Abstract
Multiple factors are involved in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), but the exact immunological mechanisms that cause inflammation and fibrosis of the liver remain enigmatic. In this current study, cellular samples of a cohort of NAFLD patients (peripheral blood mononuclear cells (PBMC): n = 27, liver samples: n = 15) and healthy individuals (PBMC: n = 26, liver samples: n = 3) were analyzed using 16-color flow cytometry, and the frequency and phenotype of 23 immune cell subtypes was assessed. PBMC of NAFLD patients showed decreased frequencies of total CD3+, CD8+ T cells, CD56dim NK cells and MAIT cells, but elevated frequencies of CD4+ T cells and Th2 cells compared to healthy controls. Intrahepatic lymphocytes (IHL) of NAFLD patients showed decreased frequencies of total T cells, total CD8+ T cells, Vd2+γδ T cells, and CD56bright NK cells, but elevated frequencies of Vδ2-γδ T cells and CD56dim NK cells compared to healthy controls. The activating receptor NKG2D was significantly less frequently expressed among iNKT cells, total NK cells and CD56dim NK cells of PBMC of NAFLD patients compared to healthy controls. More strikingly, hepatic fibrosis as measured by fibroscan elastography negatively correlated with the intrahepatic frequency of total NK cells (r2 = 0,3737, p = 0,02). Hepatic steatosis as measured by controlled attenuation parameter (CAP) value negatively correlated with the frequency of circulating NKG2D+ iNKT cells (r2 = 0,3365, p = 0,0047). Our data provide an overview of the circulating and intrahepatic immune cell composition of NAFLD patients, and point towards a potential role of NK cells and iNKT cells for the regulation of hepatic fibrosis and steatosis in NAFLD.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the western industrialized countries and is a growing burden to the public health systems with few approved therapeutic options currently available [1].NAFLD encompasses two entities of different disease severity with (I) non-alcoholic fatty liver (NAFL) which is defined as mere hepatic steatosis without inflammation, and (II) nonalcoholic steatohepatitis (NASH) being defined by the presence of intrahepatic lobular inflammation and/or hepatocellular ballooning
peripheral blood mononuclear cells (PBMC) of NAFLD patients were obtained at the outpatient clinic; a detailed overview of the cohort and respective subgroups is displayed in S1 Fig. The degree of fibrosis in patients for whom only PBMC were available, was solely determined by fibroscan, whereas for patients of whom liver biopsies were available the result of the fibroscan and histological evaluation were used
Invariant Natural killer T cells were defined as TCRVα24Jα18+ and CD3+, γδT cells were defined as pan γδ TCR+ with a subdivision in Vδ2+ γδT cells and Vδ2- γδT cells, mucosal associated invariant T (MAIT) cells were defined as CD3+, CD4, CD161+, TCR Vα7.2+
Summary
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the western industrialized countries and is a growing burden to the public health systems with few approved therapeutic options currently available [1]. NAFLD encompasses two entities of different disease severity with (I) non-alcoholic fatty liver (NAFL) which is defined as mere hepatic steatosis without inflammation, and (II) nonalcoholic steatohepatitis (NASH) being defined by the presence of intrahepatic lobular inflammation and/or hepatocellular ballooning. A close relationship between NAFLD and metabolic. Immune landscape of human NAFLD analysis, decision to publish, or preparation of the manuscript
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