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Considerable heterogeneity exists across studies assessing intestinal mucosal recovery in celiac (CD) patients on a gluten-free diet (GFD). We aimed at investigating histological and immunohistochemical features in CD patients on a long-term GFD and to correlate them to the GFD duration. Morphometrical and immunohistochemical analysis were retrospectively performed on duodenal biopsies in three groups of children: 33 on a long-term (>2 years) GFD (GFD-group), four of which remained seropositive despite dietary adherence, 31 with villous atrophy (ACD-group) and 76 heathy, non-celiac (CTR-group). Moreover, in the GFD-group, we correlated immunohistochemical alterations to the GFD duration. The villous to crypt (V/C) ratio significantly improved after the GFD and completely normalized in all patients, becoming even higher than in the CTR-group (median value 3.2 vs. 3, p = 0.007). In parallel, the number of CD3+ and TCRγδ+ cells in the epithelium were significantly reduced in the GFD compared to ACD patients, even if they remained higher than in the CTR-group (p < 0.05). In contrast, CD25+ cells in the lamina propria significantly decreased after the GFD (p < 0.05) and become comparable to the CTR-group (p = 0.9). In the GFD-group there was no difference in the immunohistochemical parameters between seropositive and seronegative patients and alterations did not correlate to GFD length. In conclusion, a GFD is able to both restore a normal V/C ratio and reduce inflammation, but the epithelium maintains some stigmata of the disorder, such as an increased number of CD3+ and TCRγδ+ cells. These alterations persist regardless of the duration of the GFD.

It has been hypothesized that gluten-dependent production of anti-tissue-transglutaminase 2 (anti-TG2) antibodies may occur only at an intestinal level. We have investigated intestinal production of anti-TG2 antibodies in 136 patients with normal serum levels of anti-TG2 antibodies and normal duodenal mucosa. Intestinal deposits of anti-TG2 antibodies were evaluated by immunofluorescence and anti-TG2 antibodies released in organ culture supernatants measured by ELISA. Intestinal antibody libraries were obtained from 10 subjects. Immunohistochemistry for CD25+, CD3+, and TCR-γδ+ was assessed in subjects with positive (n = 32) and negative (n = 31) intestinal anti-TG2 antibodies. Globally 33/136 (24%) seronegative patients produced anti-TG2 autoantibodies at an intestinal level. Antibody libraries analysis confirmed the anti-TG2 antibodies mucosal production in all (n = 8) positive subjects. Lamina propria CD25+ cell count was significantly (p < 0.05) higher in patients with intestinal anti-TG2. Moreover, 13/32 (41%) of them showed high TCR-γδ+/CD3+ ratios. Intestinal anti-TG2 antibody production does not show absolute specificity for CD. It is seen more often in association with inflamed mucosa. Further investigations are necessary to prove the possible role of dietary gluten.