The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease

Zaruhi Hovhannisyan, Angela Weiss, Alexandra Martin, Martina Wiesner, Stig Tollefsen, Kenji Yoshida, Cezary Ciszewski, Shane A. Curran, Joseph A. Murray, Chella S. David, Ludvig M. Sollid, Frits Koning, Luc Teyton and Bana Jabri ()
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Zaruhi Hovhannisyan: Pathology, Pediatrics and Committee of Immunology, University of Chicago, Chicago, Illinois 60637, USA
Angela Weiss: Princeton University, Princeton, New Jersey 08544, USA
Alexandra Martin: Pathology, Pediatrics and Committee of Immunology, University of Chicago, Chicago, Illinois 60637, USA
Martina Wiesner: Leiden University, 2300 RC, Leiden, The Netherlands
Stig Tollefsen: Centre for Immune Regulation, Institute of Immunology, Rikshospitalet University Hospital
Kenji Yoshida: The Scripps Research Institute, La Jolla, California 92037, USA
Cezary Ciszewski: Pathology, Pediatrics and Committee of Immunology, University of Chicago, Chicago, Illinois 60637, USA
Shane A. Curran: Pathology, Pediatrics and Committee of Immunology, University of Chicago, Chicago, Illinois 60637, USA
Joseph A. Murray: Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
Chella S. David: Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA
Ludvig M. Sollid: Centre for Immune Regulation, Institute of Immunology, Rikshospitalet University Hospital
Frits Koning: Leiden University, 2300 RC, Leiden, The Netherlands
Luc Teyton: The Scripps Research Institute, La Jolla, California 92037, USA
Bana Jabri: Pathology, Pediatrics and Committee of Immunology, University of Chicago, Chicago, Illinois 60637, USA

Nature, 2008, vol. 456, issue 7221, 534-538

Abstract: Coeliac disease onset Certain genetic variants of the major histocompatibility complex (MHC) proteins are linked to increased susceptibility to autoimmune diseases. Hovhannisyan et al. propose a mechanism that accounts in part for one such association, the onset of coeliac disease, which is tightly associated with the expression of human HLA-DQ8 alleles and the mouse equivalent, IAg7 . This new work shows that the structural properties associated with the lack of an Asp57 found in all other MHC alleles alters the specificity of HLA-DQ8 and IAg7 . This leads to transaminase-mediated deamination of glutamine residues in dietary gluten peptides, causing them to bind more tightly to disease-associated MHC alleles and to mount an amplified anti-gluten response. HLA-DQ8 and IAg7 are also closely linked to type I diabetes, though it is not clear whether a similar mechanism is involved.

Date: 2008
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DOI: 10.1038/nature07524

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