Clonal Lymphocyte Expansions and JAK-STAT Pathway Mutations Define a Pathogenic Continuum Driving Resistance to Gluten-Free Diet in Celiac Disease

Georgia Malamut; Nicolas Guégan; Francesco Carbone; Antoine de Giacomoni; Adélaïde Ferment; Cécile Masson; Marine Luka; Sascha Cording; Christine Bole; Mathurin Fumery; Tamara Matysiak-Budnik; Guillaume Bouguen; Vered Abitbol; Romain Coriat; Benoît Terris; Barbara Burroni; Frédéric Beuvon; Ludovic Lhermitte; Chantal Brouzes; Henri Duboc; Isabelle Nion-Larmurier; Mathieu Uzzan; David Sibon; Vahid Asnafi; Olivier Hermine; Mickaël Ménager; Nadine Cerf-Bensussan; Anaïs Levescot

doi:10.1053/j.gastro.2026.03.025

Clonal Lymphocyte Expansions and JAK-STAT Pathway Mutations Define a Pathogenic Continuum Driving Resistance to Gluten-Free Diet in Celiac Disease

Gastroenterology. 2026 Apr 17:S0016-5085(26)00347-1. doi: 10.1053/j.gastro.2026.03.025. Online ahead of print.

Authors

Georgia Malamut¹, Nicolas Guégan², Francesco Carbone³, Antoine de Giacomoni², Adélaïde Ferment², Cécile Masson⁴, Marine Luka³, Sascha Cording², Christine Bole⁵, Mathurin Fumery⁶, Tamara Matysiak-Budnik⁷, Guillaume Bouguen⁸, Vered Abitbol⁹, Romain Coriat⁹, Benoît Terris¹⁰, Barbara Burroni¹⁰, Frédéric Beuvon¹⁰, Ludovic Lhermitte¹¹, Chantal Brouzes¹¹, Henri Duboc¹², Isabelle Nion-Larmurier¹³, Mathieu Uzzan¹⁴, David Sibon¹⁵, Vahid Asnafi¹¹, Olivier Hermine¹⁶, Mickaël Ménager³, Nadine Cerf-Bensussan¹⁷, Anaïs Levescot¹⁸

Affiliations

¹ Université Paris Cité, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France; Department of Gastroenterology, AP-HP, Centre- Université Paris Cité, Hôpital Cochin, Paris, France.
² Université Paris Cité, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France.
³ Université Paris Cité, Imagine Institute, Laboratory of Inflammatory Responses and Transcriptomic Networks in Disease, INSERM UMR 1163, Paris, France.
⁴ Imagine Institute, Bioinformatics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163, INSERM US24/CNRS UAR3633, Université Paris Cité, Paris, France.
⁵ Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163, INSERM US24/CNRS UAR3633, Université Paris Cité, Paris, France.
⁶ Department of Hepato-Gastroenterology, CHU Amiens Picardie, France.
⁷ Hépato-Gastroentérologie & Oncologie Digestive, Institut des Maladies de l'Appareil Digestif, Hôtel Dieu, CHU de Nantes, France.
⁸ Department of Gastroenterology, Pontchaillou University Hospital, INSERM U991, CIC1414, Univeristé de Rennes, France.
⁹ Department of Gastroenterology, AP-HP, Centre- Université Paris Cité, Hôpital Cochin, Paris, France.
¹⁰ Department of Pathology, AP-HP, Université Paris Cité, Hôpital Cochin, Paris, France.
¹¹ Université Paris Cité, Institut Necker-Enfants Malades, INSERM UMR 1151, Paris, France; Clinical Haematology, AP-HP, Hôpital Necker Enfants-Malades, Université Paris Cité, Paris, France.
¹² Department of Gastroenterology, AP-HP, Hôpital Louis Mourier, Université Paris Cité, Colombes, France.
¹³ Department of Gastroenterology, AP-HP, Hôpital Saint Antoine, Université Paris Sorbonne, Paris, France.
¹⁴ Department of Gastroenterology, AP-HP, Hôpitaux Universitaires Henri-Mondor, Université Paris Est Créteil, Créteil, France.
¹⁵ Lymphoid Hematology Department, AP-HP, Hôpitaux Universitaires Henri-Mondor, Université Paris Est Créteil, Institut Mondor de Recherche Biomédicale INSERM U955, Créteil, France.
¹⁶ Laboratory of Onco-Haematology, AP-HP, Hôpital Necker Enfants-Malades, Université Paris Cité, Paris, France; Université Paris Cité, Imagine Institute, Laboratory of Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM UMR 1163, Paris, France.
¹⁷ Université Paris Cité, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France. Electronic address: nadine.cerf-bensussan@inserm.fr.
¹⁸ Université Paris Cité, Imagine Institute, Laboratory of Intestinal Immunity, INSERM UMR 1163, Paris, France. Electronic address: anais.levescot@inserm.fr.

PMID: 42002153
DOI: 10.1053/j.gastro.2026.03.025

Abstract

Background & aims: Despite recent advances, refractory celiac disease (RCD) poses challenging questions. In type 2 RCD (RCD2), the lack of response to the gluten-free diet is attributed to an intestinal intraepithelial lymphoma-carrying driver JAK1 or STAT3 mutations. However, it remains unclear whether these can be safely targeted for therapy. In RCD1, pathogenic insights are still lacking.

Methods: Duodenal biopsy specimens and peripheral blood mononuclear cells from patients with RCD1, RCD2, active celiac disease (CeD), CeD in remission, and controls were analyzed. Lymphocyte populations were characterized using single-cell transcriptomic, genomic, and TCR repertoire profiling. Functional and exome sequencing analyses were performed on patient-derived RCD2 cell lines exposed to JAK inhibitors.

Results: We show that clonal malignant RCD2 lymphocytes exhibit interpatient similarities but substantial intratumoral heterogeneity, and provide in vitro evidence that JAK inhibitors can select drug-resistant tumor cells, arguing against their use as monotherapy. In RCD1, we identified clonal T-cell expansions harboring mutations that enhance the JAK-STAT pathway. The detection of both RCD2 and a CD4⁺ lymphoproliferation in a patient initially diagnosed with RCD1 further illustrates the diversity of lymphoproliferative outcomes in CeD.

Conclusions: These findings suggest that RCD subtypes may share underlying mechanisms driven by clonal evolution and JAK-STAT dysregulation. They also highlight the potential limitations of JAK inhibitor monotherapy and the importance of molecularly informed therapeutic strategies.

Keywords: Clonal Expansions; Intratumor Heterogeneity; JAK-STAT Pathway; Refractory Celiac Disease.