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In celiac disease (CD), gluten induces both adaptive and innate immune responses. Non-celiac gluten sensitivity (NCGS) is another form of gluten intolerance where the immune response is less characterized. The aim of our study was to explore and compare the early mucosal immunological events in CD and NCGS.We challenged 30 HLA-DQ2+ NCGS and 15 CD patients, all on a gluten-free diet, with four slices of gluten-containing bread daily for 3 days. Duodenal biopsy specimens were collected before and after challenge. The specimens were examined for cytokine mRNA by quantitative reverse transcriptase-PCR and for MxA-expression and CD3+ intraepithelial lymphocytes (IELs) by immunohistochemistry and compared with specimens from untreated CD patients and disease controls.In CD patients, tumor necrosis factor alpha (P=0.02) and interleukin 8 (P=0.002) mRNA increased afterin vivogluten challenge. The interferon gamma (IFN-γ) level of treated CD patients was high both before and after challenge and did not increase significantly (P=0.06). Four IFN-γ-related genes increased significantly. Treated and untreated CD patients had comparable levels of IFN-γ. Increased expression of MxA in treated CD patients after challenge suggested that IFN-α was activated on gluten challenge. In NCGS patients only IFN-γ increased significantly (P=0.03). mRNA for heat shock protein (Hsp) 27 or Hsp70 did not change in any of the groups. Importantly, we found that the density of IELs was higher in NCGS patients compared with disease controls, independent of challenge, although lower than the level for treated CD patients.CD patients mounted a concomitant innate and adaptive immune response to gluten challenge. NCGS patients had increased density of intraepithelial CD3+ T cells before challenge compared with disease controls and increased IFN-γ mRNA after challenge. Our results warrant further search for the pathogenic mechanisms for NCGS.