title: Functional consequences of HLA-DQ8 homozygosity versus heterozygosity for islet autoimmunity in type 1 diabetes.
abstract: Human leukocyte antigen (HLA) class II haplotypes are established risk factors in type 1 diabetes (T1D). The heterozygous DQ2/8 genotype confers the highest risk, whereas the DQ6/8 genotype is protective. We hypothesized that DQ2/8 trans-molecules composed of α and β chains from DQ2 and DQ8 express unique β-cell epitopes, whereas DQ6 may interfere with peptide binding to DQ8. Here we show that a single insulin epitope (InsB13-21) within the T1D prototype antigenic InsB6-22 peptide can bind to both cis- and trans-dimers, although these molecules display different peptide binding patterns. DQ6 binds a distinct insulin epitope (InsB6-14). The phenotype of DQ8-restricted T cells from a T1D patient changed from proinflammatory to anti-inflammatory in the presence of DQ6. Our data provide new insights into both susceptible and protective mechanism of DQ, where protecting HLA molecules bind autoantigens in a different (competing) binding register leading to 'epitope stealing', thereby inducing a regulatory, rather than a pathogenic immune response.
authors.affiliation: Department of Immunohaematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: Eerligh
authors.forename: M
authors.initials: M
authors.lastname: van Lummel
authors.forename: A
authors.initials: A
authors.lastname: Zaldumbide
authors.forename: A K
authors.initials: AK
authors.lastname: Moustakas
authors.forename: G
authors.initials: G
authors.lastname: Duinkerken
authors.forename: G
authors.initials: G
authors.lastname: Bondinas
authors.forename: B P C
authors.initials: BP
authors.lastname: Koeleman
authors.forename: G K
authors.initials: GK
authors.lastname: Papadopoulos
authors.forename: B O
authors.initials: BO
authors.lastname: Roep
mesh_terms: D000293:Adolescent; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018985:Epitopes, B-Lymphocyte / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000235:genetics; D007515:Islets of Langerhans / Q000276:immunology*; D008297:Male; D011485:Protein Binding; D053667:Syndecans / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D013947:Thymosin / Q000378:metabolism; D000099201:Thymosin beta(4)
chemical_list: D018985:Epitopes, B-Lymphocyte; D006683:HLA-DQ Antigens; D007328:Insulin; D053667:Syndecans; D013947:Thymosin; D000099201:Thymosin beta(4); C053186:HLA-DQ2 antigen; C063831:HLA-DQ6 antigen; C109756:HLA-DQ8 antigen