Cross-regulation of TNF and IFN-α in autoimmune diseases
Cross-regulation of TNF and IFN-α in autoimmune diseases
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DOI：
10.1073/pnas.0408506102
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发表时间：
2005-03-01
影响因子：
11.1
通讯作者：
Banchereau, J
中科院分区：
文献类型：
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作者：
Palucka, AK;Blanck, JP;Banchereau, J
细胞因子，最特别是TNF和I型IFN（IFN-α），长期以来被认为是自身免疫发展中的基本要素。类风湿性关节炎发病机制中TNF的鉴定和TNF拮抗剂治疗代表了免疫学的成功。IFN-α在系统性红斑狼疮（SLE）中起主要作用，SLE是一种以对核组分的耐受性破坏为特征的原型自身免疫性疾病。在这里，我们表明，TNF调节IFN-α的生产在体外在两个水平。首先，它抑制了从CD 34（+）造血祖细胞产生浆细胞样树突状细胞（pDC），这是IFN-α的主要生产者。第二，它抑制暴露于流感病毒的未成熟pDC的IFN-α释放。内源性TNF的中和维持pDC的IFN-α分泌。这些发现具有临床意义，因为接受TNF拮抗剂治疗的5例全身性幼年关节炎患者中有5例在其血液白细胞中显示IFN-α调节基因的过表达。这些结果，因此，可能提供了一个机制的解释抗dsDNA抗体和狼疮样综合征的患者接受抗TNF治疗的发展。
Cytokines, most particularly TNF and type I IFN (IFN-alphabeta), have been long considered essential elements in the development of auto-immunity. Identification of TNF in the pathogenesis of rheumatoid arthritis and TNF antagonist therapy represent successes of immunology. IFN-alphabeta plays a major role in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. Here, we show that TNF regulates IFN-alpha production in vitro at two levels. First, it inhibits the generation of plasmacytoid dendritic cells (pDCs), a major producer of IFN-alphabeta, from CD34(+) hematopoietic progenitors. Second, it inhibits IFN-a release by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-a secretion by pDCs. These findings are clinically relevant, as five of five patients with systemic juvenile arthritis treated with TNF antagonists display overexpression of IFN-alpha-regulated genes in their blood leukocytes. These results, therefore, might provide a mechanistic explanation for the development of anti-dsDNA antibodies and lupus-like syndrome in patients undergoing anti-TNF therapy.