Immunization with DNA topoisomerase I and Freund's complete adjuvant induces skin and lung fibrosis and autoimmunity via interleukin-6 signaling

Arthritis Rheum. 2011 Nov;63(11):3575-85. doi: 10.1002/art.30539.


Objective: The presence of anti-DNA topoisomerase I (anti-topo I) antibody correlates positively with disease severity in patients with systemic sclerosis (SSc). However, the role of induction of anti-topo I antibody production and its potential contribution to the pathogenesis of SSc remain unclear. The aim of this study was to examine the role of anti-topo I antibody in the pathogenesis of SSc.

Methods: To assess the contribution of anti-topo I antibody to the pathogenetic process, dermal sclerosis, pulmonary fibrosis, and cytokine production were examined in mice treated with topo I and either Freund's complete adjuvant (CFA) or Freund's incomplete adjuvant (IFA).

Results: Treatment with topo I and CFA, in contrast to treatment with topo I and IFA, induced skin and lung fibrosis with increased interleukin-6 (IL-6), transforming growth factor β1, and IL-17 production and decreased IL-10 production. Anti-topo I antibody levels were greater in mice treated with topo I and CFA than in mice treated with topo I and IFA. Furthermore, treatment with topo I and CFA increased Th2 and Th17 cell frequencies in bronchoalveolar lavage fluid, whereas treatment with topo I and IFA increased Th1 and Treg cell frequencies. Moreover, loss of IL-6 expression ameliorated skin and lung fibrosis, decreased Th2 and Th17 cell frequencies, and increased Th1 and Treg cell frequencies.

Conclusion: This study is the first to show that treatment with topo I and CFA induces SSc-like skin and lung fibrosis and autoimmune abnormalities. We also suggest that IL-6 plays important roles in the development of fibrosis and autoimmune abnormalities in this novel SSc model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmunity / immunology*
  • DNA Topoisomerases, Type I / immunology*
  • Freund's Adjuvant / immunology*
  • Immunization
  • Interleukin-6 / metabolism*
  • Mice
  • Pulmonary Fibrosis / etiology
  • Pulmonary Fibrosis / immunology*
  • Pulmonary Fibrosis / pathology
  • Scleroderma, Systemic / etiology
  • Scleroderma, Systemic / immunology*
  • Scleroderma, Systemic / pathology
  • Skin / immunology
  • Skin / pathology
  • Th1 Cells / immunology
  • Th1 Cells / pathology
  • Th2 Cells / immunology
  • Th2 Cells / pathology


  • Interleukin-6
  • Freund's Adjuvant
  • DNA Topoisomerases, Type I