Taft, Justin, Markson, Michael, Legarda, Diana, Patel, Roosheel, Chan, Mark, Malle, Louise, Richardson, Ashley, Gruber, Conor, Martin-Fernandez, Marta, Mancini, Grazia M. S., van Laar, Jan A. M., van Pelt, Philomine, Buta, Sofija, Wokke, Beatrijs H. A., Sabli, Ira K. D., Sancho-Shimizu, Vanessa, Chavan, Pallavi Pimpale, Schnappauf, Oskar, Khubchandani, Raju, and Cuceoglu, Muserref Kasap
TANK binding kinase 1 (TBK1) regulates IFN-I, NF-kappa B, and TNF-induced RIPK1-dependent cell death (RCD). In mice, biallelic loss of TBK1 is embryonically lethal. We discovered four humans, ages 32, 26, 7, and 8 from three unrelated consanguineous families with homozygous loss-of-function mutations in TBK1. All four patients suffer from chronic and systemic autoinflammation, but not severe viral infections. We demonstrate that TBK1 loss results in hypomorphic but sufficient IFN-I induction via RIG-I/MDA5, while the system retains near intact IL-6 induction through NF-kappa B. Autoinflammation is driven by TNF-induced RCD as patient-derived fibroblasts experienced higher rates of necroptosis in vitro, and CC3 was elevated in peripheral blood ex vivo. Treatment with anti-TNF dampened the baseline circulating inflammatory profile and ameliorated the clinical condition in vivo. These findings highlight the plasticity of the IFN-I response and underscore a cardinal role for TBK1 in the regulation of RCD.