title: HLA-DMA polymorphisms differentially affect MHC class II peptide loading.
abstract: During the adaptive immune response, MHCII proteins display antigenic peptides on the cell surface of APCs for CD4(+) T cell surveillance. HLA-DM, a nonclassical MHCII protein, acts as a peptide exchange catalyst for MHCII, editing the peptide repertoire. Although they map to the same gene locus, MHCII proteins exhibit a high degree of polymorphism, whereas only low variability has been observed for HLA-DM. As HLA-DM activity directly favors immunodominant peptide presentation, polymorphisms in HLA-DM (DMA or DMB chain) might well be a contributing risk factor for autoimmunity and immune disorders. Our systematic comparison of DMA*0103/DMB*0101 (DMA-G155A and DMA-R184H) with DMA*0101/DMB*0101 in terms of catalyzed peptide exchange and dissociation, as well as direct interaction with several HLA-DR/peptide complexes, reveals an attenuated catalytic activity of DMA*0103/DMB*0101. The G155A substitution dominates the catalytic behavior of DMA*0103/DMB*0101 by decreasing peptide release velocity. Preloaded peptide-MHCII complexes exhibit ∼2-fold increase in half-life in the presence of DMA*0103/DMB*0101 when compared with DMA*0101/DMB*0101. We show that this effect leads to a greater persistence of autoimmunity-related Ags in the presence of high-affinity competitor peptide. Our study therefore reveals that HLA-DM polymorphic residues have a considerable impact on HLA-DM catalytic activity.
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, 14195 Berlin, Germany; and.
authors.forename: Miguel
authors.initials: M
authors.lastname: Álvaro-Benito
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, 14195 Berlin, Germany; and Leibniz Institute for Molecular Pharmacology, 13125 Berlin, Germany.
authors.forename: Marek
authors.initials: M
authors.lastname: Wieczorek
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, 14195 Berlin, Germany; and.
authors.forename: Jana
authors.initials: J
authors.lastname: Sticht
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, 14195 Berlin, Germany; and.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kipar
authors.affiliation: Institut für Chemie und Biochemie, Freie Universität Berlin, 14195 Berlin, Germany; and Leibniz Institute for Molecular Pharmacology, 13125 Berlin, Germany christian.freund@fu-berlin.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Freund
mesh_terms: D017951:Antigen Presentation / Q000235:genetics / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001324:Autoantigens / Q000235:genetics / Q000276:immunology; D006681:HLA-D Antigens / Q000235:genetics / Q000276:immunology; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D010455:Peptides / Q000235:genetics / Q000276:immunology; D011110:Polymorphism, Genetic / Q000276:immunology*
chemical_list: D001324:Autoantigens; D006681:HLA-D Antigens; C084245:HLA-DM antigens; D006684:HLA-DR Antigens; D010455:Peptides