title: Strong acceleration of murine lupus by injection of the SmD1(83-119) peptide.
abstract: 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 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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité University Hospital, Humboldt University of Berlin, Germany. gabriela.riemekasten@charite.de
authors.forename: G
authors.initials: G
authors.lastname: Riemekasten
authors.forename: A
authors.initials: A
authors.lastname: Kawald
authors.forename: C
authors.initials: C
authors.lastname: Weiss
authors.forename: A
authors.initials: A
authors.lastname: Meine
authors.forename: J
authors.initials: J
authors.lastname: Marell
authors.forename: R
authors.initials: R
authors.lastname: Klein
authors.forename: B
authors.initials: B
authors.lastname: Hocher
authors.forename: C
authors.initials: C
authors.lastname: Meisel
authors.forename: G
authors.initials: G
authors.lastname: Hausdorf
authors.forename: R
authors.initials: R
authors.lastname: Manz
authors.forename: T
authors.initials: T
authors.lastname: Kamradt
authors.forename: G R
authors.initials: GR
authors.lastname: Burmester
authors.forename: F
authors.initials: F
authors.lastname: Hiepe
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D005260:Female; D007114:Immunization; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000503:physiopathology; D051379:Mice; D010446:Peptide Fragments / Q000276:immunology; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology*; D055517:snRNP Core Proteins
chemical_list: D001324:Autoantigens; D010446:Peptide Fragments; D017411:Ribonucleoproteins, Small Nuclear; C489793:Snrpd1 protein, mouse; D055517:snRNP Core Proteins