title: Progression from Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis Is Marked by a Higher Frequency of Th17 Cells in the Liver and an Increased Th17/Resting Regulatory T Cell Ratio in Peripheral Blood and in the Liver.
abstract: Nonalcoholic fatty liver disease is increasing in prevalence. It can be subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). Five to twenty percent of cases progress from NAFL to NASH. Increased hepatic Th17 cells and IL-17 expression were observed in NASH mice and patients, respectively. We analyzed CD4(+) effector T cells and regulatory T cells (Tregs) from peripheral blood and livers of NAFL and NASH patients. A total of 51 NAFL patients, 30 NASH patients, 31 nonalcoholic fatty liver disease patients (without histology), and 43 healthy controls were included. FACS analysis was performed on PBMCs and intrahepatic lymphocytes. Compared with healthy controls, a lower frequency of resting Tregs (rTregs; CD4(+)CD45RA(+)CD25(++)) and higher frequencies of IFN-γ(+) and/or IL-4(+) cells were detected among CD4(+) T cells of peripheral blood in NASH, and to a lesser degree in NAFL. In hepatic tissue, NAFL to NASH progression was marked by an increase in IL-17(+) cells among intrahepatic CD4(+) T cells. To define immunological parameters in peripheral blood to distinguish NAFL from NASH, we calculated different ratios. Th17/rTreg and Th2/rTreg ratios were significantly increased in NASH versus NAFL. The relevance of our findings for NASH pathogenesis was highlighted by the normalization of all of the changes 1 y after bariatric surgery. In conclusion, our data indicate that NAFL patients show changes in their immune cell profile compared with healthy controls. NAFL to NASH progression is marked by an increased frequency of IL-17(+) cells among intrahepatic CD4(+) T cells and higher Th17/rTreg and Th2/rTreg ratios in peripheral blood.
authors.affiliation: Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany;
authors.forename: Monika
authors.identifier: http://orcid.org/0000-0003-1219-4044
authors.initials: M
authors.lastname: Rau
authors.affiliation: Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany;
authors.forename: Anne-Kristin
authors.identifier: http://orcid.org/0000-0002-1986-8817
authors.initials: AK
authors.lastname: Schilling
authors.affiliation: Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Meertens
authors.affiliation: Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany;
authors.forename: Ilona
authors.initials: I
authors.lastname: Hering
authors.affiliation: Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany;
authors.forename: Johannes
authors.initials: J
authors.lastname: Weiss
authors.affiliation: Department of General and Visceral Surgery, University Hospital Würzburg, 97080 Würzburg, Germany;
authors.forename: Christian
authors.identifier: http://orcid.org/0000-0001-6805-9699
authors.initials: C
authors.lastname: Jurowich
authors.affiliation: Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany;
authors.forename: Theodor
authors.identifier: http://orcid.org/0000-0001-7481-4769
authors.initials: T
authors.lastname: Kudlich
authors.affiliation: Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany;
authors.forename: Heike M
authors.initials: HM
authors.lastname: Hermanns
authors.affiliation: Department of Gastroenterology, Hepatology, and Endocrinology, Hannover Medical School, 30625 Hannover, Germany; and.
authors.forename: Heike
authors.initials: H
authors.lastname: Bantel
authors.affiliation: Institute for Virology and Immunobiology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Niklas
authors.initials: N
authors.lastname: Beyersdorf
authors.affiliation: Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg, 97080 Würzburg, Germany; geier_a2@ukw.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
mesh_terms: D000328:Adult; D000818:Animals; D050110:Bariatric Surgery; D002478:Cells, Cultured; D018450:Disease Progression; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology; D020381:Interleukin-17 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000276:immunology; D008099:Liver / Q000166:cytology* / Q000473:pathology; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000473:pathology*; D011446:Prospective Studies; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*
chemical_list: C508598:IL4 protein, human; D020381:Interleukin-17; D015847:Interleukin-4; D007371:Interferon-gamma