Inflammation and neutrophil oxidative burst in a family with <em>NFKB1</em> p.R157X LOF and sterile necrotizing fasciitis
Santaniemi, Wenny; Åström, Pirjo; Glumoff, Virpi; Pernaa, Nora; Tallgren, Ella-Noora; Palosaari, Sanna; Nissinen, Antti; Kaustio, Meri; Kuismin, Outi; Saarela, Janna; Nurmi, Katariina; Eklund, Kari K.; Seppänen, Mikko R. J.; Hautala, Timo (2023-03-09)
Santaniemi, W., Åström, P., Glumoff, V. et al. Inflammation and Neutrophil Oxidative Burst in a Family with NFKB1 p.R157X LOF and Sterile Necrotizing Fasciitis. J Clin Immunol 43, 1007–1018 (2023). https://doi.org/10.1007/s10875-023-01461-3
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https://urn.fi/URN:NBN:fi-fe2023052648387
Tiivistelmä
Abstract
Loss-of-function (LOF) mutations in NFKB1, coding for p105, may cause common variable immunodeficiency due to dysregulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κΒ) pathway. Monoallelic LOF variants of NFKB1 can predispose to uncontrolled inflammation including sterile necrotizing fasciitis or pyoderma gangrenosum. In this study, we explored the impact of a heterozygous NFKB1 c.C936T/p.R157X LOF variant on immunity in sterile fasciitis patients and their family members. The p50 or p105 protein levels were reduced in all variant carriers. Interleukin-1β (IL-1β) and interleukin-8 (IL-8) levels were elevated in vitro, potentially contributing to the very high neutrophil counts observed during fasciitis episodes. Phosphorylation of p65/RelA was reduced in p.R157X neutrophils suggesting defective activation of canonical NF-κB. Oxidative burst after NF-κB-independent phorbol 12-myristate 13-acetate (PMA) stimulation was similar in both p.R157X and control neutrophils. Comparable amounts of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex subunits were found in p.R157X and control neutrophils. However, a compromised oxidative burst was observed in p.R157X neutrophils following activation of NF-κB-dependent mechanisms following stimulation of toll-like receptor 2 (TLR2) and Dectin-1. Neutrophil extracellular trap formation was not affected by p.R157X. In summary, the NFKB1 c.C936T/p.R157X LOF variant has an impact on inflammation and neutrophil function and may play a role in the pathogenesis of sterile necrotizing fasciitis.
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