Research ArticleHepatologyImmunology Open Access | 10.1172/jci.insight.184544

Lara Henze,1 Nico Will,1 Dakyung Lee,1 Victor Haas,1 Christian Casar,1,2 Jasper Meyer,1 Stephanie Stein,1 Franziska Mangler,1 Silja Steinmann,1 Tobias Poch,1 Jenny Krause,1 Johannes Fuss,3 Johanna Schröder,4 Alexandra E. Kulle,5 Paul-Martin Holterhus,5 Stefan Bonn,6,7 Marcus Altfeld,8 Samuel Huber,1,9 Ansgar W. Lohse,1,9 Dorothee Schwinge,1 and Christoph Schramm1,9,10

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Henze, L. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Will, N. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Lee, D. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Haas, V. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Casar, C. in: JCI | PubMed | Google Scholar |

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Meyer, J. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Stein, S. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Mangler, F. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Steinmann, S. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Poch, T. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Krause, J. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Fuss, J. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Schröder, J. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Kulle, A. in: JCI | PubMed | Google Scholar |

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Holterhus, P. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Bonn, S. in: JCI | PubMed | Google Scholar |

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Altfeld, M. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Huber, S. in: JCI | PubMed | Google Scholar |

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Lohse, A. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Schwinge, D. in: JCI | PubMed | Google Scholar

11st Department of Medicine, and

2Bioinformatics Core, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

3Institute of Forensic Psychiatry and Sex Research, Center for Translational Neuro and Behavioral Sciences, University of Duisburg-Essen, Essen, Germany.

4Institute for Clinical Psychology and Psychotherapy, Department for Psychology, Medical School Hamburg, Hamburg, Germany.

5Division of Pediatric Endocrinology and Diabetes, Department of Children and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

6Institute of Medical Systems Biology and

7Center for Biomedical AI, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

8Research Department Virus Immunology, Leibniz Institute of Virology, Hamburg, Germany.

9Hamburg Center for Translational Immunology and

10Martin Zeitz Center for Rare Diseases and, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Address correspondence to: Christoph Schramm or Dorothee Schwinge, Martin Zeitz Center for Rare Diseases and 1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52; 20246 Hamburg, Germany. Phone: 49.40.7410.52545; Email: c.schramm@uke.de or d.schwinge@uke.de.

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Find articles by Schramm, C. in: JCI | PubMed | Google Scholar

Authorship note: LH and NW contributed equally to this work. DS and CS have been designated as co–senior authors.

Published April 22, 2025 - More info

Published in Volume 10, Issue 8 on April 22, 2025
JCI Insight. 2025;10(8):e184544. https://doi.org/10.1172/jci.insight.184544.
© 2025 Henze et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Published April 22, 2025 - Version history
Received: July 11, 2024; Accepted: March 4, 2025 View PDF Abstract

Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) are autoimmune liver diseases with strong female predominance. They are caused by T cell–mediated injury of hepatic parenchymal cells, but the mechanisms underlying this sex bias are unknown. Here, we investigated whether testosterone contributes to T cell activation in women with PBC. Compared with sex- and age-matched healthy controls (n = 23), cisgender (cis) women with PBC (n = 24) demonstrated decreased testosterone serum levels and proinflammatory CD4+ T cell profile in peripheral blood. Testosterone suppressed the expression of TNF and IFN-γ by human CD4+ T cells in vitro. In trans men receiving gender-affirming hormone therapy (GAHT) (n = 25), testosterone affected CD4+ T cell function by inhibiting Th1 and Th17 differentiation and by supporting the differentiation into regulatory Treg. Mechanistically, we provide evidence for a direct effect of testosterone on T cells using mice with T cell–specific deletion of the cytosolic androgen receptor. Supporting a role for testosterone in autoimmune liver disease, we observed an improved disease course and profound changes in T cell states in a trans man with AIH/primary sclerosing cholangitis (PSC) variant syndrome receiving GAHT. We here report a direct effect of testosterone on CD4+ T cells that may contribute to future personalized treatment strategies.

Graphical Abstract Introduction

There is increasing interest in sex- and gender-related differences in immune responses. Whereas females show better control of viral infections, they are generally more prone to develop autoimmune diseases (1–4). This partly relates to sex, as determined by the sex chromosomes, for example via selective X-chromosomal inactivation (5, 6). However, sex hormones also directly or indirectly contribute to the regulation of the immune system (7). A substantial role in modulating the immune system has been described for 17-β estradiol (E2). The effects of E2 on immune cells varies depending on factors such as the concentration, the specific immune cell type, and the context of the immune response. Low concentrations of E2 have been associated with proinflammatory immune responses, whereas high concentrations of estrogens have been reported to be antiinflammatory and to augment Th2 responses and humoral immunity (8). Immunomodulatory effects have also been demonstrated for androgens, and testosterone has been shown to suppress the activity of immune cells, leading to immunosuppression. Thus, testosterone has been demonstrated to reduce proinflammatory responses of macrophages and to suppress extracellular signal–regulated kinases and leukotriene formation in neutrophils (9, 10). It has also been shown that healthy female mice have higher numbers of ILC2 cells in multiple tissues and that they can be modulated by testosterone (11). In murine-derived splenocytes, testosterone reduced the production of proinflammatory cytokines such as IL-1, IL-6, and TNF, while potentially increasing the production of antiinflammatory cytokines such as IL-10 in antigen-specific stimulated CD4+ T cells (12). Little is known about the effects of androgens on T cells in humans, but lower CD8+ T cell and higher CD4+ T cell frequencies, and specifically a higher frequency of circulating Treg, have been described in cisgender (cis) women compared with cis men (13, 14). Moreover, in serum from men with androgen deficiency, higher concentrations of proinflammatory cytokines and higher CD4+/CD8+ T cell ratios were reported (15–17). Notably, lower serum levels of testosterone were reported for autoimmune diseases, including systemic lupus erythematosus (SLE), multiple sclerosis (MS), and rheumatoid arthritis (RA) (18, 19). So far, it is unclear whether those effects might contribute to T cell regulation in autoimmune diseases.

In this study, we sought to investigate the effects of testosterone on T cell function in healthy humans and humans affected by primary biliary cholangitis (PBC), an autoimmune liver disease (AILD) with a particularly high female predominance (female/male ratio of 9:1) (20, 21). We found that testosterone levels associated with proinflammatory T cell phenotype in women with PBC affect T cell differentiation in trans men and that testosterone exerts direct effects on murine T cel