title: MHC class II super-enhancer increases surface expression of HLA-DR and HLA-DQ and affects cytokine production in autoimmune vitiligo.
abstract: Genetic risk for autoimmunity in HLA genes is most often attributed to structural specificity resulting in presentation of self-antigens. Autoimmune vitiligo is strongly associated with the MHC class II region. Here, we fine-map vitiligo MHC class II genetic risk to three SNPs only 47 bp apart, located within a predicted super-enhancer in an intergenic region between HLA-DRB1 and HLA-DQA1, localized by a genome-wide association study of 2,853 Caucasian vitiligo patients. The super-enhancer corresponds to an expression quantitative trait locus for expression of HLA-DR and HLA-DQ RNA; we observed elevated surface expression of HLA-DR (P = 0.008) and HLA-DQ (P = 0.02) on monocytes from healthy subjects homozygous for the high-risk SNP haplotype. Unexpectedly, pathogen-stimulated peripheral blood mononuclear cells from subjects homozygous for the high-risk super-enhancer haplotype exhibited greater increase in production of IFN-γ and IL-1β than cells from subjects homozygous for the low-risk haplotype. Specifically, production of IFN-γ on stimulation of dectin-1, mannose, and Toll-like receptors with Candida albicans and Staphylococcus epidermidis was 2.5- and 2.9-fold higher in high-risk subjects than in low-risk subjects, respectively (P = 0.007 and P = 0.01). Similarly, production of IL-1β was fivefold higher in high-risk subjects than in low-risk subjects (P = 0.02). Increased production of immunostimulatory cytokines in subjects carrying the high-risk haplotype may act as an "adjuvant" during the presentation of autoantigens, tying together genetic variation in the MHC with the development of autoimmunity. This study demonstrates that for risk of autoimmune vitiligo, expression level of HLA class II molecules is as or more important than antigen specificity.
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045; Internal Medicine and Clinical Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute and Vita-Salute San Raffaele University, 20132 Milan, Italy; cavalli.giulio@hsr.it cdinare333@aol.com.
authors.forename: Giulio
authors.initials: G
authors.lastname: Cavalli
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO 80045; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Ying
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Daniel
authors.initials: D
authors.lastname: Yorgov
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO 80045; Department of Mathematical & Statistical Science, University of Colorado Denver, Denver, CO 80217;
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Santorico
authors.affiliation: Department of Human Genetics, Roche Molecular Systems, Pleasanton, CA 94588;
authors.forename: Cherie
authors.initials: C
authors.lastname: Holcomb
authors.affiliation: Department of Human Genetics, Roche Molecular Systems, Pleasanton, CA 94588;
authors.forename: Melinda
authors.initials: M
authors.lastname: Rastrou
authors.affiliation: Department of Human Genetics, Roche Molecular Systems, Pleasanton, CA 94588;
authors.forename: Henry
authors.initials: H
authors.lastname: Erlich
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Isak W
authors.initials: IW
authors.lastname: Tengesdal
authors.affiliation: Internal Medicine and Clinical Immunology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), San Raffaele Scientific Institute and Vita-Salute San Raffaele University, 20132 Milan, Italy;
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Dagna
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: C Preston
authors.initials: CP
authors.lastname: Neff
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Brent E
authors.initials: BE
authors.lastname: Palmer
authors.affiliation: Human Medical Genetics and Genomics Program, University of Colorado School of Medicine, Aurora, CO 80045; Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO 80045;
authors.forename: Richard A
authors.initials: RA
authors.lastname: Spritz
authors.affiliation: Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045; Department of Medicine, Radboud University Medical Center, HB6500 Nijmegen, The Netherlands cavalli.giulio@hsr.it cdinare333@aol.com.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Dinarello
mesh_terms: D001327:Autoimmune Diseases / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D004742:Enhancer Elements, Genetic; D006683:HLA-DQ Antigens / Q000276:immunology*; D006684:HLA-DR Antigens / Q000276:immunology*; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D014820:Vitiligo / Q000276:immunology*
chemical_list: D016207:Cytokines; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II
keywords: MHC transcription; antigen presentation; autoimmunity; inflammation; vitiligo