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PMID: 22805744 Published · epublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Review

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.

Expert reviews in molecular medicine ·Vol. 14 ·2012-07-06 ·Pages e15

Busch R, De Riva A, Hadjinicolaou AV, Jiang W, Hou T, Mellins ED

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.

MeSH Terms
Alleles Animals Celiac Disease/genetics,immunology Diabetes Mellitus, Type 1/genetics,immunology Genetic Variation/genetics H-2 Antigens/genetics,immunology HLA-DQ Antigens/genetics,immunology Humans Peptides/genetics,immunology
Chemicals
H-2 Antigens H-2A antigen HLA-DQ Antigens Peptides
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Busch Robert
Department of Medicine, University of Cambridge, Cambridge, UK. [email protected]
De Riva Alessandra
Hadjinicolaou Andreas V
Jiang Wei
Hou Tieying
Mellins Elizabeth D
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Article Info
Journal
Expert reviews in molecular medicine
Abbr.
Expert Rev Mol Med
ISSN
1462-3994
DOI
10.1017/erm.2012.9
Email
[email protected]
Published
2012-07-06
Epub
2012-00-06
Pages
e15
Language
English
Region
England
NLM ID
100939725
PMCID
PMC4157902
Subset
IM
Grants
NIDDK NIH HHS · R21 DK079163 · United States
NIAMS NIH HHS · R01 AR061297 · United States
NIAID NIH HHS · AI095813 · United States
NIAID NIH HHS · AI089080 · United States
NCRR NIH HHS · UL1 RR025744 · United States
NCATS NIH HHS · UL1 TR001085 · United States
NIAMS NIH HHS · AR061297 · United States
NIAID NIH HHS · F32 AI089080 · United States
Versus Arthritis · 18543 · United Kingdom
Arthritis Research UK · 18543 · United Kingdom
NIAID NIH HHS · R21 AI095813 · United States
External Links
PubMed source DOI: 10.1017/erm.2012.9 PMC Full Text View journal details
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