Immunization With DNA Topoisomerase I and Freund's Complete Adjuvant Induces Skin and Lung Fibrosis and Autoimmunity via Interleukin-6 Signaling

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 beta 1, 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.