title: CD74/DQA1 dimers predispose to the development of arthritis in humanized mice.
abstract: Rheumatoid arthritis (RA) is associated with the presence of certain HLA class II genes. However, why some individuals carrying RA non-associated alleles develop arthritis is still unexplained. The trans-heterodimer between two RA non-associated HLA genes can render susceptibility to develop arthritis in humanized mice, DQA1*0103/DQB1*0604, suggesting a role for DQ α chains in pathogenesis. In this study we determined the role of DQA1 in arthritis by using mice expressing DQA1*0103 and lacking endogenous class II molecules. Proximity ligation assay showed that DQA1*0103 is expressed on the cell surface as a dimer with CD74. Upon immunization with type II collagen, DQA1*0103 mice generated an antigen-specific cellular and humoral response and developed severe arthritis. Structural modelling suggests that DQA1*0103/CD74 form a pocket with similarity to the antigen binding pocket. DQA1*0103 mice present type II collagen-derived peptides that are not presented by an arthritis-resistant DQA1*0103/DQB1*0601 allele, suggesting that the DQA1*0103/CD74 dimer may result in presentation of unique antigens and susceptibility to develop arthritis. The present data provide a possible explanation by which the DQA1 molecule contributes to susceptibility to develop arthritis.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Luckey
authors.initials: L
authors.lastname: David
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Ameya
authors.initials: A
authors.lastname: Gokhale
authors.affiliation: Department of Basic Pharmaceutical Sciences, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Seetharama
authors.initials: S
authors.lastname: Jois
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Aaron
authors.initials: A
authors.lastname: Johnson
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Marshall
authors.initials: M
authors.lastname: Behrens
authors.affiliation: Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Harvinder
authors.initials: H
authors.lastname: Luthra
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN, USA.|Division of Rheumatology, Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Veena
authors.initials: V
authors.lastname: Taneja
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000944:Antigens, Differentiation, B-Lymphocyte / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism*; D001665:Binding Sites; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D024043:Collagen Type II; D005260:Female; D059848:HLA-DQ alpha-Chains / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000737:chemistry / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007111:Immunity, Cellular; D056724:Immunity, Humoral; D008213:Lymphocyte Activation; D008297:Male; D008822:Mice, Transgenic; D062105:Molecular Docking Simulation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D055503:Protein Multimerization; D013154:Spleen / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
chemical_list: D000944:Antigens, Differentiation, B-Lymphocyte; D024043:Collagen Type II; D059848:HLA-DQ alpha-Chains; C069050:HLA-DQA1 antigen; D000949:Histocompatibility Antigens Class II; C045084:invariant chain
keywords: CD74; DQA1*0103; heterodimer; humanized mice; rheumatoid arthritis