title: Differential responses to Smith D autoantigen by mice with HLA-DR and HLA-DQ transgenes: dominant responses by HLA-DR3 transgenic mice with diversification of autoantibodies to small nuclear ribonucleoprotein, double-stranded DNA, and nuclear antigens.
abstract: Anti-Smith (Sm) D autoantibodies are specific for systemic lupus erythematosus. In this investigation, the influence of HLA-D genes on immune responses to SmD was investigated. Mice with HLA-DR3, HLA-DR4, HLA-DQ0601, HLA-DQ0604, or HLA-DQ8 transgenes were immunized with recombinant SmD1, and their Ab responses were analyzed. Analysis by ELISA showed that all strains responded well to SmD. However, when synthetic SmD peptides were used as substrate, DR3 mice had the highest Ab response followed by DQ8, DQ0604, DQ0601, and DR4. A similar trend was observed in Western blot analysis using WEHI 7.1 cell lysate as the substrate, with the exception that DR4 mice did not generate detectable amounts of Abs. Only sera from DR3 and DQ0604 mice immunoprecipitated A-ribonucleoprotein (RNP), SmB, and SmD. Intermolecular epitope spreading to A-RNP and SmB was evident in DR3 and DQ0604 mice, as sera depleted of anti-SmD Abs were reactive with these proteins. DR3 mice also generated an immune response to C-RNP. Anti-nuclear Abs were detected in the majority of the DR3 mice, whereas moderate reactivities were seen in DQ0604 and DQ8 mice. Interestingly, only DR3 mice mounted an anti-dsDNA Ab response. Approximately half of the anti-dsDNA Abs were cross-reactive with SmD. Ab responses correlated with the strength of the T cell responses. Thus, HLA-DR3 appears to be the dominant HLA-D gene that determines the magnitude and quality of the anti-SmD immune response. In addition, our findings provide insights into the origin of the anti-dsDNA Abs often detected in patients with systemic lupus erythematosus.
authors.affiliation: Division of Rheumatology and Immunology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA 22908, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Jiang
authors.forename: Umesh S
authors.initials: US
authors.lastname: Deshmukh
authors.forename: Felicia
authors.initials: F
authors.lastname: Gaskin
authors.forename: Harini
authors.initials: H
authors.lastname: Bagavant
authors.forename: Julie
authors.initials: J
authors.lastname: Hanson
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Shu Man
authors.initials: SM
authors.lastname: Fu
mesh_terms: D000818:Animals; D000916:Antibody Diversity; D034961:Antigens, Nuclear / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D015551:Autoimmunity; D004247:DNA / Q000276:immunology; D006683:HLA-DQ Antigens / Q000235:genetics / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology*; D015803:HLA-DR3 Antigen / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology; D055517:snRNP Core Proteins
chemical_list: D034961:Antigens, Nuclear; D001323:Autoantibodies; D001324:Autoantigens; D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D015803:HLA-DR3 Antigen; D017411:Ribonucleoproteins, Small Nuclear; C489793:Snrpd1 protein, mouse; D055517:snRNP Core Proteins; D004247:DNA