Strong acceleration of murine lupus by injection of the SmD183-119 peptide

Objective The mechanisms of IgG anti–double-stranded DNA (anti-dsDNA) antibody induction are incompletely understood. We recently demonstrated a high prevalence of autoantibodies to the C-terminus of SmD1 in patients with systemic lupus erythematosus (SLE) that was closely associated with anti-dsDNA 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 in a murine model of SLE. Methods Female lupus-prone prenephritic (NZB × NZW)F1 mice (NZB/NZW mice) as well as female control BALB/c, NZW, and (BALB/c × NZW)F1 mice (CWF1 mice) were subcutaneously injected with keyhole limpet hemocyanin (KLH)–coupled SmD183–119. Controls received injections of recombinant SmD1 (rSmD1), KLH-rSmD1, KLH-coupled randomized peptide of SmD183–119, ovalbumin, or saline. Animals were monitored for survival and proteinuria and for levels of plasma creatinine, urea, and autoantibodies. In addition, histologic examinations were performed and T cell responses against SmD183–119 peptide and rSmD1 protein were determined in SmD183–119-treated and -untreated NZB/NZW mice. Results Immunization with KLH-SmD183–119, 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-SmD183–119 antibodies detectable even after immunization. In contrast to findings in control mice, a T cell response against SmD183–119 was already present in unmanipulated NZB/NZW mice, and this response was further amplified after immunization. Conclusion The SmD183–119 peptide can influence the pathogenic anti-dsDNA response in the NZB/NZW murine lupus model. The data suggest that an SmD183–119-specific T cell response is critical. Therefore, modulation of these autoantigen-specific T cells by tolerance induction may provide a therapeutic approach to specific immunosuppression in lupus.