Strong acceleration of murine lupus by injection of the SmD1(83-119) peptide

Objective. The mechanisms of IgG anti-double-stranded DNA (anti-dsDNA) anti body induction are incompletely understood. We recently demonstrated a high prevalence of autoantibodies to the C-terminus of SmD1 in patients with sy stemic lupus erythematosus (SLE) that was closely associated with anti-dsDN A reactivity. The aim of the present study was to analyze the influence of the SmD1 C-terminus on the generation of pathogenic anti-dsDNA antibodies i n a murine model of SLE. Methods. Female lupus-prone prenephritic (NZB x NZW)F-1 mice (NZB/NZW mice) as well as female control BALB/c, NZW, and (BALB/c x NZW)F-1 mice (CWF1 mi ce) were subcutaneously injected with keyhole limpet hemocyanin (KLH)-coupl ed SmD1(83-119). Controls received injections of recombinant SmD1 (rSmD1), KLH-rSmD1, KLH-coupled randomized peptide of SmD1(83-119), ovalbumin, or sa line. Animals were monitored for survival and proteinuria and for levels of plasma creatinine, urea, and autoantibodies. In addition, histologic exami nations were performed and T cell responses against SmD1(83-119) peptide an d rSmD1 protein were determined in SmD1(83-119)-treated and -untreated NZB/ NZW mice. Results. Immunization with KLH-SmD1(83-119), but not with control peptide, significantly accelerated the natural course of lupus in NZB/NZW mice, with premature renal failure and increased development of anti-dsDNA antibodies . Control strains of mice remained healthy, with no relevant anti-SmD1(83-1 19) antibodies detectable even after immunization. In contrast to findings in control mice, a T cell response against SmD1(83-119) was already present in unmanipulated NZB/NZW mice, and this response was further amplified aft er immunization. Conclusion. The SmD1(83-119) peptide can influence the pathogenic anti-dsDN A response in the NZB/NZW murine lupus model. The data suggest that an SmD1 (83-119)-specific T cell response is critical. Therefore, modulation of the se autoantigen-specific T cells by tolerance induction may provide a therap eutic approach to specific immunosuppression in lupus.