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

Abstract

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 ␤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.

Effects of adjuvants for human use in systemic lupus erythematosus (SLE)-prone (New Zealand black/New Zealand white) F1 mice

“…Whether or not a subcutaneous posterior foot injection may have caused tissue stress and the release of higher amounts of DNA from dying host cells, as observed with aluminium [14], triggering hypersensitivity reactions, toxicity and/or higher stimulation than occurs with intraperitoneal route immunization, remains to be evaluated. The notably earlier onset and higher amount of proteinuria observed in the IFA compared to the CFA group may be explained by considering the two different cytokine profiles probably induced by the two adjuvants: CFA has been reported to induce a significantly higher production of interleukin (IL)-17, IL-6 and transforming growth factor (TGF)-β, while IFA appears to enhance IL-10 production [48,49]; this cytokine is known to be involved in autoantibody production and to contribute to the pathogenesis of SLE [50,51].…”

Cellular interactions in the pathogenesis of interstitial lung diseases

“…In IPF, plasma B-lymphocyte stimulator (BLyS) concentrations correlate with poor prognosis and disease manifestations [107]. Experimental data demonstrated that treatment with anti-topoisomerase I antibody induces skin and lung fibrosis stimulating IL-6 production [108]. Moreover, IL-6 is an independent predictor of decline in diffusing capacity of the lung for carbon monoxide (DLCO), in both IPF and SSc-ILD patients [109].…”

Physiopathologie de la sclérodermie systémique

“…Dans les modèles animaux, une invalidation du gène codant l'IL-6, ou l'inhibition de l'action de la cytokine, préviennent la fibrose induite (ou déjà établie) par la bléomycine. Elles réduisent également les fibroses cutanée et pulmonaire dans le modèle d'immunisation à la topo-isomérase I 6 [15]. En revanche, bloquer l'IL-6 est inefficace dans le modèle non inflammatoire des souris Tsk1.…”