Nature:减少SLE治疗中强效免疫抑制药物用量的方法

2010-06-17 00:00 · Vivien

“系统性红斑狼疮”(SLE)是一种自免疫疾病,在这种疾病中,对自身核酸的先天耐受性被破坏,产生毁灭性后果。近年来在治疗方法上取得的进展非常少,患者大部分仍用高剂量糖皮质激素等强效免疫抑制药物来治疗,经常引起严重副作用。 生物谷启用新域名 www.bioon.net 事实上,红斑狼

“系统性红斑狼疮”(SLE)是一种自免疫疾病,在这种疾病中,对自身核酸的先天耐受性被破坏,产生毁灭性后果。近年来在治疗方法上取得的进展非常少,患者大部分仍用高剂量糖皮质激素等强效免疫抑制药物来治疗,经常引起严重副作用。

生物谷启用新域名 www.bioon.net

事实上,红斑狼疮患者所需要的糖皮质激素剂量要比在如风湿性关节炎等其他自免疫疾病中所需的剂量高得多。现在,对糖皮质激素的这种低敏感度的一个可能的解释已被发现。在SLE患者中,Toll类受体TLR7和 TLR9(先天免疫中的关键成分)识别B细胞和“浆细胞样树突状细胞” (PDC)上的自体核酸。现在研究发现,在SLE患者和易患红斑狼疮的小鼠中,用TLR7/9刺激PDCs会降低糖皮质激素的免疫抑制功效。

这表明,TLR 7/9信号作用的抑制药物,如被称为“免疫调控序列”(IRSs)的新的一类寡核苷酸,有可能会被证明是有效的、可减少皮质类固醇用量的药物。


推荐原文出处:

Nature doi:10.1038/nature09102

TLR recognition of self nucleic acids hampers glucocorticoid activity in lupus

Cristiana Guiducci, Mei Gong, Zhaohui Xu, Michelle Gill, Damien Chaussabel, Thea Meeker, Jean H. Chan, Tracey Wright, Marilynn Punaro, Silvia Bolland, Vassili Soumelis, Jacques Banchereau, Robert L. Coffman, Virginia Pascual " Franck J. Barrat

Glucocorticoids are widely used to treat patients with autoimmune diseases such as systemic lupus erythematosus (SLE)1, 2. However, regimens used to treat many such conditions cannot maintain disease control in the majority of SLE patients and more aggressive approaches such as high-dose methylprednisolone pulse therapy are used to provide transient reductions in disease activity3, 4. The primary anti-inflammatory mechanism of glucocorticoids is thought to be NF-κB inhibition5. Recognition of self nucleic acids by toll-like receptors TLR7 and TLR9 on B cells and plasmacytoid dendritic cells (PDCs) is an important step in the pathogenesis of SLE6, promoting anti-nuclear antibodies and the production of type I interferon (IFN), both correlated with the severity of disease1, 7. Following their activation by self-nucleic acid-associated immune complexes, PDCs migrate to the tissues8, 9. We demonstrate, in vitro and in vivo, that stimulation of PDCs through TLR7 and 9 can account for the reduced activity of glucocorticoids to inhibit the IFN pathway in SLE patients and in two lupus-prone mouse strains. The triggering of PDCs through TLR7 and 9 by nucleic acid-containing immune complexes or by synthetic ligands activates the NF-κB pathway essential for PDC survival. Glucocorticoids do not affect NF-κB activation in PDCs, preventing glucocorticoid induction of PDC death and the consequent reduction of systemic IFN-α levels. These findings unveil a new role for self nucleic acid recognition by TLRs and indicate that inhibitors of TLR7 and 9 signalling could prove to be effective corticosteroid-sparing drugs.

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