Genetic variants associated with autoimmunity drive NFκB signaling and responses to inflammatory stimuli

Genetic variants associated with multiple sclerosis result in increased NFκB signaling in CD4 T cells and a decreased threshold for activation. Lowering the bar for autoimmunity In patients with autoimmune diseases, such as multiple sclerosis, immune cells attack the tissues that they are supposed to protect. However, it remains unclear why these self-targeted cells become activated in some individuals and not in others. Now, Housley et al. show that at least some multiple sclerosis patients have genetic variants that result in increased NFκB signaling after TNFα stimulation. These variants, in effect, lower the activation threshold of CD4 T cells, making them more responsive to inflammation and thus more likely to contribute to autoimmunity. Patients with these variants may be good candidates for therapies that block either NFκB signaling or inflammatory cytokines. 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.