Serum Concentrations of Th17-Associated Interleukins and Autoimmune Phenomena are Associated with the Degree of Liver Damage in Alcoholic Liver Disease

Abstract

Background & Aims: Recent reports suggest an involvement of Th17 responses in inflammatory and autoimmune reactions in alcoholic liver disease (ALD). Our study aimed to assess serum levels of Th17-interleukins in ALD with regard to the frequency of liver-specific autoantibodies and degree of liver damage.Methods: Ninety-five patients with ALD were enrolled. Serum concentrations of IL-17F, IL-17A, IL-22 were assessed by ELISA. The presence of autoantibodies AMA-M2, SLA/LP, LKM-1, LC1, anti-F-actin, anti-desmin and anti-myosin in serum was assessed by immunoblotting, ANA antibodies were detected by ELISA. The results were analysed with regard to the degree of hepatic damage.Results: Serum IL-17F was significantly elevated in ALD patients compared to controls (p=0.03). There was a correlation between serum IL-17F and degree of liver failure evaluated by the MELD score (rs=0.23, p=0.03). Serum IL-22 also correlated with MELD score (rs=0.32, p=0.007) and CTP score (rs=0.28, p=0.02). Anti-F-actin antibodies were present in 19% and ANA-antibodies in 11% of the patients in the study group, and in no subjects in the control group. The prevalence of anti-F-actin autoantibodies was higher in subjects with more advanced liver diseases but also independently associated with IL-17A in the regression analysis. Furthermore, serum IL-22 in anti-F-actin(+)-patients was significantly higher compared to anti-F-actin(-)-patients (p=0.03).Conclusions: Elevation of serum IL-17A, IL-17F, IL-22 correlated with the progression of liver damage and also with presence of F-actin in ALD. Alcoholic liver disease may trigger autoimmunity and formation of autoantibodies, especially anti-F-actin, with possible engagement of Th17-related cytokines in this process.Abbreviations: AA: acetaldehyde; Abs: antibodies; AFP: α-fetoprotein; ALD: alcoholic liver disease; ALT: alanine aminotransferase; AMA-M2: antimitochondrial antibodies; ANA: antinuclear antibodies; ASMA: anti-smooth muscle antibodies; α-SMA: alpha smooth muscle actin; CTP Score: Child-Turcotte-Pugh Score; GAHS: Glasgow Alcoholic Hepatitis Score; GGT: γ-glutamyl transpeptidase; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV: human immunodeficiency virus; HSCs: hepatic stellate cells; IL-β1: interleukin β1; IL-6: interleukin 6; IL-17A: interleukin 17A; IL-17F: interleukin 17F; IL-22: interleukin 22; KCs: Kupffer cells; LC1: liver cytosol antigen type 1; LKM-1: liver kidney microsomal antigen; MA: malondialdehyde; MELD: Model of End-Stage Liver Disease; NASH: non-alcoholic steatoheptatitis; SLA/LP: soluble liver antigen/liver-pancreas; TGF-β: tumour growth factor β; TNF-α: tumour necrosis factor α.

Mitochondrial Dysfunction: At the Nexus between Alcohol-Associated Immunometabolic Dysregulation and Tissue Injury

“…Mechanistically, it was shown that alcohol increased mitochondrial double-stranded RNA in hepatocyte-derived extracellular vesicles that signal to activate Kupffer cells to produce IL-1β, subsequently increasing IL-17 production in γδ T cells [41]. Similarly, in people with ARLD, serum IL-17F was significantly increased and, together with IL-22, was associated with a higher Model For End-Stage Liver Disease (MELD) score [42]. Moreover, Treg cells decreased during alcohol-related hepatitis [43].…”

The Interleukin-20 Cytokine Family in Liver Disease

“…In this context, alcohol consumption induces hepatotoxicity through intermediaries of ethanol metabolism, or by generating different mediators of the inflammatory response, like products of the oxidative stress response or proinflammatory cytokines secreted by liver Kupffer cells, such as TNF-α ( 103 ). Serum concentrations of both IL-17 cytokine protein isoforms, together with IL-22 levels, have been proposed as correlates of liver damage progression in ALD ( 86 ). Moreover, high-IL-22 levels seem to be a good prognostic marker ( 87 ).…”