Palucka A Karolina, Blanck Jean-Philippe, Bennett Lynda, Pascual Virginia, Banchereau Jacques
Baylor Institute for Immunology Research, 3434 Live Oak Street, Dallas, TX 75214, USA.
Proc Natl Acad Sci U S A. 2005 Mar 1;102(9):3372-7. doi: 10.1073/pnas.0408506102. Epub 2005 Feb 22.
Cytokines, most particularly TNF and type I IFN (IFN-alphabeta), have been long considered essential elements in the development of autoimmunity. 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-alpha release by immature pDCs exposed to influenza virus. Neutralization of endogenous TNF sustains IFN-alpha 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.
细胞因子，尤其是肿瘤坏死因子（TNF）和I型干扰素（IFN-αβ），长期以来一直被认为是自身免疫性疾病发展的关键因素。类风湿性关节炎发病机制中TNF的发现以及TNF拮抗剂疗法是免疫学的成功范例。IFN-αβ在系统性红斑狼疮（SLE）中起主要作用，SLE是一种典型的自身免疫性疾病，其特征是对核成分的耐受性被打破。在此，我们表明TNF在体外从两个层面调节IFN-α的产生。首先，它抑制浆细胞样树突状细胞（pDC）的生成，pDC是IFN-αβ的主要产生者，由CD34 +造血祖细胞分化而来。其次，它抑制暴露于流感病毒的未成熟pDC释放IFN-α。中和内源性TNF可维持pDC分泌IFN-α。这些发现具有临床相关性，因为接受TNF拮抗剂治疗的五名系统性幼年型关节炎患者的血液白细胞中均显示出IFN-α调节基因的过表达。因此，这些结果可能为接受抗TNF治疗的患者中抗双链DNA抗体和狼疮样综合征的发展提供一个机制性解释。
