Expert Reviews in Molecular Medicine

Table of Contents - Volume 14 - 2012  

Review Article

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

Robert Buscha1 c1, Alessandra De Rivaa1†, Andreas V. Hadjinicolaoua1a2†, Wei Jianga2, Tieying Houa2 and Elizabeth D. Mellinsa2 c1

a1 Department of Medicine, University of Cambridge, Cambridge, UK

a2 Department of Pediatrics, Stanford University Medical Center, Stanford, CA, USA

Abstract

This review discusses mechanisms that link allelic variants of major histocompatibility complex (MHC) class II molecules (MHCII) to immune pathology. We focus on HLA (human leukocyte antigen)-DQ (DQ) alleles associated with celiac disease (CD) and type 1 diabetes (T1D) and the role of the murine DQ-like allele, H2-Ag7 (I-Ag7 or 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 because of 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.

Correspondence:

c1 Corresponding author: Robert Busch, Division of Rheumatology, Department of Medicine, University of Cambridge, Box 157, Level 5, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, UK. E-mail: rb468@medschl.cam.ac.uk or Elizabeth D. Mellins, CCSR 2105c Stanford School of Medicine, 300 Pasteur Drive, Stanford, CA 94305, USA. E-mail: mellins@stanford.edu

Footnotes

† Equal contributors.