Abstract
B7-H3 immune modulatory molecule has been implicated in the generation and pathogenesis of autoimmune diseases, the mechanism of action is less known. We explored the role of B7-H3 in the induction of autoantibodies and organ-directed inflammation in a murine systemic lupus erythematosus (SLE) model in which the immunization with DNA extracted from activated T cells induced the production of anti-DNA autoantibodies and subsequent glomerulonephritis, two hallmarks of human SLE. Mice deficient of B7-H3 or treated with a B7-H3 specific antibody produced significantly higher levels of anti-DNA autoantibodies and more severe glomerulonephritis than wild-type mice, indicating an inhibitory function of B7-H3 in this model. Interestingly, immunization of mice with DNA-pulsed dendritic cells induced severe SLE symptoms while B7-H3 on dendritic cells is required in this process. Importantly, treatment of mice with recombinant B7-H3Ig fusion protein effectively ameliorated progression of murine SLE, accompanied with decreased level of anti-DNA autoantibodies and alleviated glomerulonephritis, decreased autoantibody deposition and complement deposition in kidney. Our findings implicate a potential role of B7-H3 on dendritic cells in the induction of SLE and as a potential target for the treatment of autoimmune diseases.
Highlights
B7-H3, a cell surface molecule of the extended CD28/B7 family, was discovered in our laboratory in 2001 by searching databases for molecules with homology to previously identified B7 molecules[1]
Upon the immunization with activated lymphocyte-derived DNA (ALD-DNA), WT B6 mice were treated with 14 M or control immunoglobulin (Ig) and 4 weeks later, the levels of anti-dsDNA Abs in sera were tested by specific enzyme-linked immunosorbent assay (ELISA)
By ablation of B7-H3, either genetic deficiency or blocking monoclonal antibody (mAb), our results indicate that B7-H3 may play an important role in the generation of anti-dsDNA Abs and subsequent promotion of renal inflammation in a Systemic lupus erythematosus (SLE) mouse model
Summary
B7-H3, a cell surface molecule of the extended CD28/B7 family, was discovered in our laboratory in 2001 by searching databases for molecules with homology to previously identified B7 molecules[1]. Anti-dsDNA Abs are thought to be diagnostic markers in SLE and their presence in humans and mice often correlates with disease pathogenesis[13,14,15,16] These Abs contribute to disease progression of SLE, as indicated by glomerulonephritis, an inflammation largely due to deposition of antigen (Ag)Abs complex and subsequent activation of complement. Qiao et al.[17] showed that mice immunized with activated lymphocyte-derived DNA (ALD-DNA) produced high levels of anti-dsDNA Abs, and subsequently developed SLE-like syndrome, including aggravated glomerulonephritis, increased autoantibody and complement deposition. These observations resemble closely human SLE and this may provide a good model for studying human SLE pathogenesis
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