptin-deficient (ob/ob) and wild-type (WT) mice were fed control or methionine-choline deficient (MCD) diet. Liver tissues were assessed by Sirius-red, OPN and αSMA IHC, and qRT-PCR for fibrogenic genes. In vitro, HSC with stable OPN (or control) knockdown were treated with recombinant (r)leptin and OPN-neutralizing or sham-aptamers. HSC response to OPN loss was assessed by wound healing assay. OPN-aptamers were also added to precision-cut liver slices (PCLS), and administered to MCD-fed WT (leptin-intact) mice to determine if OPN neutralization abrogated fibrogenesis. Results: MCD-fed WT mice developed NASH-fibrosis, upregulated OPN, and accumulated αSMA + cells. Conversely, MCD-fed ob/ob mice developed less fibrosis and accumulated fewer αSMA + and OPN + cells. In vitro, leptin-treated HSC upregulated OPN, αSMA, collagen 1α1 and TGFβ mRNA by nearly 3-fold, but this effect was blunted by OPN loss. Inhibition of PI3K and transduction of dominant negative-Akt abrogated leptin-mediated OPN induction, while constitutive active-Akt upregulated OPN. Finally, OPN neutralization reduced leptin-mediated fibrogenesis in both PCLS and MCD-fed mice. Conclusion: OPN overexpression in NASH enhances leptin-mediated fibrogenesis via PI3K/Akt. OPN neutralization significantly reduces NASH fibrosis, reinforcing the potential utility of targeting OPN in the treatment of patients with advanced NASH. © 2015 Elsevier B.V.. Source

Howarth M.,The Institute of Hepatology | Riva A.,The Institute of Hepatology | Marks P.,The Institute of Hepatology | Williams R.,The Institute of Hepatology
Alcohol and Alcoholism

Aims: To test the hypothesis that regional variations in the prevalence of alcoholic liver disease are contributed to by regional variations in 'softness' of drinking water, i.e. its mineral content. Methods: Annual hospital admission rates for alcoholic liver disease per 100,000 population in the 28 Strategic Health Authorities (SHAs) existing in England over the period 2003-2006 were compared with regional measures of water hardness, alcohol consumption and social deprivation. As corroborative evidence, the same relations were examined for hospital admission rates for osteoporosis, a disorder with an already established link with calcium deficiency in drinking water (as well as with heavy drinking). Results: Hospital admissions rates for alcoholic liver disease were higher in predominant-soft-water SHAs than with hard water SHAs. These areas, with one exception, were also associated with high alcohol consumption, but not with greater social deprivation. Hospital admission rates for osteoporosis were found to vary in a way similar to that for alcoholic liver disease, with significant correlations with soft water and alcohol consumption. Conclusion: Given experimental evidence that magnesium deficiency can aggravate liver damage from alcohol, soft water with its low magnesium concentration may be a factor additional to alcohol consumption in the development of liver damage. The parallel findings with osteoporosis admissions, explainable by low calcium and magnesium levels present in soft water, along with the known effect of heavy drinking on bone metabolism, provide corollary support for the hypothesis linking soft water with the pathogenesis of these two diseases. © The Author 2012. Medical Council on Alcohol and Oxford University Press. All rights reserved. Source

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