A Structural and Immunological Basis for the Role of Human Leukocyte Antigen DQ8 in Celiac Disease

Abstract

The risk of celiac disease is strongly associated with human leukocyte antigen (HLA) DQ2 and to a lesser extent with HLA DQ8. Although the pathogenesis of HLA-DQ2-mediated celiac disease is established, the underlying basis for HLA-DQ8-mediated celiac disease remains unclear. We showed that T helper 1 (Th1) responses in HLA-DQ8-associated celiac pathology were indeed HLA DQ8 restricted and that multiple, mostly deamidated peptides derived from protease-sensitive sites of gliadin were recognized. This pattern of reactivity contrasted with the more absolute deamidation dependence and relative protease resistance of the dominant gliadin peptide in DQ2-mediated disease. We provided a structural basis for the selection of HLA-DQ8-restricted, deamidated gliadin peptides. The data established that the molecular mechanisms underlying HLA-DQ8-mediated celiac disease differed markedly from the HLA-DQ2-mediated form of the disease. Accordingly, nondietary therapeutic interventions in celiac disease might need to be tailored to the genotype of the individual.

The interplay between citrullination and HLA-DRB1 polymorphism in shaping peptide binding hierarchies in rheumatoid arthritis

“…Whether the hierarchy of peptides reflects the immunodominant epitopes responsible for RA disease development in patients carrying specific RA-susceptible alleles will depend on T cell studies in vivo and structural analysis with the TCR. There are some parallels with other autoimmune-like diseases, such as celiac disease, where PTM peptides could bind to HLA allomorphs with higher affinity and subsequently form more stable peptide-MHC complexes and prolong antigen presentation to the autoreactive T cells at the site of inflammation (36)(37)(38)(39). Further studies aimed at determining if a correlation between the rank order of RA associated epitopes and disease pathogenesis exists, will help to identify key autoantigens involved in RA development.…”

Large-Scale Characterization of Natural Ligands Explains the Unique Gluten-Binding Properties of HLA-DQ2

“…The association of HLA-DQ2 with celiac disease is extraordinarily strong: ϳ95% of celiac disease patients express HLA-DQ2, whereas in the general population, the frequency of this allele is between 20 and 30% (4). Virtually all HLA-DQ2-negative patients are HLA-DQ8 positive and it has been described that several gluten-derived peptides can bind to HLA-DQ8 and elicit T cell responses (5,6). Together, these data indicate that the ability to present gluten-derived peptides is a unique feature of HLA-DQ2 and HLA-DQ8 molecules.…”

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“…Astacin (1AST) [38], Matrix metalloproteases (1HOV) [39], Predicted metal-dependent hydrolase (1XM5) [40] and gliadin (2NNA) [41] were downloaded from Protein Data Bank. All three of them have complete crystal structures except for gliadin protein.…”

“…Gliadin based PDB-BLAST search has listed PDB id: 2NNA [41] as the crystal structure which is a 18mer. This is an antigen associated with T-cell receptor which shows a conserved 'HNVVH' motif which resembles with the metalloprotease domain "HExxH" (Figure 3a).…”