Innate immune dysregulation in celiac disease and refractory celiac disease: mechanisms, management and emerging therapies

Abstract

Celiac disease is traditionally regarded as T-cell mediated autoimmune disorder driven by gluten-specific adaptive immune responses. In this review, we synthesise recent data showing how epithelial stress, IL-15 driven innate circuits and intraepithelial lymphocyte reprogramming contribute to both classical and refractory disease. It affects 1-3% of people worldwide, caused by gluten intake in individuals carrying HLA-DQ2/DQ8 haplotypes. Gliadin peptides such as 33-mer and p31-43, resist digestion, trigger zonulin release through CXCR3, disrupt epithelial barrier and induce an innate immune response through oxidative stress, EGFR signalling, and trans presentation of IL-15. In refractory celiac disease, this reprograms intraepithelial lymphocytes into cytotoxic, NK-like effectors expressing NKG2D and NKp30. These target MICA/B stressed epithelium independently of adaptive immunity, maintaining villous atrophy despite a strict gluten-free diet. Type I RCD shows polyclonal surface CD3+/CD8+ IELs whereas type II shows clonal aberrant IELs lacking surface CD3 and hypersensitive to IL-15 due to JAK/STAT mutations leading to enteropathy-associated T-cell lymphoma. This circuit is strengthened by gut dysbiosis, viral triggers and epigenetic changes. Emerging therapies including budesonide, cladribine, IL-15/JAK inhibitors, nutraceuticals and microbiota modulation are assessed against this framework. The manuscript proposes viewing RCD as a failure of innate immune regulation rather than solely as an adaptive response.