International Immunology, Vol 10, 1229-1236, Copyright © 1998 by Oxford University Press
H Quarsten, G Paulsen, BH Johansen, CJ Thorpe, A Holm, S Buus and LM Sollid
Susceptibility and resistance to type 1 diabetes are associated with MHC
class II alleles that carry non-Asp and Asp at residue 57 of their beta
chain respectively. The effect of Asp or non-Aspbeta57 may relate to a
differential ability of distinct class II molecules to bind specific
immuno-pathogenic peptides. Recent studies in man and mouse have revealed
that some type 1 diabetes-predisposing non-Aspbeta57 class II molecules
(i.e. DQ8, DR4Dw15 and I-Ag7) preferentially bind peptides with a
negatively charged anchor residue at P9. It has been suggested that this is
a common feature of type 1 diabetes-predisposing class II molecules. The
molecular explanation for such a phenomenon could be that class II beta
chains with Aspbeta57 form a salt bridge between Aspbeta57 and a conserved
Arg of the a chain, whereas in non- Aspbeta57 molecules the Arg is
unopposed and free to interact with negatively charged P9 peptide anchor
residues. We have investigated the specificity of the P9 pocket of the type
1 diabetes-associated DQ2 molecule and in particular examined for charge
effects at this anchor position. Different approaches were undertaken. We
analyzed binding of a high-affinity binding ligand and P9-substituted
variants of this peptide, and we analyzed the binding of a set of synthetic
random peptide libraries. The binding analyses were performed with
wild-type DQ2 and a mutated DQ2 with Ala at beta57 substituted with Asp.
Our results indicate that the wild-type DQ2 (non-Aspbeta57) prefers large
hydrophobic residues at P9 and that there is no particular preference for
binding peptides with negatively charged residues at this position. The
specificity of the P9 pocket in the mutated DQ molecule is altered,
indicating that the beta57 residue contributes to determining the
specificity of the P9 pocket. Our data do not lend support to the
hypothesis that all non-Asp beta57 class II molecules predispose to
development of disease by binding peptides with negatively charged P9
anchor residues.
ARTICLES
The P9 pocket of HLA-DQ2 (non-Aspbeta57) has no particular preference for negatively charged anchor residues found in other type 1 diabetes- predisposing non-Aspbeta57 MHC class II molecules
Institute of Transplantation Immunology, Rikshospitalet, University of Oslo, Norway.
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