Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli.
Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli.
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DOI：
10.1126/scitranslmed.aaa9223
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发表时间：
2015-06-10
影响因子：
17.1
通讯作者：
Hafler DA
中科院分区：
文献类型：
--
作者：
Housley WJ;Fernandez SD;Vera K;Murikinati SR;Grutzendler J;Cuerdon N;Glick L;De Jager PL;Mitrovic M;Cotsapas C;Hafler DA
转录因子NFκB是炎症的中心调节因子，在自身免疫性疾病患者中进行的全基因组关联研究已经确定了NFκB信号级联中的许多变体。此外，因果变异精细图谱表明，多发性硬化症(MS)和溃疡性结肠炎的自身免疫性疾病易感性变异在NFkB的结合位点内高度丰富。在这里，我们报告了在肿瘤坏死因子κ刺激后，肿瘤坏死因子κB1近端和TNFRSF1a内含子(TNFR 1)上的MS相关变异与增加的NFαB信号有关。这两个变体都导致IκBα的降解增加，并导致p65 NFκB的核转位。NFκB1近端的变体通过改变NFκB本身的表达来控制信号反应，其中GG风险基因型表达20倍以上的p50 NFκB，并减少NFκB途径的负调控因子TNFAIP3、bcl3和cIAP1的表达。最后，多发性硬化症患者的原始CD4T细胞表达p65 NFκB的增强激活。这些结果表明，与发生多发性硬化症的风险相关的基因变异改变了NFκB信号通路，导致NFκB的激活增强，对炎症刺激的反应性更强。因此，这表明快速基因筛查与NFκB信号相关的变异可能识别出服从于NFκB或细胞因子阻断的个体。
The transcription factor NFκB is a central regulator of inflammation and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NFκB signaling cascade. In addition, causal variant fine-mapping has demonstrated that autoimmune disease susceptibility variants for multiple sclerosis (MS) and ulcerative colitis are strongly enriched within binding sites for NFkB. Here, we report that MS-associated variants proximal to NFκB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFκB signaling after TNFα stimulation. Both variants result in increased degradation of IκBα, a negative regulator of NFκB, and nuclear translocation of p65 NFκB. The variant proximal to NFκB1 controls signaling responses by altering expression of NFκB itself, with the GG risk genotype expressing 20-fold more p50 NFκB and diminished expression of the negative regulators of the NFκB pathway TNFAIP3, BCL3, and CIAP1. Finally naïve CD4 T cells from patients with MS express enhanced activation of p65 NFκB. These results demonstrate that genetic variants associated with risk of developing MS alter NFκB signaling pathways, resulting in enhanced NFκB activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NFκB signaling may identify individuals amenable to NFκB or cytokine blockade.