title: A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease.
abstract: 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.
authors.affiliation: The Protein Crystallography Unit, Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Kate N
authors.initials: KN
authors.lastname: Henderson
authors.forename: Jason A
authors.initials: JA
authors.lastname: Tye-Din
authors.forename: Hugh H
authors.initials: HH
authors.lastname: Reid
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Chen
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Borg
authors.forename: Tim
authors.initials: T
authors.lastname: Beissbarth
authors.forename: Arthur
authors.initials: A
authors.lastname: Tatham
authors.forename: Stuart I
authors.initials: SI
authors.lastname: Mannering
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.forename: Nadine L
authors.initials: NL
authors.lastname: Dudek
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.forename: James
authors.initials: J
authors.lastname: McCluskey
authors.forename: Jamie
authors.initials: J
authors.lastname: Rossjohn
authors.forename: Robert P
authors.initials: RP
authors.lastname: Anderson
mesh_terms: 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
chemical_list: D000577:Amides; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D010446:Peptide Fragments; D005903:Gliadin; D010447:Peptide Hydrolases