Characterization of intestinal immune responses in generalized human and murine lipodystrophy
Marilena Letizia, Toka Omar, Patrick Weidner, Manuel O. Jakob, Inka Freise, Susanne M. Krug, Britt-Sabina Löscher, Elisa Rosati, Benedikt Obermayer, Reyes Gamez-Belmonte, Julia Hecker, Jörn-Felix Ziegler, Benjamin Weixler, Patrick Asbach, Desiree Kunkel, Michael Stumvoll, Konstanze Miehle, Christoph Becker, Christoph S.N. Klose, Rainer Glauben, Dieter Beule, Anja A. Kühl, Thomas Conrad, Frank Tacke, Stefan Wirtz, Andre Franke, Ashley D. Sanders, Britta Siegmund, Carl Weidinger
Marilena Letizia, Toka Omar, Patrick Weidner, Manuel O. Jakob, Inka Freise, Susanne M. Krug, Britt-Sabina Löscher, Elisa Rosati, Benedikt Obermayer, Reyes Gamez-Belmonte, Julia Hecker, Jörn-Felix Ziegler, Benjamin Weixler, Patrick Asbach, Desiree Kunkel, Michael Stumvoll, Konstanze Miehle, Christoph Becker, Christoph S.N. Klose, Rainer Glauben, Dieter Beule, Anja A. Kühl, Thomas Conrad, Frank Tacke, Stefan Wirtz, Andre Franke, Ashley D. Sanders, Britta Siegmund, Carl Weidinger
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Research Article Autoimmunity Endocrinology Gastroenterology

Characterization of intestinal immune responses in generalized human and murine lipodystrophy

Abstract

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

Marilena Letizia, Toka Omar, Patrick Weidner, Manuel O. Jakob, Inka Freise, Susanne M. Krug, Britt-Sabina Löscher, Elisa Rosati, Benedikt Obermayer, Reyes Gamez-Belmonte, Julia Hecker, Jörn-Felix Ziegler, Benjamin Weixler, Patrick Asbach, Desiree Kunkel, Michael Stumvoll, Konstanze Miehle, Christoph Becker, Christoph S.N. Klose, Rainer Glauben, Dieter Beule, Anja A. Kühl, Thomas Conrad, Frank Tacke, Stefan Wirtz, Andre Franke, Ashley D. Sanders, Britta Siegmund, Carl Weidinger

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Figure 3

Lipodystrophic Ppargfl/fl Adipoq-Cre mice mimic the hepatic phenotype of the patient with AGLCD and show defects in the development of NK and T cells under steady-state conditions.

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Lipodystrophic Ppargfl/fl Adipoq-Cre mice mimic the hepatic phenotype of...
(A) Representative images of Ppargfl/fl Adipoq-Cre (Lipo) and WT mice showing the complete absence of fat tissue and H&E-stained images of mesenteric adipose tissue (arrows indicate mesenteric and gonadal fat tissue). Scale bars: 100 μm. (B) Leptin plasma levels (WT n = 4; Lipo n = 4). (C) Liver weights of WT mice (n = 16) and Ppargfl/fl Adipoq-Cre mice (n = 12) from 2 independent experiments with a representative image. (D–G) Flow cytometric assessment of splenic NK cells from Ppargfl/fl Adipoq-Cre mice (n = 9–24) compared with WT littermate cells (n = 10–23). Data were pooled from 3 independent experiments. (H) Representative H&E-stained images and immune cell counts (millions/cm) in the terminal ileum or colon as assessed by histology (WT: n = 12–16; Lipo: n = 8–12). Scale bars: 100 μm. (I) Gating strategy of T cells and CD4+FoxP3+ Tregs. The line in the box indicates the median. Boxes range from the 25th to 75th percentiles. Whisker plots show the minimum (smallest) and maximum (largest) values while the line in the box indicates the median. *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by unpaired 2-tailed t test with Welch’s correction.