{
  "abstract": "Introduction The genetic background may influence the development and the severity of systemic sclerosis (SSc). Available SSc mouse models do not mimic the full spectrum of SSc-related manifestations (i.e. association of fibrosis, vasculopathy and autoimmunity). Nonetheless, the recombinant topoisomerase injection (rTOPO) model proposed by Yoshizaki et al. (PMID: 21792823) reproduced these key components of SSc pathogenesis, and previous publications suggested that genetic background largely influenced the outcomes in this model. The objective of this study was to optimize the rTOPO model by using several genetic backgrounds.Material and Methods Male C57BL/6J and 129/Sv mice were exposed to 4 subcutaneous injections of rTOPO coupled to Freund’s complete adjuvant (CFA), two weeks apart. After 8 weeks, the mice were euthanized and we collected blood for cell counts and autoantibody detection by ELISA, skin and lung biopsies for histological analysis and mRNA marker quantification of fibrotic and inflammatory markers, and lung biopsy for immune cell analysis using cytometry.Results In C57BL/6J mice, the rTOPO/CFA model did not result neither in pulmonary fibrosis or inflammation nor in the production of anti-TOPO autoantibodies.In the autoimmune prone 129/Sv mice, the rTOPO/CFA injections increased the level of anti-TOPO (p<0.05) and antinuclear antibody production. The Ashcroft score showed an induction of fibrosis in the lung (p<0.001), confirmed by the Sirius Red quantification (sub-pleural and parenchymal, p<0.01). There was a significant increase of mRNA level of fibrotic markers (such as TGFβ, FN1, COL1A2, COL1A3, COL3A1), of matrix remodeling markers (MMP9, TIMP1) and of inflammatory markers (IL6, TNFα, CXCL10, IL10, IL13, IL4) in both lung and skin. We also observed a significant increase of mRNA level of vascular damage (EDN1 and eNOS) in the lung.In both strains, rTOPO/CFA tended to induce a reduction of the red blood cells and an increase of circulating neutrophils and of LT CD4/CD8 ratio in the lung.Conclusions The results suggest that the rTOPO/CFA injection model in 129/Sv mice could be a promising model to investigate the role of autoantibodies in the pathogenesis of SSc-ILD, confirming that the genetic background has a part to play in the SSc severity in mice.",
  "authors": [
    {
      "affiliations": [
        "Univ Rennes, INSERM, EHESP, IRSET UMR S 1085, Rennes, France"
      ],
      "name": "Salomé Patry"
    },
    {
      "affiliations": [
        "Univ Rennes, INSERM, EHESP, IRSET UMR S 1085, Rennes, France"
      ],
      "name": "Laura Morin"
    },
    {
      "affiliations": [
        "Univ Rennes, INSERM, EHESP, IRSET UMR S 1085, Rennes, France"
      ],
      "name": "Marie Lelong"
    },
    {
      "affiliations": [
        "Univ Rennes, CHU Rennes, INSERM, UMR 1236, Etablissement Français du Sang Bretagne, Rennes, France"
      ],
      "name": "Erwan Dumontet"
    },
    {
      "affiliations": [
        "INSERM, Univ Lille, CHU Lille, U1286 INFINITE, Lille, France"
      ],
      "name": "David Launay"
    },
    {
      "affiliations": [
        "Univ Rennes, CHU Rennes, INSERM, EHESP, IRSET UMR S 1085, Rennes, France"
      ],
      "name": "Alain Lescoat"
    },
    {
      "affiliations": [
        "Univ Rennes, INSERM, EHESP, IRSET UMR S 1085, Rennes, France"
      ],
      "name": "Valerie Lecureur"
    }
  ],
  "title": "P.046 Impact of genetic background on topoisomerase immunization in mouse model",
  "uid": "789c4167-f22b-52c0-af56-025ca1e90af0"
}