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Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation

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Abstract

Celiac disease driven by an antigluten T cell response is strongly associated with the histocompatibility antigen HLA-DQ2.5 but is barely associated with HLA-DQ2.2. Yet these molecules have very similar peptide-binding motifs and both present gluten T cell epitopes. We found that DQ2.5+ antigen-presenting cells (APCs) had greater stability of bound peptides and protracted gluten presentation relative to that of DQ2.2+ cells. The improved ability of DQ2.5 to retain its peptide cargo can be ascribed to a polymorphism of DQα22 whereby DQ2.5 (tyrosine) can establish a hydrogen bond to the peptide main chain but DQ2.2 (phenylalanine) cannot. Our findings suggest that the kinetic stability of complexes of peptide and major histocompatibility complex (MHC) is of importance for the association of HLA with disease.

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Figure 1: Different amounts of CLIP1 peptides are eluted from variants of DQ2.
Figure 2: Function of DQα22 in determining the CLIP1 phenotype.
Figure 3: Hydrogen-bonding network surrounding the polymorphic tyrosine residue at position α22 in HLA-DQ2.
Figure 4: Antigen presentation after encounter with gluten antigen is protracted for cells expressing DQ2.5 relative to those expressing DQ2.2.
Figure 5: Critical function for DQα22 in the presentation of gliadin peptides to T cell clones isolated from lesions of patients with celiac disease.
Figure 6: Residue variation directly dictates whether hydrogen-bond formation is permissive or nonpermissive.

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  • 13 September 2009

    NOTE: In the version of this article initially published online, the symbols for 0 h and 18 h were reversed in the legend for Figure 4 . The correct symbols are 0 h () and 18 h (). The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

We thank E. Mellins (Stanford University) for 8.1.6 B-LCLs and S2 cells expressing soluble HLA-DM; B. Roep (Leiden University Medical Center) for 721.82 B-LCLs; H. Soltani for flow-assisted cell sorting; T. Svingerud for assistance in making the sDQ2.2 and sDQ2.2 Fα22Y constructs; C. Khosla (Stanford University) and U. Jüse (University of Oslo) for fluorescence-labeled peptides; and B. Jabri and S. Buus for critical reading of the manuscript. Supported by the Research Council of Norway (L.M.S.), the Biomedical Research Council of Singapore (C.-Y.K.) and the Life Sciences Institute, National University of Singapore (C.-Y.K).

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L.-E.F. and E.B. designed and did experiments, analyzed data and contributed to the writing of the manuscript; K.H. contributed to data analysis and revised the manuscript; A.B.-L. did experiments, contributed to data analysis and revised the manuscript; C.-Y.K. contributed to data analysis and to the writing of the manuscript; and L.M.S. directed the research, designed experiments, analyzed data and wrote the manuscript.

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Correspondence to Ludvig M Sollid.

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Fallang, LE., Bergseng, E., Hotta, K. et al. Differences in the risk of celiac disease associated with HLA-DQ2.5 or HLA-DQ2.2 are related to sustained gluten antigen presentation. Nat Immunol 10, 1096–1101 (2009). https://doi.org/10.1038/ni.1780

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