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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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 biopsies and peripheral blood mononuclear cells (PBMCs) from patients with RCD1, RCD2, active 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 celiac disease.
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.
What You Need to Know
BACKGROUND AND CONTEXT
Refractory celiac disease (RCD) can lead to intestinal lymphoma, but the biological processes driving immune cell transformation and therapy resistance remain incompletely understood.
NEW FINDINGS
Single-cell analyses reveal clonal evolution, JAK-STAT pathway dysregulation, and shared molecular features between RCD subtypes, with implications for disease progression and treatment response.
LIMITATIONS
Sample size and reliance on ex vivo models limit generalizability; further in vivo validation of resistance mechanisms is needed to confirm therapeutic implications.
CLINICAL RESEARCH RELEVANCE
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.
BASIC RESEARCH RELEVANCE
This work uncovers mechanisms of immune cell transformation in chronic intestinal inflammation and provides insight into how tumor heterogeneity and somatic mutations drive disease progression and therapeutic resistance.
Lay summary
This study reveals shared mechanisms in refractory celiac disease subtypes driven by clonal evolution and JAK-STAT activation, highlighting limits of JAK inhibitor monotherapy and the need for personalized treatments.
