On the perils of poor editing: regulation of peptide loading by HLA-DQ and H2-A molecules associated with celiac disease and type 1 diabetes

Abstract

This review discusses mechanisms that link allelic variants of MHC class II molecules (MHCII) to immune pathology. We focus on HLA-DQ (DQ) alleles associated with celiac disease (CD) and type 1 diabetes (T1D) and the role of the murine DQ-like allele, H2-Ag7 (Ag7), in murine T1D. MHCII molecules bind peptides, and alleles vary in their peptide-binding specificity. Disease-associated alleles permit binding of disease-inducing peptides, such as gluten-derived, Glu-/Pro-rich gliadin peptides in CD and peptides from islet autoantigens, including insulin, in T1D. In addition, the CD-associated DQ2.5 and DQ8 alleles are unusual in their interactions with factors that regulate their peptide loading, invariant chain (Ii) and HLA-DM (DM). The same alleles, as well as other T1D DQ risk alleles (and Ag7) share nonpolar residues in place of Asp at β57 and prefer peptides that place acidic side chains in a pocket in the MHCII groove (P9). Antigen-presenting cells from T1D-susceptible mice and humans retain CLIP due to poor DM editing, although underlying mechanisms differ between species. We propose that these effects on peptide presentation make key contributions to CD and T1D pathogenesis.

Systemic Manifestations of Mucosal Diseases

“…Furthermore, small intestinal biopsies from children who later develop T1D show an increased lymphocytic infiltrate and immune activation within the lamina propria which supports the association between celiac disease and T1D, both of which share genetic risk determinants (DR3-DQ2) (Busch et al, 2012). On a mechanistic level, the association of celiac disease with T1D could involve either shared recognition and presentation of antigenic epitopes or gluten-induced activation of immune mechanisms in the gut, leading to subsequent breakdowns in immune tolerance to pancreatic islets.…”

Positional Identification ofRT1-B(HLA-DQ) as Susceptibility Locus for Autoimmune Arthritis

“…In RT1-D, as well as in the human and mouse orthologs, this pocket is occupied by large hydrophobic amino acids. This hydrophobic P1 pocket is not conserved in RT1-B or its orthologous molecules (49,50). The least susceptible strains in our panel, DA.1UR10 and DA.1HR61, both encode His at position 24 in RT1-Ba, which was associated with a binding preference for Glu in P1.…”

“…Our data suggest that amino acid variation in the P1 pocket influences the stability and editing susceptibility of RT1-B and consequently the development of PIA. Variant interaction of MHC-II molecules with DM and DO and efficiency of peptide editing are increasingly discussed to play a significant role in the pathogenesis of autoimmune diseases (50,52,53). PIA is a valuable model system to dissect the complex association between MHC genes and autoimmunity.…”

Interplay between Type 1 Diabetes Mellitus and Celiac Disease: Implications in Treatment

“…This is well elucidated for CD, in which negatively charged gliadin peptides as such or modified by tTG bind to DQ2/ DQ8 with high affinity. The lysine position at β71 in DQ2 binds to these residues at positions P4, P6, P7, and position β57 in DQ8 binds at P9 [37,38]. However, these mechanisms have not been fully resolved in T1DM, as the triggering factor is not known in the latter case, but it is anticipated that the "diabetogenic peptide" may be binding to DQ2 and DR3 accompanies it due to linkage disequilibrium.…”