PMID- 31211759 OWN - NLM STAT- MEDLINE DCOM- 20200924 LR - 20240103 IS - 2155-384X (Electronic) IS - 2155-384X (Linking) VI - 10 IP - 6 DP - 2019 Jun TI - Alcohol Abstinence Does Not Fully Reverse Abnormalities of Mucosal-Associated Invariant T Cells in the Blood of Patients With Alcoholic Hepatitis. PG - e00052 LID - 10.14309/ctg.0000000000000052 [doi] LID - e00052 AB - OBJECTIVES: Alcoholic hepatitis (AH) develops in approximately 30% of chronic heavy drinkers. The immune system of patients with AH is hyperactivated, yet ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are highly enriched in liver, mucosa, and peripheral blood and contribute to antimicrobial immunity. We aimed to determine whether MAIT cells were dysregulated in heavy drinkers with and without AH and the effects of alcohol abstinence on MAIT cell recovery. METHODS: MR1 tetramers loaded with a potent MAIT cell ligand 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil were used in multiparameter flow cytometry to analyze peripheral blood MAIT cells in 59 healthy controls (HC), 56 patients with AH, and 45 heavy drinkers without overt liver disease (HDC) at baseline and 6- and 12-month follow-ups. Multiplex immunoassays were used to quantify plasma levels of cytokines related to MAIT cell activation. Kinetic Turbidimetric Limulus Amebocyte Lysate Assay and ELISA were performed to measure circulating levels of 2 surrogate markers for bacterial translocation (lipopolysaccharide and CD14), respectively. RESULTS: At baseline, patients with AH had a significantly lower frequency of MAIT cells than HDC and HC. HDC also had less MAIT cells than HC (median 0.16% in AH, 0.56% in HDC, and 1.25% in HC). Further, the residual MAIT cells in patients with AH expressed higher levels of activation markers (CD69, CD38, and human leukocyte antigen [HLA]-DR), the effector molecule granzyme B, and the immune exhaustion molecule PD-1. Plasma levels of lipopolysaccharide and CD14 and several cytokines related to MAIT cell activation were elevated in patients with AH (interferon [IFN]-alpha, interleukin [IL]-7, IL-15, IL-17, IL-18, IL-23, IFN-gamma, and tumor necrosis factor alpha). Decreased MAIT cell frequency and upregulated CD38, CD69, and HLA-DR correlated negatively and positively, respectively, with aspartate aminotransferase level. MAIT cell frequency negatively correlated with IL-18. HLA-DR and CD38 levels correlated with several cytokines. At follow-ups, abstinent patients with AH had increased MAIT cell frequency and decreased MAIT cell activation. However, MAIT cell frequency was not fully normalized in patients with AH (median 0.31%). DISCUSSION: We showed that HDC had a reduction of blood MAIT cells despite showing little evidence of immune activation, whereas patients with AH had a severe depletion of blood MAIT cells and the residual cells were highly activated. Alcohol abstinence partially reversed those abnormalities. FAU - Li, Wei AU - Li W AD - Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA. FAU - Lin, Edward L AU - Lin EL AD - Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA. FAU - Liangpunsakul, Suthat AU - Liangpunsakul S AD - Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. AD - Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA. AD - Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA. FAU - Lan, Jie AU - Lan J AD - Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA. FAU - Chalasani, Sai AU - Chalasani S AD - Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA. FAU - Rane, Sushmita AU - Rane S AD - Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA. FAU - Puri, Puneet AU - Puri P AD - Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA. FAU - Kamath, Patrick S AU - Kamath PS AD - Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA. FAU - Sanyal, Arun J AU - Sanyal AJ AD - Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA. FAU - Shah, Vijay H AU - Shah VH AD - Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA. FAU - Radaeva, Svetlana AU - Radaeva S AD - National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, USA. FAU - Crabb, David W AU - Crabb DW AD - Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. AD - Internal Medicine, Eskenazi Health, Indianapolis, Indiana, USA. FAU - Chalasani, Naga AU - Chalasani N AD - Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. FAU - Yu, Qigui AU - Yu Q AD - Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA. LA - eng GR - UL1 TR002649/TR/NCATS NIH HHS/United States GR - R01 AA021171/AA/NIAAA NIH HHS/United States GR - U01 AA021840/AA/NIAAA NIH HHS/United States GR - UH2 AA026218/AA/NIAAA NIH HHS/United States GR - UH3 AA026218/AA/NIAAA NIH HHS/United States GR - R37 AA021171/AA/NIAAA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PL - United States TA - Clin Transl Gastroenterol JT - Clinical and translational gastroenterology JID - 101532142 RN - 0 (Biomarkers) RN - 0 (Cytokines) RN - 0 (HLA-DR Antigens) RN - 0 (Interleukin-18) SB - IM MH - Adult MH - *Alcohol Abstinence MH - Biomarkers/blood MH - Case-Control Studies MH - Cytokines/*blood MH - Female MH - Flow Cytometry MH - HLA-DR Antigens/blood MH - Hepatitis, Alcoholic/blood/*immunology MH - Humans MH - Interleukin-18/blood MH - Male MH - Middle Aged MH - Mucosal-Associated Invariant T Cells/*immunology PMC - PMC6613857 EDAT- 2019/06/19 06:00 MHDA- 2020/09/25 06:00 PMCR- 2019/06/18 CRDT- 2019/06/19 06:00 PHST- 2019/06/19 06:00 [pubmed] PHST- 2020/09/25 06:00 [medline] PHST- 2019/06/19 06:00 [entrez] PHST- 2019/06/18 00:00 [pmc-release] AID - CTG-19-0139 [pii] AID - 10.14309/ctg.0000000000000052 [doi] PST - ppublish SO - Clin Transl Gastroenterol. 2019 Jun;10(6):e00052. doi: 10.14309/ctg.0000000000000052.