{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T09:08:56Z","timestamp":1789463336360,"version":"build-2803163510"},"reference-count":125,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T00:00:00Z","timestamp":1789430400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1926029","type":"journal-article","created":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T08:09:34Z","timestamp":1789459774000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Innate immune dysregulation in celiac disease and refractory celiac disease: mechanisms, management and emerging therapies"],"prefix":"10.3389","volume":"17","author":[{"given":"Sara","family":"Shaikh","sequence":"first","affiliation":[{"name":"Department of Life Sciences, Somaiya School of Basic and Applied Sciences, Somaiya Vidyavihar University","place":["Mumbai, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Preeti","family":"Jain","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, Somaiya School of Basic and Applied Sciences, Somaiya Vidyavihar University","place":["Mumbai, India"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3390\/foods14060959","article-title":"Celiac disease\u2014narrative review on progress in celiac disease","volume":"14","author":"Kowalski","year":"2025","journal-title":"Foods"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1177\/2472555217697435","article-title":"A screening approach for identifying gliadin neutralizing antibodies on epithelial intestinal Caco-2 cells","volume":"22","author":"Hundsberger","year":"2017","journal-title":"SLAS Discov"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/ijms241612800","article-title":"Old and new adjunctive therapies in celiac disease and refractory celiac disease: a review","volume":"24","author":"Valvano","year":"2023","journal-title":"Int J Mol 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