In support of the autoimmune, adaptive nature of CD, there is a strong genetic association with the MHC class II haplotype in CD patients, about 95% of whom carry HLA-DQ2, and the remainder HLA-DQ8 [6]. Conversely, only about 50% of patients with GS carry the HLA-DQ2 or -DQ8 haplotype, a percentage slightly higher than in the general population. The diversity of gluten-induced conditions suggests that the immune system reacts to and deals with the triggering environmental factor, e.g. gliadin, in distinct ways. The identification of interleukin (IL)-17-producing CD4+ T helper cells, Th17 cells, has had major impact on understanding immune processes not readily explained by the Th1/Th2 paradigm [7]. Aside from their possible involvement in host defense against microbes, Th17 cells have been linked to the pathogenesis of inflammatory and autoimmune diseases such as collagen-induced arthritis and colitis [7,8,9].

CD has been considered a classical Th1-mediated disorder because of the enhanced mucosal mRNA expression of interferon-γ, but not IL-4, in patients with untreated disease [10]. Following the identification of the Th17 T cell subset and the growing appreciation that these cells are centrally involved in the pathogenesis of autoimmune disorders, it has become important to investigate the possible involvement of Th17 cells in CD. A recent report by Castellanos-Rubio et al. [11] shows indeed that the expression of Th17-associated cytokines, e.g. IL-17A, is increased in patients with active CD as opposed to patients on a gluten-free diet. Furthermore, we have shown that gliadin can induce the production of the Th17-polarizing cytokines IL-1β and IL-23 in peripheral blood monocytes, providing a possible causative link between exposure to gluten and the expansion of IL-17-producing clones in CD [12].

As shown in figure ​figure2,2, IL-17A gene expression, measured by real-time quantitative PCR in biopsy specimens, was significantly elevated in active CD patients (mean ± SE: 0.0088 ± 0.002% of 18S) compared to GS patients (0.0025 ± 0.0008%; p = 0.03) and controls (0.0022 ± 0.0013%; p = 0.024). The level of variance across the groups was also statistically significant (p < 0.025). Interestingly, as figure ​figure22 shows, this difference appeared to be sustained by a subgroup (7 out of 13) of CD patients. The significance of this finding is at present unclear, as this subgroup did not seem to differ from the other CD patients with respect to clinical, histological, and serological parameters or the MHC haplotypes, with the exception of a trend toward increased positivity for anti-gliadin antibodies. Immunofluorescence staining of intestinal mucosal sections from this IL-17^high subgroup documented an increased percentage (35.6 ± 3.7%) of T cells expressing the constitutive Th17 surface marker CCR6 relative to IL-17^low CD (24.8 ± 8.1%) or control groups (24.0 ± 3.6%; a typical staining is shown in fig. ​fig.3),3), but these differences did not reach statistical significance, presumably due to the small sample size and a high degree of interindividual variability. It can be speculated that this variability might reflect different stages of the condition, or imply an as yet unappreciated level of heterogeneity in the immune mechanisms involved in CD pathogenesis. Longitudinal studies in larger populations might help elucidate these issues.

Together, these data show that the expression of IL-17, a cytokine that is thought to be involved in inflammatory and autoimmune processes [8,9,12], is elevated in CD but not in GS. Our work confirms and extends the study by Castellanos-Rubio et al. [11] showing gluten-dependent expression of IL-17A in active CD. In addition, combined with the other observed clinical and histological differences, it further supports the idea that CD and GS are distinct entities and that the immune system deals with gluten in different ways, possibly depending on the genetic makeup [2,3,18]. Where in GS as well as in wheat allergy the gluten-induced response leads to immunity toward a non-self diet component, i.e. gliadin, in CD a deviated, self-directed adaptive response leads, in addition, to the onset of a full-fledged autoimmune process. In clear contrast to GS, CD results from a complex, as yet undetermined, interplay of increased intestinal permeability, mucosal damage, environmental factors additional to gluten, and genetic predisposition, which involves both MHC and non-MHC genes [Sapone et al., manuscript in preparation] [6]. Based on our recent work, we can speculate that gliadin may directly affect the expansion of Th17 clones by inducing the expression of IL-23 among other cytokines [12]. Studies are needed to elucidate whether the unique involvement of these cells in CD versus GS reflects differential expansion in response to gliadin-induced factors versus other mechanisms, including mucosal recruitment.