title: Low levels of IgM antibodies recognizing oxidation-specific epitopes are associated with human non-alcoholic fatty liver disease.
abstract: Lipid oxidation of membrane phospholipids is accompanied by the formation of oxidation-specific epitopes (OSE). These epitopes are recognized by specific antibodies and represent danger-associated molecular patterns that are generated during chronic inflammatory processes. In a murine model for hepatic inflammation during non-alcoholic fatty liver disease (NAFLD), increased antibody levels targeting OSE were found to be protective. Here, our aim was to determine an association between OSE-specific antibody titers and NAFLD in humans.
  
  
  
  IgM and IgG levels with specificity for various OSE were assessed in the plasma of patients with NAFLD (n = 71) and healthy controls (n = 68). Antibody titers were comprehensively analyzed in patients with NAFLD after classification by histological evaluation of liver biopsies. Statistical analysis was performed to determine significant correlations and odds ratios. To study the specificity for NAFLD, plasma antibody titers were measured in patients with hepatitis C (n = 40) and inflammatory bowel disease (n = 62).
  
  
  
  IgM titers against OSE were lower in patients with NAFLD compared to controls. Further biopsy-based classification of patients with NAFLD did not show any difference in IgM levels. Plasma IgM titers towards the P1 mimotope demonstrated an inverse correlation with markers for obesity, systemic inflammation, and liver damage. In contrast, hepatitis C and increased disease activity during inflammatory bowel disease was not associated with reduced IgM titers.
  
  
  
  Our data highlight the importance of immune recognition of OSE by IgM antibodies in the pathophysiology of NAFLD.
authors.affiliation: Departments of Molecular Genetics, Pathology, and Internal Medicine, Division of Gastroenterology and Hepatology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School of Oncology and Developmental Biology (GROW), Maastricht University and Maastricht University Medical Center (MUMC), PO Box 616, 6200 MD, Maastricht, The Netherlands.|Departments of Laboratory Medicine, Surgery, and Internal Medicine III, Division of Gastroenterology And Hepatology, Medical University of Vienna, Vienna, Austria.|Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Tim
authors.initials: T
authors.lastname: Hendrikx
authors.affiliation: Departments of Laboratory Medicine, Surgery, and Internal Medicine III, Division of Gastroenterology And Hepatology, Medical University of Vienna, Vienna, Austria.|Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Martin L
authors.initials: ML
authors.lastname: Watzenböck
authors.affiliation: Departments of Molecular Genetics, Pathology, and Internal Medicine, Division of Gastroenterology and Hepatology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School of Oncology and Developmental Biology (GROW), Maastricht University and Maastricht University Medical Center (MUMC), PO Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Sofie M A
authors.initials: SM
authors.lastname: Walenbergh
authors.affiliation: Departments of Laboratory Medicine, Surgery, and Internal Medicine III, Division of Gastroenterology And Hepatology, Medical University of Vienna, Vienna, Austria.|Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Shahzada
authors.initials: S
authors.lastname: Amir
authors.affiliation: Departments of Laboratory Medicine, Surgery, and Internal Medicine III, Division of Gastroenterology And Hepatology, Medical University of Vienna, Vienna, Austria.|Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Gruber
authors.affiliation: Departments of Laboratory Medicine, Surgery, and Internal Medicine III, Division of Gastroenterology And Hepatology, Medical University of Vienna, Vienna, Austria.|Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Maria Ozsvar
authors.initials: MO
authors.lastname: Kozma
authors.affiliation: Departments of Molecular Genetics, Pathology, and Internal Medicine, Division of Gastroenterology and Hepatology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School of Oncology and Developmental Biology (GROW), Maastricht University and Maastricht University Medical Center (MUMC), PO Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Heike I
authors.initials: HI
authors.lastname: Grabsch
authors.affiliation: Departments of Molecular Genetics, Pathology, and Internal Medicine, Division of Gastroenterology and Hepatology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School of Oncology and Developmental Biology (GROW), Maastricht University and Maastricht University Medical Center (MUMC), PO Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Ger H
authors.initials: GH
authors.lastname: Koek
authors.affiliation: Departments of Molecular Genetics, Pathology, and Internal Medicine, Division of Gastroenterology and Hepatology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School of Oncology and Developmental Biology (GROW), Maastricht University and Maastricht University Medical Center (MUMC), PO Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Marieke J
authors.initials: MJ
authors.lastname: Pierik
authors.affiliation: Departments of Laboratory Medicine, Surgery, and Internal Medicine III, Division of Gastroenterology And Hepatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Staufer
authors.affiliation: Departments of Laboratory Medicine, Surgery, and Internal Medicine III, Division of Gastroenterology And Hepatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Trauner
authors.affiliation: Department of Pathobiology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH, USA.
authors.forename: Satish C
authors.initials: SC
authors.lastname: Kalhan
authors.affiliation: Departments of Molecular Genetics, Pathology, and Internal Medicine, Division of Gastroenterology and Hepatology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School of Oncology and Developmental Biology (GROW), Maastricht University and Maastricht University Medical Center (MUMC), PO Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Daisy
authors.initials: D
authors.lastname: Jonkers
authors.affiliation: Department of Pathology & Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: Marten H
authors.initials: MH
authors.lastname: Hofker
authors.affiliation: Departments of Laboratory Medicine, Surgery, and Internal Medicine III, Division of Gastroenterology And Hepatology, Medical University of Vienna, Vienna, Austria.|Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.affiliation: Departments of Molecular Genetics, Pathology, and Internal Medicine, Division of Gastroenterology and Hepatology, School of Nutrition and Translational Research in Metabolism (NUTRIM) and School of Oncology and Developmental Biology (GROW), Maastricht University and Maastricht University Medical Center (MUMC), PO Box 616, 6200 MD, Maastricht, The Netherlands. r.sverdlov@maastrichtuniversity.nl.
authors.forename: Ronit
authors.initials: R
authors.lastname: Shiri-Sverdlov
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D000939:Epitopes; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood*; D007075:Immunoglobulin M / Q000097:blood*; D050356:Lipid Metabolism / Q000276:immunology; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000097:blood / Q000276:immunology*; D010084:Oxidation-Reduction
chemical_list: D015415:Biomarkers; D000939:Epitopes; D007074:Immunoglobulin G; D007075:Immunoglobulin M
keywords: Adaptive immune response; Fatty liver; IgM; Lipid oxidation; Non-alcoholic steatohepatitis