title: A Central Role for HLA-DR3 in Anti-Smith Antibody Responses and Glomerulonephritis in a Transgenic Mouse Model of Spontaneous Lupus.
abstract: MHC, especially HLA-DR3 and HLA-DR2, is one of the most important genetic susceptibility regions for systemic lupus erythematosus. Human studies to understand the role of specific HLA alleles in disease pathogenesis have been hampered by the presence of strong linkage disequilibrium in this region. To overcome this, we produced transgenic mice expressing HLA-DR3 (DRβ1*0301) and devoid of endogenous class II (both I-A and I-E genes, AE(0)) on a lupus-prone NZM2328 background (NZM2328.DR3(+)AE(0)). Both NZM2328 and NZM2328.DR3(+)AE(0) mice developed anti-dsDNA and glomerulonephritis, but anti-dsDNA titers were higher in the latter. Although kidney histological scores were similar in NZM2328 and NZM2328.DR3(+)AE(0) mice (7.2 ± 4.3 and 8.6 ± 5.7, respectively, p = 0.48), the onset of severe proteinuria occurred earlier in NZM2328.DR3(+)AE(0) mice compared with NZM2328 mice (median, 5 and 9 mo respectively, p < 0.001). Periarterial lymphoid aggregates, classic wire loop lesions, and occasional crescents were seen only in kidneys from NZM2328.DR3(+)AE(0) mice. Interestingly, NZM2328.DR3(+)AE(0) mice, but not NZM2328 mice, spontaneously developed anti-Smith (Sm) Abs. The anti-Sm Abs were seen in NZM2328.DR3(+)AE(0) mice that were completely devoid of endogenous class II (AE(-/) (-)) but not in mice homozygous (AE(+/+)) or heterozygous (AE(+/-)) for endogenous MHC class II. It appears that only HLA-DR3 molecules can preferentially select SmD-reactive CD4(+) T cells for generation of the spontaneous anti-Sm immune response. Thus, our mouse model unravels a critical role for HLA-DR3 in generating an autoimmune response to SmD and lupus nephritis in the NZM2328 background.
authors.affiliation: Division of Rheumatology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905; chowdhary.vaidehi@mayo.edu sf2e@virginia.edu.
authors.forename: Vaidehi R
authors.initials: VR
authors.lastname: Chowdhary
authors.affiliation: Center of Immunity, Inflammation, and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, VA 22908;
authors.forename: Chao
authors.initials: C
authors.lastname: Dai
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905;
authors.forename: Ashenafi Y
authors.initials: AY
authors.lastname: Tilahun
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905;
authors.forename: Julie A
authors.initials: JA
authors.lastname: Hanson
authors.affiliation: Infectious Diseases Research, Mayo Clinic College of Medicine, Rochester, MN 55905;
authors.forename: Michele K
authors.initials: MK
authors.lastname: Smart
authors.affiliation: Department of Anatomic Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905;
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Grande
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905;
authors.forename: Govindarajan
authors.initials: G
authors.lastname: Rajagopalan
authors.affiliation: Division of Rheumatology, Department of Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905; Center of Immunity, Inflammation, and Regenerative Medicine, Department of Medicine, University of Virginia, Charlottesville, VA 22908; Division of Rheumatology, Department of Medicine, School of Medicine, University of Virginia, Charlottesville, VA 22908; and Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, VA 22908 chowdhary.vaidehi@mayo.edu sf2e@virginia.edu.
authors.forename: Shu-Man
authors.identifier: http://orcid.org/0000-0001-5158-3494
authors.initials: SM
authors.lastname: Fu
authors.affiliation: Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905;
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004247:DNA / Q000276:immunology; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology*; D015802:HLA-DR2 Antigen / Q000276:immunology; D015803:HLA-DR3 Antigen / Q000235:genetics / Q000276:immunology*; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D055517:snRNP Core Proteins / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D015802:HLA-DR2 Antigen; D015803:HLA-DR3 Antigen; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D055517:snRNP Core Proteins; D004247:DNA