title: Discovery of a Selective Islet Peptidome Presented by the Highest-Risk HLA-DQ8trans Molecule.
abstract: HLA-DQ2/8 heterozygous individuals are at far greater risk for type 1 diabetes (T1D) development by expressing HLA-DQ8trans on antigen-presenting cells compared with HLA-DQ2 or -DQ8 homozygous individuals. Dendritic cells (DC) initiate and shape adaptive immune responses by presenting HLA-epitope complexes to naïve T cells. To dissect the role of HLA-DQ8trans in presenting natural islet epitopes, we analyzed the islet peptidome of HLA-DQ2, -DQ8, and -DQ2/8 by pulsing DC with preproinsulin (PPI), IA-2, and GAD65. Quality and quantity of islet epitopes presented by HLA-DQ2/8 differed from -DQ2 or -DQ8. We identified two PPI epitopes solely processed and presented by HLA-DQ2/8 DC: an HLA-DQ8trans-binding signal-sequence epitope previously identified as CD8 T-cell epitope and a second epitope that we previously identified as CD4 T-cell epitope with increased binding to HLA-DQ8trans upon posttranslational modification. IA-2 epitopes retrieved from HLA-DQ2/8 and -DQ8 DC bound to HLA-DQ8cis/trans. No GAD65 epitopes were eluted from HLA-DQ. T-cell responses were detected against the novel islet epitopes in blood from patients with T1D but scantly detected in healthy donor subjects. We report the first PPI and IA-2 natural epitopes presented by highest-risk HLA-DQ8trans. The selective processing and presentation of HLA-DQ8trans-binding islet epitopes provides insight in the mechanism of excessive genetic risk imposed by HLA-DQ2/8 heterozygosity and may assist immune monitoring of disease progression and therapeutic intervention as well as provide therapeutic targets for immunotherapy in subjects at risk for T1D.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Menno
authors.initials: M
authors.lastname: van Lummel
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Peter A
authors.initials: PA
authors.lastname: van Veelen
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Arnoud H
authors.initials: AH
authors.lastname: de Ru
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Pool
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Nikolic
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Sandra
authors.initials: S
authors.lastname: Laban
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Antoinette
authors.initials: A
authors.lastname: Joosten
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Jan W
authors.initials: JW
authors.lastname: Drijfhout
authors.affiliation: Department of Immunobiology, School of Medicine, King's College London, London, U.K.
authors.forename: Iria
authors.initials: I
authors.lastname: Gómez-Touriño
authors.affiliation: Department of Immunobiology, School of Medicine, King's College London, London, U.K.
authors.forename: Sefina
authors.initials: S
authors.lastname: Arif
authors.affiliation: Diabeter, Center for Pediatric and Adolescent Diabetes Care and Research, Rotterdam, the Netherlands.
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Aanstoot
authors.affiliation: Department of Immunobiology, School of Medicine, King's College London, London, U.K.
authors.forename: Mark
authors.initials: M
authors.lastname: Peakman
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands Department of Diabetes Immunology, Diabetes & Metabolism Research Institute at the Beckman Research Institute of City of Hope, Duarte, CA boroep@lumc.nl.
authors.forename: Bart O
authors.initials: BO
authors.lastname: Roep
mesh_terms: D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007328:Insulin / Q000276:immunology; D008297:Male; D010455:Peptides; D011498:Protein Precursors / Q000276:immunology; D011499:Protein Processing, Post-Translational; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D055815:Young Adult
chemical_list: D001324:Autoantigens; D000939:Epitopes; D006683:HLA-DQ Antigens; C053186:HLA-DQ2 antigen; C109756:HLA-DQ8 antigen; D007328:Insulin; D010455:Peptides; D011498:Protein Precursors; C013737:preproinsulin; C516862:PTPRN protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2