Immune Response to Rotavirus and Gluten Sensitivity

Abstract

Rotavirus is a double-stranded RNA virus belonging to the family of Reoviridae. The virus is transmitted by the faecal-oral route and infects intestinal cells causing gastroenteritis. Rotaviruses are the main cause of severe acute diarrhoea in children less than 5 years of age worldwide. In our previous work we have shown a link between rotavirus infection and celiac disease. Nonceliac gluten sensitivity (NCGS) is emerging as new clinical entity lacking specific diagnostic biomarkers which has been reported to occur in 6-10% of the population. Clinical manifestations include gastrointestinal and/or extraintestinal symptoms which recede with gluten withdrawal. The pathogenesis of the disease is still unknown. Aim of this work is to clarify some aspects of its pathogenesis using a gene array approach. Our results suggest that NCGS may have an autoimmune origin. This is based both on gene expression data (i.e., TH17-interferon signatures) and on the presence of TH17 cells and of serological markers of autoimmunity in NCGS. Our results also indicate a possible involvement of rotavirus infection in the pathogenesis of nonceliac gluten sensitivity similarly to what we have previously shown in celiac disease.

Figure 1

Flow cytometric analysis of CD4+T cells releasing IL-17 in patients with NCGS. Panel displays the mean percentage of CD4+T cells releasing IL-17 of 10 healthy donors and 8 NCGS patients. PBMCs were stimulated overnight with anti-CD3/-CD28-coated beads. p value calculated with the Mann–Whitney nonparametric statistical test was 0.0159.

Figure 2

Serum levels of selected soluble mediators in NCGS patients and in normal subject sera. The histograms represent the mean of the results obtained in 20 healthy donors and in 16 NCGS patients. p values calculated with the Wilcoxon nonparametric statistical test for paired samples were: p < 0.0001 for sCTLA-4, p < 0.001 for sPD-1, and p < 0.05 for sgp130.

Figure 3

Protein-protein interaction (PPI) network of DEGs in NCGS patients.

Figure 4

Modules originated from the network analysis of DEGs in NCGS patients.

Figure 5

(a) List of diseases which are most likely to be statistically significantly associated and compatible with the transcriptional profile observed in NCGS. (b) DEGs in NCGS showing a modulation consistent with a viral infection process. (c) Detection of antibodies directed against the rotavirus VP7 peptide in the sera of patients with NCGS. Each circle represents a measurement for one patient, and the dashed horizontal line indicates the threshold for positivity (O.D. 0.140). The statistical p value was calculated with the Mann–Whitney test (p < 0.0001).