The clinical distinction between type 1 and type 2 refractory coeliac disease (RCD1 and RCD2, respectively) may not reflect a true biological boundary. Using single-cell transcriptomic, TCR, and exome profiling across 20 patients with refractory coeliac disease, we demonstrate that clonal, JAK-STAT-driven lymphoproliferation is not restricted to RCD2 but also occurs within the RCD1 compartment, in cells currently classified as non-malignant.
Clonal expansions of tissue-resident CD8+ T cells were identified in 7 of 8 RCD1 patients. In two of these, the expanded clones carried somatic mutations directly activating the JAK-STAT pathway, a JAK1 gain-of-function variant and loss-of-function mutations in SOCS1 and SOCS3, mechanistically equivalent to the oncogenic drivers of the malignant intraepithelial compartment in RCD2. Together with concurrent work, we provide independent evidence of somatic, pathway-activating mutations within clonally expanded tissue-resident memory T cells in an autoimmune-type disease, independent of established lymphoma, indicating that a subset of RCD1 patients harbors molecular precursors of transformation despite lacking the aberrant intraepithelial lymphocytes immunophenotype that defines RCD2.
In parallel, RCD2 tumor cells showed strong interpatient transcriptional convergence but marked intratumor heterogeneity that increased with disease progression. In vitro exposure to JAK inhibitors selected for resistant subclones enriched for CDK13 and RASAL1 mutations, providing a mechanistic basis for the discordance between histologic improvement and persistent tumor burden observed clinically with JAK inhibitor monotherapy.
Together, these findings indicate that RCD1 and RCD2 share a common molecular substrate of convergent JAK-STAT activation and clonal selection, consistent with a disease continuum rather than two categorically distinct entities. This supports incorporating molecular clonal profiling into the diagnostic and monitoring framework for refractory coeliac disease, both to identify RCD1 patients at risk of transformation and to anticipate resistance to JAK-targeted therapy in RCD2.