Celiac Disease: Caught Between a Rock and a Hard Place

Interaction between the T-cell receptor on T cells and a gluten-derived peptide bound to HLA-DQ2 on APCs leads to T-cell activation. CD-predisposing HLA-DQ2 dimers can be formed in a number of ways. HLA-DQ expression is linked to HLA-DR expression as indicated. The DQα*0501 and DQα*0505 chains are very similar and so are the DQβ*0201 and DQβ*0202 chains. The other HLA-DQ chains shown are distinct. HLA-DQ2 dimers with identical peptide-binding properties thus can be formed by all red–green combinations. Accordingly, CD is observed most frequently in DR3+- and DR5/7+-positive individuals.

Binding of peptides to HLA-DQ2. HLA-DQ2 has a preference for particular amino acids (anchor residues) at 5 positions in bound peptides: at p1, p4, p6, p7, and p9. In a peptide that is present abundantly in HLA-DQ2 molecules (natural ligand), all 5 anchor residues are present. The HLA-DQ2–gliadin crystal structure indicates that only 4 anchors are used and that not all are optimal.¹⁴ Likewise, in the glutenin peptide only 4 anchors are used.⁶¹ The binding of peptide is facilitated by additional hydrogen bonds between HLA-DQ2 and the peptide backbone (not shown).

tTG activity either results in cross-linking of proteins by formation of a covalent bond between a glutamine in 1 protein to a lysine in another or to the conversion of glutamine into glutamic acid.

(A) Formation of HLA-DQ molecules in HLA-DQ2 homozygous and HLA-DQ2/DQx heterozygous individuals. The HLA locus is encoded on chromosome 6. HLA-DQ2 homozygous individuals encode identical DQα and -α chains on both of their chromosome 6 whereas HLA-DQ2/DQx heterozygous individuals will encode HLA-DQ2 on 1 and another HLA-DQα and -β chains on the other chromosome 6. Consequently, HLA-DQ2 homozygous individuals can form only 1 HLA-DQ dimer whereas HLA-DQ2/DQx heterozygous individuals can form 4. (B) Formation of HLA-DQ2 gluten peptide as a function of the number of available HLA-DQ2 molecules and gluten peptides. HLA-DQ2 homozygotes will be able to form larger numbers of immunogenic complexes and break through the threshold although heterozygotes still are the safe zone. Adapted from Vader et al.³⁸

Caught between a rock and a hard place. In the lamina propria, T cells respond to multiple gluten peptides bound to HLA-DQ2 and/or HLA-DQ8 on APCs, which results in a release of inflammatory cytokines, including interferon-γ. Interferon-γ–induced up-regulation of HLA-DQ expression will enhance gluten–peptide binding. Cellular damage caused by the inflammation will release intracellular tTG. This will result in additional gluten modification, contributing to enhanced T-cell reactivity toward gluten. APC activation also may lead to an increase in IL-15 production. Simultaneously and independent of the gluten-specific T-cell response, gluten can induce IL-15 production though an unidentified mechanism (unidentified receptor on enterocytes?). The increase in IL-15 levels leads to NKG2D and MICA up-regulation on IELs and enterocytes, respectively, and results in enterocyte destruction.