Modulation of nuclear factor-κB activity can influence the susceptibility to systemic lupus erythematosus
Modulation of nuclear factor-κB activity can influence the susceptibility to systemic lupus erythematosus
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DOI：
10.1111/j.1365-2567.2008.02964.x
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发表时间：
2009-09-01
期刊：
影响因子：
6.4
通讯作者：
Jacobelli, Sergio H.
中科院分区：
文献类型：
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作者：
Kalergis, Alexis M.;Iruretagoyena, Mirentxu I.;Jacobelli, Sergio H.
自身免疫性疾病，如系统性红斑狼疮(SLE)，是由于自身抗原耐受过程的缺陷造成的，这需要调节树突状细胞(DC)的功能。在这项研究中，我们在一种小鼠模型中评估了系统性红斑狼疮发病过程中DC的表型，在该模型中，抑制受体FcγRIIb的缺失导致抗核抗体的产生和肾小球肾炎。Fc-RIIb基因缺陷的SLE小鼠的脾DC显示共刺激分子的表达增加。此外，患病小鼠表现出参与DC成熟的核因子-kappa B(NF-kappa B)转录因子的功能改变。与健康动物相比，系统性红斑狼疮小鼠抑制分子I kappa B-α的表达显著降低。一贯地，对Fc-Gamma RIIb缺陷小鼠的核因子-kappa B活性的药理抑制会降低系统性红斑狼疮的易感性，并预防抗核抗体和肾脏损害等症状。我们的数据表明，核因子-kappaB功能的改变对SLE的发生有显著影响，可被认为是该疾病的一个新的治疗靶点。
P>Autoimmune diseases, such as systemic lupus erythematosus (SLE), result from deficiencies in self-antigen tolerance processes, which require regulated dendritic cell (DC) function. In this study we evaluated the phenotype of DCs during the onset of SLE in a mouse model, in which deletion of the inhibitory receptor Fc gamma RIIb leads to the production of anti-nuclear antibodies and glomerulonephritis. Splenic DCs from Fc gamma RIIb-deficient mice suffering from SLE showed increased expression of co-stimulatory molecules. Furthermore, diseased mice showed an altered function of the nuclear factor-kappa B (NF-kappa B) transcription factor, which is involved in DC maturation. Compared with healthy animals, expression of the inhibitory molecule I kappa B-alpha was significantly decreased in mice suffering from SLE. Consistently, pharmacological inhibition of NF-kappa B activity in Fc gamma RIIb-deficient mice led to reduced susceptibility to SLE and prevented symptoms, such as anti-nuclear antibodies and kidney damage. Our data suggest that the occurrence of SLE is significantly influenced by alterations of NF-kappa B function, which can be considered as a new therapeutic target for this disease.