Housley William J, Fernandez Salvador D, Vera Kenneth, Murikinati Sasidhar R, Grutzendler Jaime, Cuerdon Nicole, Glick Laura, De Jager Phillip L, Mitrovic Mitja, Cotsapas Chris, Hafler David A
Department of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA.
Program in Translational NeuroPsychiatric Genomics, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Sci Transl Med. 2015 Jun 10;7(291):291ra93. doi: 10.1126/scitranslmed.aaa9223.
The transcription factor nuclear factor κB (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 NFκB. We report that MS-associated variants proximal to NFκB1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NFκB signaling after tumor necrosis factor-α (TNFα) stimulation. Both variants result in increased degradation of inhibitor of NFκB α (IκBα), a negative regulator of NFκB, and nuclear translocation of p65 NFκB. The variant proximal to NFκB1 controls signaling responses by altering the 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: TNFα-induced protein 3 (TNFAIP3), B cell leukemia 3 (BCL3), and cellular inhibitor of apoptosis 1 (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.
转录因子核因子κB（NFκB）是炎症的核心调节因子，对自身免疫性疾病患者进行的全基因组关联研究已在NFκB信号级联反应中鉴定出多个变异体。此外，因果变异精细定位表明，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体在NFκB的结合位点内高度富集。我们报告称，靠近NFκB1以及位于肿瘤坏死因子受体超家族成员1A（TNFRSF1A，即TNFR1）内含子中的MS相关变异体与肿瘤坏死因子-α（TNFα）刺激后NFκB信号增强有关。这两种变异体均导致NFκB的负调节因子核因子κB抑制蛋白α（IκBα）降解增加以及p65 NFκB的核转位。靠近NFκB1的变异体通过改变NFκB自身的表达来控制信号反应，GG风险基因型表达的p50 NFκB多20倍，而NFκB途径的负调节因子表达减少，这些负调节因子包括：TNFα诱导蛋白3（TNFAIP3）、B细胞白血病3（BCL3）和细胞凋亡抑制蛋白1（CIAP1）。最后，MS患者的初始CD4 T细胞表达的p65 NFκB激活增强。这些结果表明，与MS发病风险相关的基因变异会改变NFκB信号通路，导致NFκB激活增强以及对炎症刺激的反应性增强。因此，这表明对与NFκB信号相关的变异体进行快速基因筛查可能会识别出适合进行NFκB或细胞因子阻断治疗的个体。
