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

• Published in: Arthritis and rheumatism 2001-10, Vol.44 (10), p.2435-2445
• Main Authors: Riemekasten, G, Kawald, A, Weiss, C, Meine, A, Marell, J, Klein, R, Hocher, B, Meisel, C, Hausdorf, G, Manz, R, Kamradt, T, Burmester, G R, Hiepe, F
• Format: Article
• Language: English
• Subjects: Animals; Autoantigens - immunology; Female; Immunization; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - physiopathology; Mice; Peptide Fragments - immunology; Ribonucleoproteins, Small Nuclear - immunology
• ISSN: 0004-3591
• DOI: 10.1002/1529-0131(200110)44:10<2435::AID-ART408>3.0.CO;2-0

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. Female lupus-prone prenephritic (NZB x NZW)F1 mice (NZB/NZW mice) as well as female control BALB/c, NZW, and (BALB/c x NZW)F, mice (CWF1 mice) were subcutaneously injected with keyhole limpet hemocyanin (KLH)-coupled SmD1(83-119). 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. 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. 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)-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.