Published January 1, 2021
| Version v1
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Human TBK1 deficiency leads to autoinflammation driven by TNF-induced cell death
Creators
- Taft, Justin
- Markson, Michael
- Legarda, Diana1
- Patel, Roosheel
- Chan, Mark2
- Malle, Louise
- Richardson, Ashley
- Gruber, Conor
- Martin-Fernandez, Marta
- Mancini, Grazia M. S.3
- van Laar, Jan A. M.4
- van Pelt, Philomine5
- Buta, Sofija
- Wokke, Beatrijs H. A.6
- Sabli, Ira K. D.
- Sancho-Shimizu, Vanessa
- Chavan, Pallavi Pimpale
- Schnappauf, Oskar7
- Khubchandani, Raju
- Cuceoglu, Muserref Kasap8
- Cuceoglu, Muserref Kasap8
- 1. Icahn Sch Med Mt Sinai, Precis Immunol Inst, New York, NY 10029 USA
- 2. Mayo Clin, Dept Immunol, Rochester, MN 55905 USA
- 3. Erasmus MC, Dept Clin Genet, NL-3015 GD Rotterdam, Netherlands
- 4. Erasmus MC, Dept Immunol, NL-3015 GD Rotterdam, Netherlands
- 5. Erasmus MC, Dept Rheumatol, NL-3015 GD Rotterdam, Netherlands
- 6. Erasmus MC, Dept Neurol, NL-3015 GD Rotterdam, Netherlands
- 7. NHGRI, Inflammatory Dis Sect, Bethesda, MD 20892 USA
- 8. Hacettepe Univ, Dept Pediat Rheumatol, Ankara, Turkey
Description
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.
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