Refractory Celiac Disease: Nutritional Failure, Immune Dysregulation, and Lymphomagenesis

Refractory celiac disease (RCeD) is a rare but severe complication of celiac disease characterized by persistent or recurrent malabsorptive symptoms and villous atrophy despite a strict gluten-free diet, after exclusion of ongoing gluten exposure, alternative enteropathies, and overt lymphoma. RCeD comprises two biologically distinct entities. RCeD-I is associated with phenotypically normal, polyclonal intraepithelial lymphocytes and generally reflects persistent gluten-independent mucosal inflammation with a relatively favorable prognosis. RCeD-II is defined by expansion of aberrant clonal intraepithelial lymphocytes lacking normal surface T-cell markers and is increasingly regarded as a low-grade intraepithelial lymphoma or in situ lymphomatous disorder, with substantial risk of progression to enteropathy-associated T-cell lymphoma (EATL). Mechanistic studies identify epithelial stress, IL-15-driven IEL survival, stromal and innate immune amplification, and cytotoxic epithelial injury as central drivers of refractory mucosal damage. In RCeD-II, aberrant IELs acquire a hybrid T/NK-like phenotype, persist through anti-apoptotic IL-15/JAK-STAT signaling, and induce enterocyte killing, while molecular alterations involving JAK1, STAT3, JAK/STAT regulators, NF-κB signaling, epigenetic regulators, and chromosomal abnormalities support stepwise lymphomagenesis. Recent single-cell multiomic studies further reveal genetically altered intestinal lymphocyte clones and intratumoral heterogeneity across the RCeD-II-EATL continuum. From a nutritional immunology perspective, RCeD illustrates a setting in which removal of the initiating dietary antigen is insufficient to restore mucosal immune homeostasis. This review summarizes the pathogenic processes that distinguish RCeD-I from RCeD-II and link failed mucosal recovery after gluten withdrawal to persistent immune-mediated epithelial injury, aberrant IEL expansion, clonal evolution, and lymphoma progression.