Strong acceleration of murine lupus by injection of the SmD1^83-119 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 SmD1^183-119. Controls received injections of recombinant SmD1 (rSmD1), KLH-rSmD1, KLH-coupled randomized peptide of SmD1^83-119, 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 SmD1^83-119 peptide and 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-SmD1^83-119 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 after immunization. Conclusion. The SmD1^83-119 peptide can influence the pathogenic anti-dsDNA response in the NZB/NZW murine lupus model. The data suggest that an SmD1^83-119-speciflc 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.