T cell-intrinsic lymphoproliferation as a key driver of intestinal autoimmunity in acquired generalized lipodystrophy

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Item Type:	Preprint
Title:	T cell-intrinsic lymphoproliferation as a key driver of intestinal autoimmunity in acquired generalized lipodystrophy
Creators Name:	Letizia, M., Omar, T., Weidner, P., Jakob, M.O., Freise, I., Krug, S.M., Löscher, B.S., Rosati, E., Obermayer, B., Gamez-Belmonte, M.D.L.R., Hecker, J., Ziegler, J.F., Weixler, B., Asbach, P., Kunkel, D., Stumvoll, M., Miehle, K., Becker, C., Klose, C.S.N., Glauben, R., Beule, D., Kühl, A., Franke, A., Sanders, A., Siegmund, B. and Weidinger, C.
Abstract:	Acquired generalized lipodystrophy (AGL) is a rare metabolic disorder frequently associated with autoimmunity. Its etiology is incompletely understood and the impact of adipose tissue loss on autoimmunity and intestinal inflammation in AGL remains unclear. Using mass cytometry and single-cell RNA sequencing, 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 pro-inflammatory T cells, which could be reversed by allogeneic fat transplantations, indicating that clonal T-cell expansion is not primarily caused by lipodystrophy. Instead, gene sequencing revealed a T cell-intrinsic de-novo NRAS mutation, pointing towards somatic mosaicism as a driver of clonal T-cell expansion and systemic autoimmunity in AGLCD.
Keywords:	Genetic Mosaicism, Acquired Generalized Lipodystrophy And Combined Crohn’s Disease (AGLCD), NRASG13D, Metabolism, Autoreactive T Cells, Adipokines, Leptin, DSS Colitis, Th17 Differentiation, Creeping Fat, Allogeneic Fat Transplantations, Intestinal Autoimmunity, Inflammatory Bowel Diseases, Animals, Mice
Source:	medRxiv
Publisher:	Cold Spring Harbor Laboratory Press
Article Number:	2025.02.19.25322160
Date:	24 February 2025
Official Publication:	https://doi.org/10.1101/2025.02.19.25322160

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