Poster Presentation International Celiac Disease Symposium 2026

A common chronic inflammatory programme underpins immune and epithelial remodelling in refractory celiac disease (#364)

Michael Li 1 2 , Arman Safavi 1 2 , Jerome Samir 3 , Raymond Louie 1 , Esmaeil Roohparvar basmenj 1 , Martina Bonomi 1 2 , Thiruni Adikari 4 , Jun Xing 2 , Katherine Jackson 5 , Andrew Calcino 6 , Dan Suan 5 , Golo Ahlenstiel 7 , Valentina Vaira 8 , Luca Elli 8 , Marco Lenti 9 , Antonio Di Sabatino 9 , Rachele Ciccocioppo 10 , Scott Read 2 , Matt Field 6 , Jason Tye-Din 11 , Chris Goodnow 5 , Manu Singh 1 2 , Fabio Luciani 1 2
  1. University of New South Wales, Sydney, NSW, Australia
  2. The Westmead Institute for Medical Research (WIMR), Sydney, NSW, Australia
  3. Mutinex, Sydney, NSW, Australia
  4. Department of Paediatrics, University of Oxford, Oxford, Oxfordshire, England
  5. Garvan Institute of Medical Research, Sydney, NSW, Australia
  6. James Cook University, Townsville, QLD, Australia
  7. Western Sydney University, Sydney, NSW, Australia
  8. University of Milan, Milan, Italy
  9. University of Pavia, Pavia, Italy
  10. Department of Medicine and Ageing, University of Chieti, Chieti, Italy
  11. Walter and Eliza Hall Institute of Medical Research (WEHI), Melbourne, Victoria, Australia

Refractory coeliac disease (RCD) is a severe complication of coeliac disease despite strict gluten avoidance. RCD type 2 (RCD2) is characterized by aberrant intraepithelial lymphocytes (IELs) [1][2] and carries a high lymphoma risk, while RCD type 1 (RCD1) remains a diagnosis of exclusion because of the lack of aberrant IELs despite having villous atrophy. We asked whether RCD1 represents a distinct biological state and whether persistent inflammation is accompanied by coordinated immune and epithelial remodelling.

Duodenal biopsies from 24 participants including 6 healthy controls, 7 active coeliac disease (ACD), 9 RCD1 and 2 RCD2 patients were profiled using single-cell RNA sequencing, CITE-seq and immune-receptor sequencing of CD45+ cells, with single-cell RNA sequencing of EPCAM+ epithelial cells. Spatial transcriptomics was performed in 8 biopsies.

Aberrant IELs that carry lymphoma-driver mutations occupied multiple transcriptionally distinct states. We discovered large molecular heterogeneity in IEL populations, with expansion of both αβ and γδ clones increasing with disease severity. IEL populations carried a shared remodelling programme in RCD1, including GZMK-expressing memory-like and cytotoxic states. Within epithelial cells, we found highly heterogeneous enterocyte, and transit-amplifying (TA) clusters. Disease-associated epithelial cells displayed progressive regenerative and immune-recognition programmes, including REG3A and HLA-E upregulation. Enteroendocrine (EEC) population increased with disease severity, with NEUROD1 activating regulon activity and upregulation of nociceptive channel in RCD1. Pseudotime analysis identified distinct epithelial differentiation trajectory in RCD1. Spatial analysis further confirmed the presence of REG3A+ and HLA-E+ enterocytes and NK-like lymphocyte clones.

Single-cell multi-omics analysis revealed a distinct molecular signature of RCD1 compared to ACD characterized by coordinated immune, epithelial reprogramming and clonal expansion. These findings provide a biological framework for distinguishing RCD1 from ACD. Analysis of larger, longitudinal RCD1 and RCD2 cohorts will be required to determine whether these conditions represent distinct disease states or stages along a shared pathogenic continuum.

 

  1. Mandeep Singh et al., Expanded T cell clones with lymphoma driver somatic mutations accumulate in refractory celiac disease. Sci. Transl. Med. DOI:10.1126/scitranslmed.adp6812
  2. Malamut et al., Clonal Lymphocyte Expansions and JAK-STAT Pathway Mutations Define a Pathogenic Continuum Driving Resistance to Gluten-Free Diet in Celiac Disease. Gastroenterology. DOI:10.1053/j.gastro.2026.03.025.