Characterization of intestinal immune responses in generalized human and murine lipodystrophy
Acquired generalized lipodystrophy (AGL) is a rare metabolic disorder frequently associated with autoimmunity. Its etiology is incompletely understood, and the effect of adipose tissue loss on intestinal inflammation in AGL remains unclear. Using mass cytometry and single-cell RNA-seq, we observed an oligoclonal expansion of T cells in the periphery and inflamed intestine in a patient with AGL and Crohn's disease (AGLCD). To explore if loss of adipose tissue triggers lymphoproliferation, we studied lipodystrophic mice as a model for AGL. Unexpectedly, lipodystrophic mice did not show T cell expansion, were protected from colitis, and displayed a defect in the development of proinflammatory T cells, which could be reversed by allogeneic fat transplantations, indicating that clonal T cell expansion in AGLCD is not primarily caused by lipodystrophy. Instead, gene sequencing revealed a T cell-intrinsic de novo neuroblastoma RAS viral oncogene homolog (NRAS) mutation, implicating somatic mosaicism as a facilitator of clonal T cell expansion and intestinal inflammation in AGLCD.
Authors
- Stefan Wirtz (ORCID: https://orcid.org/0000-0001-6936-7431)
- Désirée Kunkel (ORCID: https://orcid.org/0000-0002-0054-955X)
- Rainer Glauben
- Julia Hecker
- I Freise
- Patrick Asbach (ORCID: https://orcid.org/0000-0002-6885-3283)
- Manuel O. Jakob (ORCID: https://orcid.org/0000-0003-3638-3114)
- Carl Weidinger (ORCID: https://orcid.org/0000-0002-9948-0088)
- Anja A. Kühl (ORCID: https://orcid.org/0000-0003-2293-5387)
- Toka Omar
- Britta Siegmund (ORCID: https://orcid.org/0000-0002-0055-958X)
- Susanne M. Krug (ORCID: https://orcid.org/0000-0002-1293-2484)
- Ashley D. Sanders (ORCID: https://orcid.org/0000-0003-3945-0677)
- Marilena Letizia (ORCID: https://orcid.org/0000-0002-8039-9415)
- Benjamin Weixler (ORCID: https://orcid.org/0000-0002-3652-4792)
- Dieter Beule (ORCID: https://orcid.org/0000-0002-3284-0632)
- Patrick Weidner (ORCID: https://orcid.org/0000-0003-2448-5981)
- Britt-Sabina Löscher (ORCID: https://orcid.org/0000-0001-9022-9017)
- André Franke (ORCID: https://orcid.org/0000-0003-1530-5811)
- Elisa Rosati (ORCID: https://orcid.org/0000-0002-2635-6422)
- Frank Tacke
- Reyes Gamez-Belmonte
- Christoph S.N. Klose
- Christoph Becker
- Thomas Conrad
- Michael Stumvoll
- Jörn-Felix Ziegler
- Konstanze Miehle
- Benedikt Obermayer
Institutions
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Max Delbrück Center (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Humboldt-Universität zu Berlin (DE)
- Universitätsklinikum Erlangen (DE)
- Bipar (FR)
- University Hospital Leipzig (DE)
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
- Czech Academy of Sciences, Institute of Physiology (CZ)
- Freie Universität Berlin (DE)
- Charité - Universitätsmedizin Berlin (DE)
- Leipzig University (DE)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2026-03-15
- DOI
- https://doi.org/10.1172/jci192322
- Primary Topic
- Nuclear Structure and Function
- Type
- article
- Field-Weighted Citation Impact
- 0.00