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Dominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency

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dc.contributor.authorTan, E.E.K.
dc.contributor.authorHopkins, R.A.
dc.contributor.authorLim, C.K.
dc.contributor.authorJamuar, S.S.
dc.contributor.authorTergaonkar, V.
dc.contributor.authorConnolly, J.E.
dc.date.issued2020
dc.descriptionLink to a related website: http://www.jci.org/articles/view/98882/files/pdf, Open Access via Unpaywall
dc.description.abstractAlthough IKK-β has previously been shown as a negative regulator of IL-1β secretion in mice, this role has not been proven in humans. Genetic studies of NF-κB signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-κB pathway in suppressing IL-1β expression. Here, we report an infant with a clinical pathology comprising neutrophil-mediated autoinflammation and recurrent bacterial infections. Whole-exome sequencing revealed a de novo heterozygous missense mutation of NFKBIA, resulting in a L34P IκBα variant that severely repressed NF-κB activation and downstream cytokine production. Paradoxically, IL-1β secretion was elevated in the patient’s stimulated leukocytes, in her induced pluripotent stem cell–derived macrophages, and in murine bone marrow–derived macrophages containing the L34P mutation. The patient’s hypersecretion of IL-1β correlated with activated neutrophilia and liver fibrosis with neutrophil accumulation. Hematopoietic stem cell transplantation reversed neutrophilia, restored a resting state in neutrophils, and normalized IL-1β release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1β secretion. Our studies reveal a previously unrecognized role of human IκBα as an essential regulator of canonical NF-κB signaling in the prevention of neutrophil-dependent autoinflammatory diseases. These findings also highlight the therapeutic potential of IL-1 inhibitors in treating complications arising from systemic NF-κB inhibition.
dc.identifier.citationJournal of Clinical Investigation, 2020; 130(11):5817-5832
dc.identifier.doi10.1172/JCI98882
dc.identifier.issn0021-9738
dc.identifier.issn1558-8238
dc.identifier.urihttps://hdl.handle.net/11541.2/145448
dc.language.isoen
dc.publisherAmerican Society for Clinical Investigation
dc.rightsCopyright 2020 American Society for Clinical Investigation
dc.source.urihttps://doi.org/10.1172/JCI98882
dc.subjectNFKBIA mutation
dc.subjecthepatic disease
dc.titleDominant-negative NFKBIA mutation promotes IL-1β production causing hepatic disease with severe immunodeficiency
dc.typeJournal article
pubs.publication-statusPublished
ror.mmsid9916460906001831

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