The expansion of the presentable gluten peptide repertoire due to the release and activity of TG2 is a critical step in the pathogenesis of full-blown CD. Several lines of evidence support the notion that the level of gluten presentation to T cells critically influences the risk of disease development.
First, HLA-DQ2.5 homozygous individuals have a fivefold higher risk of CD development than HLA-DQ2.5 heterozygous individuals (Mearin et al. 1983
). This gene dose effect directly correlates with the magnitude of the CD4+
T cell response: antigen presenting cells (APC) from HLA-DQ2.5 homozygous individuals induce very strong proliferative T cell responses and IFN-γ production, while APC from HLA-DQ2.5/DQX heterozygous individuals induce much weaker responses (Vader et al. 2003b
). These data indicate that the number of HLA-DQ2.5 molecules capable of presenting gluten peptides on the surface of APC will define the magnitude of the CD4+
T cell response.
Second, whereas HLA-DQ2.5 is associated with CD development, the homologous HLA-DQ2.2 is not. Although these two variants have almost identical peptide-binding motifs, HLA-DQ2.2 can only bind a subset of the gluten peptides that can bind to HLA-DQ2.5. This difference is explained by the fact that a proline at position 3 in peptides has an adverse effect on peptide binding to HLA-DQ2.2 (van de Wal et al. 1997
). As gluten epitopes cluster in proline-rich regions (Arentz-Hansen et al. 2002
), many gluten peptides have a proline at position 3 and do not bind to HLA-DQ2.2 (Vader et al. 2003b
). Consequently, HLA-DQ2.5 is able to present a much broader repertoire of gluten peptides than HLA-DQ2.2. In addition, HLA-DQ2.5 is better at retaining gluten peptides in its binding groove compared to HLA-DQ2.2 (Fallang et al. 2009
). As a result, gluten peptide presentation by HLA-DQ2.5 is protracted compared to presentation by HLA-DQ2.2, which will increase the chance for productive CD4+
T cell stimulation.
Third, CD is associated mainly with HLA-DQ2.5 and, to a lesser extent, with HLA-DQ8. Although a variety of gluten peptides has been identified that can stimulate HLA-DQ8 restricted T cells from CD patients, one α-gliadin peptide in particular appears to be immunodominant, as this peptide invariably induces specific T cell responses in HLA-DQ8+
CD patients (Henderson et al. 2007
; Tollefsen et al. 2006
; van de Wal et al. 1998b
; Kooy et al. unpublished data). In contrast to the HLA-DQ2.5 restricted α-gliadin peptides, the HLA-DQ8 peptide is not derived from a proline-rich region of the α-gliadin protein, and therefore likely susceptible to degradation in the gastrointestinal tract. Furthermore, whereas for HLA-DQ2 a single deamidation in a gluten peptide is sufficient to evoke a CD4+
T cell response, for HLA-DQ8, deamidation at two positions is preferred (Henderson et al. 2007
), which may limit the generation of strong antigenic gluten peptides. The fact that the immunodominant HLA-DQ8 peptide is more readily degraded and requires more deamidation steps, limits the availability for antigen presentation and may therefore limit the risk to develop CD.
Fourth, further evidence that the level of gluten presentation is a critical parameter comes from a totally different angle: most CD patients tolerate oat even though it has been shown that the gluten-like molecules in oat can elicit CD4+
T cell responses in CD patients (Arentz-Hansen et al. 2004
; Vader et al. 2003a
) There are two striking differences between the relatively safe oat and the disease-inducing cereals wheat, barley, and rye: (1) while the gluten-like molecules in oat contain only two antigenic sequences, dozens are found in gluten and the gluten-like molecules of barley and rye, (2) the “gluten” content of oat is much lower compared to the other cereals. Consumption of oat thus results in a much lower exposure to antigenic peptides, in comparison with the other cereals, and this is apparently tolerated, as it does not lead to disease in the majority of patients.
Collectively, these data indicate the presence of a threshold to develop CD. Initiation of CD becomes more likely with increased T cell exposure to gluten antigens. This exposure is influenced by the type and amount of HLA-DQ, as this determines the efficiency of gluten peptide presentation to CD4+ T cells. For HLA-DQ2.5 homozygous individuals, the threshold to develop CD is most easily exceeded, whereas for HLA-DQ2.2+ and HLA-DQ8+ individuals, the threshold is much higher.