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Inflammation and Neutrophil Oxidative Burst in a Family with NFKB1 p.R157X LOF and Sterile Necrotizing Fasciitis.

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.

SUBMITTER: Santaniemi W

PROVIDER: S-EPMC10276129 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Inflammation and Neutrophil Oxidative Burst in a Family with NFKB1 p.R157X LOF and Sterile Necrotizing Fasciitis.

Santaniemi Wenny W Åström Pirjo P Glumoff Virpi V Pernaa Nora N Tallgren Ella-Noora EN Palosaari Sanna S Nissinen Antti A Kaustio Meri M Kuismin Outi O Saarela Janna J Nurmi Katariina K Eklund Kari K KK Seppänen Mikko R J MRJ Hautala Timo T

Journal of clinical immunology 20230309 5

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 m ...[more]

PMID: 36892687

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Project description:ObjectivesThe Laboratory Risk Indicator for Necrotizing Fasciitis score was developed as a clinical decision tool for distinguishing necrotizing fasciitis from other soft tissue infections. We prospectively evaluated the performance of the Laboratory Risk Indicator for Necrotizing Fasciitis score for the diagnosis of patients with necrotizing fasciitis in the extremities.MethodsWe conducted a prospective and observational cohort study of emergency department patients with necrotizing fasciitis or severe cellulitis in the extremities between April 2015 and December 2016. The Laboratory Risk Indicator for Necrotizing Fasciitis score was calculated for every enrolled patient. The sensitivity, specificity, positive predictive value, and negative predictive value of cut-off scores of 6 and 8 were evaluated. The accuracy of the Laboratory Risk Indicator for Necrotizing Fasciitis score was expressed as the area under the receiver operating characteristic curve.ResultsA total of 106 patients with necrotizing fasciitis and 825 patients with cellulitis were included. With an Laboratory Risk Indicator for Necrotizing Fasciitis cut-off score ≥6, the sensitivity was 43% (95% confidence interval 34% to 53%), specificity was 83% (95% confidence interval 80% to 86%), positive predictive value was 25% (95% confidence interval 20% to 30%), and negative predictive value was 92% (95% confidence interval 91% to 93%); with an Laboratory Risk Indicator for Necrotizing Fasciitis cut-off score ≥8, the sensitivity was 27% (95% confidence interval 19% to 37%), specificity was 93% (95% confidence interval 91% to 94%), positive predictive value was 33% (95% confidence interval 25% to 42%), and negative predictive value was 91% (95% confidence interval 90% to 92%). The area under the receiver operating characteristic curve for accuracy of the Laboratory Risk Indicator for Necrotizing Fasciitis score was 0.696 (95% CI 0.640 to 0.751).ConclusionThe Laboratory Risk Indicator for Necrotizing Fasciitis score may not be an accurate tool for necrotizing fasciitis risk stratification and differentiation between severe cellulitis and necrotizing fasciitis in the emergency department setting based on our study.

Dataset Information

Inflammation and Neutrophil Oxidative Burst in a Family with NFKB1 p.R157X LOF and Sterile Necrotizing Fasciitis.

Publications

Inflammation and Neutrophil Oxidative Burst in a Family with NFKB1 p.R157X LOF and Sterile Necrotizing Fasciitis.

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