Immunization with DNA topoisomerase I and Freund's complete adjuvant induces skin and lung fibrosis and autoimmunity via interleukin-6 signaling.
Immunization with DNA topoisomerase I and Freund's complete adjuvant induces skin and lung fibrosis and autoimmunity via interleukin-6 signaling.
复制标题
DNA 拓扑异构酶 I 和弗氏完全佐剂免疫可通过白细胞介素 6 信号传导诱导皮肤和肺纤维化以及自身免疫。
作者：
A. Yoshizaki;K. Yanaba;Asako Ogawa;Y. Asano;T. Kadono;S. Sato
目的
抗DNA拓扑异构酶I（anti-topo I）抗体的存在与系统性硬化症（SSc）患者的疾病严重程度呈正相关。然而，诱导抗拓扑I抗体产生的作用及其对SSc发病机制的潜在贡献仍不清楚。本研究的目的是研究抗Topo I抗体在SSc发病机制中的作用。
方法
为了评估抗topo I抗体对发病过程的贡献，在用topo I和弗氏完全佐剂（CFA）或弗氏不完全佐剂（IFA）治疗的小鼠中检查了皮肤硬化、肺纤维化和细胞因子产生。
结果
与topo I和IFA处理相比，topo I和CFA处理诱导皮肤和肺纤维化，白细胞介素-6（IL-6）、转化生长因子β1和IL-17产生增加，IL-10产生减少。用topo I和CFA处理的小鼠中的抗topo I抗体水平高于用topo I和IFA处理的小鼠。此外，topo I和CFA治疗增加支气管肺泡灌洗液中的Th 2和Th 17细胞频率，而topo I和IFA治疗增加Th 1和Treg细胞频率。此外，IL-6表达的丧失改善了皮肤和肺纤维化，降低了Th 2和Th 17细胞频率，并增加了Th 1和Treg细胞频率。
结论
这项研究首次表明，用topo I和CFA治疗会诱导Ssc样皮肤和肺纤维化以及自身免疫异常。我们还认为，IL-6在这种新型SSc模型中纤维化和自身免疫异常的发展中起着重要作用。
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.
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DOI：
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