Genetic variants associated with autoimmunity drive NF?B signaling and responses to inflammatory stimuli.

ABSTRACT: The transcription factor nuclear factor ?B (NF?B) is a central regulator of inflammation, and genome-wide association studies in subjects with autoimmune disease have identified a number of variants within the NF?B 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 NF?B. We report that MS-associated variants proximal to NF?B1 and in an intron of TNFRSF1A (TNFR1) are associated with increased NF?B signaling after tumor necrosis factor-? (TNF?) stimulation. Both variants result in increased degradation of inhibitor of NF?B ? (I?B?), a negative regulator of NF?B, and nuclear translocation of p65 NF?B. The variant proximal to NF?B1 controls signaling responses by altering the expression of NF?B itself, with the GG risk genotype expressing 20-fold more p50 NF?B and diminished expression of the negative regulators of the NF?B pathway: TNF?-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 NF?B. These results demonstrate that genetic variants associated with risk of developing MS alter NF?B signaling pathways, resulting in enhanced NF?B activation and greater responsiveness to inflammatory stimuli. As such, this suggests that rapid genetic screening for variants associated with NF?B signaling may identify individuals amenable to NF?B or cytokine blockade.

SUBMITTER: Housley WJ 

PROVIDER: S-EPMC4574294 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature