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SmD1 83-119 peptide accelerates disease in lupus prone mice
Arthritis Research & Therapy volume 3, Article number: 72250 (2001)
Context
Among antibodies found in sera from patients with systemic lupus erythematosus (SLE), those directed against DNA and Sm proteins are specific and have been included as one of the American College of Rheumatology classification criteria for SLE. The authors have previously identified a polypeptide (83-119) of SmD1 protein recognized by 70% of SLE patients' sera. They observed that reactivity to 83-119 polypeptide is higher in anti-dsDNA antibody positive sera than anti-dsDNA antibody negative sera. The present study was undertaken to analyze the influence of the SmD1 83-119 polypeptide on the generation of pathogenic anti-dsDNA antibodies. The authors immunized female lupus-prone prenephritic (NZB x NZW) F1 mice (NZB/NZW mice) with keyhole limpet hemocyanin (KLH)-coupled SmD1 83-119 peptide and measured survival, proteinuria, renal function and anti-dsDNA production.
Significant findings
Immunization of NZB/NZW mice with KLH-SmD1 83-119-but not with control peptide and protein-resulted in decreased survival, increased anti-dsDNA antibody production, enhanced proteinuria and immune complex nephritis, and accelerated production of autoantibodies directed against various self antigens. None of these manifestations were observed in other control mouse strains immunized with KLH-SmD1 83-119. The authors also found that splenocytes from unmanipulated NZB/NZW mice, unlike those from normal mice, proliferated in response to peptide 83-119; this response was further amplified after immunization. Cells from both untreated and treated NZB/NZW mice seldom recognized the recombinant SmD1 protein used as a control.
Comments
This study showed that injection of polypeptide 83-119 of SmD1, previously identified as a B-cell epitope in SLE patients, induced an accelerated disease in prenephritic NZB/NZW mice. As shown with cellular experiments, 83-119 polypeptide seems to be also a T-cell epitope in NZB/NZW mice. Based on unpublished observations (i.e. that the highly positively charged C-terminal SmD1 peptide binds to DNA) the authors proposed that SmD1-DNA complexes could activate T cells via SmD1 peptides and B cells via DNA. This mechanism suggests a role for SmD1 83-119 polypeptide in accelerating the production of anti-dsDNA antibodies via T-cell stimulation. Indeed, this hypothesis seems very attractive. Application to the human disease, however, would require the identification of T-cell epitopes in SLE patients. A recent study identified regions of SmD1 recognized by T-cell clones from SLE patients in residues 35-53 and 53-67 (see Additional information [1]). Such sequences have also been well documented as B-cell epitopes in lupus-prone mice (see Additional information [2]) and in humans.
Methods
Immunization, ELISA, immunohistology, T-cell proliferation
Additional information
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1.
Talken BL, Shafermeyer KR, Bailey CW, Lee DR, Hoffman RW: T cell epitope mapping of the Smith antigen reveals that highly conserved Smith antigen motif are the dominant target of T cell immunity in systemic lupus erythematosus. J Immunol 2001, 167:562-568.
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2.
James JA, Mamula MJ, Harley JB: Sequential autoantigenic determinants of the small nuclear ribonucleoprotein SmD shared by human lupus autoantibodies and MRL lpr/lpr antibodies. Clin Exp Immunol 1994, 98:419-426.
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3.
Riemekasten G, Marell J, Trebeljahr G, Klein R, Hausdorf G, Haupl T, Schneider-Mergener J, Burmester GR, Hiepe F: A novel epitope on the C-terminus of SmD1 is recognized by the majority of sera from patients with systemic lupus erythematosus. J Clin Invest 1998, 102: 754-763.
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4.
Barakat S, Briand J-P, Weber J-C, Van Regenmortel MHV, Muller S: Recognition of synthetic peptides of Sm-D autoantigen by lupus sera. Clin Exp Immunol 1990, 81:256-262.
References
- 1.
Riemekasten G, Kawald A, Weiss C, Meine A, Marell J, Klein R, Hocher B, Meisel C, Hausdorf G, Manz R, Kamradt T, Burmester GR, Hiepe F: Strong acceleration of murine lupus by injection of the SmD1 83-119 peptide. Arthritis Rheum. 2001, 44: 2435-2445.
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Monneaux, F. SmD1 83-119 peptide accelerates disease in lupus prone mice. Arthritis Res Ther 3, 72250 (2001). https://doi.org/10.1186/ar-2001-72250
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Keywords
- Anti-dsDNA antibodies
- lupus mice
- SmD1 peptides
- systemic lupus erythematosus
