Decoy receptor 3 (DcR3), a tumor necrosis factor receptor family member, is a secreted protein that can enhance cell survival by interfering with multiple apoptosis pathways. This study was undertaken to investigate the role of DcR3 in the pathogenesis of autoimmune disease.
We generated transgenic mice with actin promoter-driven expression of human DcR3 and investigated the development of autoimmune disease in these mice.
T cell immune responses were compromised in young DcR3-transgenic mice. Beyond 5-6 months of age, transgenic mice developed a systemic lupus erythematosus (SLE)-like syndrome, with numerous features of the disease. They produced autoantibodies against double-stranded DNA. Their kidneys showed pathologic changes indicative of glomerular nephritis and IgG and C3 deposition, and proteinuria, leukocyturia, and hematuria, were evident. Aged transgenic mice also developed skin lesions and lymphocyte infiltration in the liver, and exhibited leukopenia, anemia, and thrombocytopenia. The SLE-like syndrome penetrance in DcR3-transgenic mice was sex associated, occurring in approximately 60% of females versus 20% of males. Exogenous recombinant DcR3 or endogenous DcR3 produced by transgenic T cells effectively protected T cells against activation-induced apoptosis in vitro. Probably as a consequence of this, CD4 cells with a phenotype of previous activation were increased in the peripheral blood of transgenic mice beyond 6 months of age.
These results show that DcR3 overexpression could lead to an SLE-like syndrome in mice.