University of Oulu

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 (2023).

Inflammation and neutrophil oxidative burst in a family with NFKB1 p.R157X LOF and sterile necrotizing fasciitis

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Author: Santaniemi, Wenny1; Åström, Pirjo1,2; Glumoff, Virpi1;
Organizations: 1Research Unit of Biomedicine, University of Oulu, Oulu, Finland
2Biocenter Oulu, University of Oulu, Oulu, Finland
3Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
4Institute for Molecular Medicine Finland, HiLIFE, University of Helsinki, Helsinki, Finland
5Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
6Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway
7Faculty of Medicine, Clinicum, Translational Immunology Program, University of Helsinki, Helsinki, Finland
8Department of Rheumatology, Inflammation Center, University of Helsinki and Helsinki University Hospital and Orton Orthopedic Hospital, Helsinki, Finland
9Adult Immunodeficiency Unit, Infectious Diseases, Inflammation Center, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
10Rare Disease Center and Pediatric Research Center, Children and Adolescents, University of Helsinki and HUS Helsinki University Hospital, Helsinki, Finland
11Infectious Diseases, Oulu University Hospital, Oulu, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 4 MB)
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Language: English
Published: Springer Nature, 2023
Publish Date: 2023-05-26


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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Series: Journal of clinical immunology
ISSN: 0271-9142
ISSN-E: 1573-2592
ISSN-L: 0271-9142
Issue: Online first
DOI: 10.1007/s10875-023-01461-3
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
Funding: Open Access funding provided by University of Oulu including Oulu University Hospital. This study was supported by Oulu University Hospital VTR (K74809) and Jane and Aatos Erkko foundation (KE, MS).
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