Spontaneous lupus-like syndrome in HLA-DQ2 transgenic mice with a mixed genetic background

To investigate the role of HLA-DQ2 in the pathogenesis of associated immune disorders, we generated transgenic mice that expressed HLA-DQ2 in the absence of endogenous murine class II molecules (AE⁰DQ2). These AE ⁰DQ2 mice with a mixed genetic background spontaneously developed skin lesions on their ears, whereas control AE⁰DQ6 genotype control mice (also with a mixed genetic background) did not. The skin lesions were characterized by deep subepidermal blistering with hydropic degeneration and lymphoid infiltration in the subepidermal area as determined by histopathology. Immunofluorescence analysis revealed thick band-like granular deposition of IgG, IgM, and a thin band of IgA deposition along the basement membrane. AE ⁰DQ2 mice also developed significant and progressive hematuria and proteinuria as compared with the AE⁰DQ6 mice (p < 0.05). Histopathology showed immune complex deposits in the glomeruli of AE ⁰DQ2 mice. Immunofluorescence analysis showed progressive mesangial and capillary wall deposition of IgA, IgM, IgG and C1q in the kidney. With electron microscopy, the deposits showed a 'fingerprint' substructure; and tubuloreticular structures were identified within endothelial cells. Conversely, these changes were not observed in AE⁰DQ6 mice. Serum anti-double stranded (ds)DNA IgM and IgG levels were also significantly elevated among AE⁰DQ2 mice compared with AE⁰DQ6 mice (p < 0.001). In conclusion, AE⁰DQ2 mice spontaneously develop an autoimmune lupus-like syndrome and are useful model for this disease. It remains to be determined whether genetic admixture played a role in the development of this systemic lupus erythematosus-like syndrome in HLA-DQ2 transgenic mice.