Gastroenterology · 2026
Clonal Lymphocyte Expansions and JAK-STAT Pathway Mutations Define a Pathogenic Continuum Driving Resistance to Gluten-Free Diet in Celiac Disease.
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Malamut Georgia, Guégan Nicolas, Carbone Francesco, de Giacomoni Antoine, Ferment Adélaïde, Masson Cécile, Luka Marine, Cording Sascha, Bole Christine, Fumery Mathurin, Matysiak-Budnik Tamara, Bouguen Guillaume, Abitbol Vered, Coriat Romain, Terris Benoît, Burroni Barbara, Beuvon Frédéric, Lhermitte Ludovic, Brouzes Chantal, Duboc Henri, Nion-Larmurier Isabelle, Uzzan Mathieu, Sibon David, Asnafi Vahid, Hermine Olivier, Ménager Mickaël, Cerf-Bensussan Nadine, Levescot Anaïs
Аннотация
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 T cell receptor (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.
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 T cell receptor (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.