Autoantibody Responses and Pathology Regulated by B7-1 and B7-2 Costimulation in MRL/lprLupus

Abstract

The activation of T lymphocytes requires both Ag-mediated signaling through the TCR as well as costimulatory signals transmitted through B7-1 and/or B7-2 with CD28. The interference of B7-mediated costimulatory signals has been proposed as one immunotherapeutic intervention for the prevention autoimmune disease. This study has examined autoantibody responses and autoimmune pathology in a murine model of human systemic lupus erythematosus (SLE), the MRL-lpr/lpr mouse, genetically deficient in B7-1 or B7-2, or in mice treated with B7-1/B7-2 blocking Abs. In contrast to other studies of murine models of SLE, MRL-lpr/lpr mice treated with B7 blocking Abs exhibit strong anti-small nuclear ribonucleoprotein (snRNP) and anti-DNA autoantibody responses with some changes in isotype switching as compared with untreated animals. All MRL-lpr/lpr mice deficient in B7-1 or B7-2 produce anti-snRNP and anti-DNA titers with isotypes virtually identical with wild-type animals. However, the absence of B7-2 costimulation did interfere with the spontaneous activation and the accumulation of memory CD4+ or CD8+ T lymphocytes characteristic of wild-type MRL-lpr/lpr mice. IgG and C3 complement deposition was less pronounced in the kidneys of B7-2 deficient MRL-lpr/lpr mice, reflecting their lessor degree of glomerulonephritis. By comparison, B7-1-deficient MRL-lpr/lpr mice had more severe IgG and C3 deposits in glomeruli.

Costimulation Requirements of Induced Murine Systemic Autoimmune Disease

“…It is unclear why individual B7 molecules differentially influence development of ANoA in mHgIA. Subtly different effects of B7 molecules on development of idiopathic autoimmunity (11,12) and induced autoimmunity (39) have been reported, suggesting that partial suppression of CD28-B7 interaction can influence multiple facets of autoimmunity.…”

“…Absence of either CD80 or CD86, ligands for CD28, does not affect autoantibody levels compared with wild-type mice (11,12). However, CD80-deficient mice have more severe renal disease than wild type, while CD86 knockouts have less severe disease compared with wild-type MRL-Fas lpr (11,12). The less active disease of MRL-Fas lpr CD86 Ϫ/Ϫ mice is associated with a reduction in activated T cells (12).…”

“…CD28 deficiency in lupus prone MRL-Fas lpr mice results in reductions in serum IgG, IgG autoantibodies, and renal pathology, but serum IgM and IgM rheumatoid factor are unaffected (10). Absence of either CD80 or CD86, ligands for CD28, does not affect autoantibody levels compared with wild-type mice (11,12). However, CD80-deficient mice have more severe renal disease than wild type, while CD86 knockouts have less severe disease compared with wild-type MRL-Fas lpr (11,12).…”

“…However, CD80-deficient mice have more severe renal disease than wild type, while CD86 knockouts have less severe disease compared with wild-type MRL-Fas lpr (11,12). The less active disease of MRL-Fas lpr CD86 Ϫ/Ϫ mice is associated with a reduction in activated T cells (12). Absence of both CD80 and CD86 in MRLFas lpr mice is associated with reductions in most features of systemic lupus, including serum IgG, autoantibodies, IFN-␥ and IL-12, renal pathology, and proteinuria (13).…”

Genomic view of systemic autoimmunity in MRLlpr mice

“…Breeding of various transgenic and knockout alleles onto the MRLlpr background has successfully identified genes that modify disease course. 13 These include B7.1, 14 B7.2, 15 Fyn, 16 IL-12, 17 IFN-gamma, 18 and complement C3. 19 We set out to visualize disease pathogenesis in MRLlpr mice at the genomic level, by performing gene expression profiling of spleens and kidneys throughout the lifespan of the mice.…”