A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease.
The risk of celiac disease is strongly associated with human leukocyte antigen (HLA) DQ2 and to a lesser extent with HLA DQ8. Although the pathogenesis of HLA-DQ2-mediated celiac disease is established, the underlying basis for HLA-DQ8-mediated celiac disease remains unclear. We showed that T helper 1 (Th1) responses in HLA-DQ8-associated celiac pathology were indeed HLA DQ8 restricted and that multiple, mostly deamidated peptides derived from protease-sensitive sites of gliadin were recognized. This pattern of reactivity contrasted with the more absolute deamidation dependence and relative protease resistance of the dominant gliadin peptide in DQ2-mediated disease. We provided a structural basis for the selection of HLA-DQ8-restricted, deamidated gliadin peptides. The data established that the molecular mechanisms underlying HLA-DQ8-mediated celiac disease differed markedly from the HLA-DQ2-mediated form of the disease. Accordingly, nondietary therapeutic interventions in celiac disease might need to be tailored to the genotype of the individual.
Henderson
Kate N
KN
The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
Tye-Din
Jason A
JA
Reid
Hugh H
HH
Chen
Zhenjun
Z
Borg
Natalie A
NA
Beissbarth
Tim
T
Tatham
Arthur
A
Mannering
Stuart I
SI
Purcell
Anthony W
AW
Dudek
Nadine L
NL
van Heel
David A
DA
McCluskey
James
J
Rossjohn
Jamie
J
Anderson
Robert P
RP
D000577:Amides / Q000378:metabolism; D000595:Amino Acid Sequence; D017951:Antigen Presentation / Q000276:immunology; D002446:Celiac Disease / Q000276:immunology* / Q000378:metabolism*; D002478:Cells, Cultured; D002999:Clone Cells; D018360:Crystallography, X-Ray; D005903:Gliadin / Q000276:immunology / Q000378:metabolism / Q000648:ultrastructure; D006683:HLA-DQ Antigens / Q000737:chemistry* / Q000502:physiology* / Q000648:ultrastructure; D006801:Humans; D006868:Hydrolysis; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology / Q000378:metabolism; D010447:Peptide Hydrolases / Q000737:chemistry; D013329:Structure-Activity Relationship; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism
D000577:Amides; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D010446:Peptide Fragments; D005903:Gliadin; D010447:Peptide Hydrolases