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

Autor:	Tan EE; Department of Paediatric Subspecialties, KK Women's and Children's Hospital, Singapore.; Duke-NUS Medical School, Singapore., Hopkins RA; Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore., Lim CK; Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore., Jamuar SS; Department of Paediatric Subspecialties, KK Women's and Children's Hospital, Singapore.; Duke-NUS Medical School, Singapore., Ong C; Duke-NUS Medical School, Singapore.; Department of Paediatrics and., Thoon KC; Duke-NUS Medical School, Singapore.; Department of Paediatrics and., Koh MJ; Duke-NUS Medical School, Singapore.; Dermatology Service, KK Women's and Children's Hospital, Singapore., Shin EM; Institute of Molecular and Cell Biology, A*STAR, Singapore.; Cancer Science Institute of Singapore, Singapore.; National University of Singapore, Singapore., Lian DW; Department of Paediatric Subspecialties, KK Women's and Children's Hospital, Singapore.; Duke-NUS Medical School, Singapore.; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Weerasooriya M; Department of Microbiology and Immunology and.; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore., Lee CZ; Singapore Immunology Network and., Soetedjo AAP; Institute of Molecular and Cell Biology, A*STAR, Singapore., Lim CS; Institute of Molecular and Cell Biology, A*STAR, Singapore., Au VB; Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore., Chua E; Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore., Lee HY; Institute of Molecular and Cell Biology, A*STAR, Singapore., Jones LA; Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore., James SS; Department of Microbiology and Immunology and.; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore., Kaliaperumal N; Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore., Kwok J; Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore., Tan ES; Duke-NUS Medical School, Singapore.; Department of Paediatrics and., Thomas B; Duke-NUS Medical School, Singapore.; Department of Paediatrics and., Wu LX; Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore., Ho L; Institute of Molecular and Cell Biology, A*STAR, Singapore., Fairhurst AM; Institute of Molecular and Cell Biology, A*STAR, Singapore., Ginhoux F; Singapore Immunology Network and., Teo AK; Institute of Molecular and Cell Biology, A*STAR, Singapore., Zhang YL; Department of Microbiology and Immunology and.; Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore., Ong KH; Institute of Molecular and Cell Biology, A*STAR, Singapore., Yu W; Institute of Molecular and Cell Biology, A*STAR, Singapore., Venkatesh B; Institute of Molecular and Cell Biology, A*STAR, Singapore., Tergaonkar V; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.; Laboratory of NF-κB Signaling, Institute of Molecular and Cell Biology, A*STAR, Singapore.; Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.; Faculty of Health Sciences, University of Macau, Macau, China., Reversade B; Institute of Molecular and Cell Biology, A*STAR, Singapore.; Department of Medical Genetics, School of Medicine, Koç University, Istanbul, Turkey.; Department of Paediatrics, National University of Singapore, Singapore.; Institute of Medical Biology, A*STAR, Singapore., Chin KC; Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore.; Department of Physiology and., Tan AM; Singapore Immunology Network and., Liew WK; Duke-NUS Medical School, Singapore.; Department of Paediatrics and., Connolly JE; Program in Translational Immunology, Institute of Molecular and Cell Biology, A*STAR, Singapore.; Department of Paediatrics and.; Department of Microbiology and Immunity, National University of Singapore, Singapore.; Institute of Biomedical Studies, Baylor University Medical Center, Waco, Texas, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2020 Nov 02; Vol. 130 (11), pp. 5817-5832.
DOI:	10.1172/JCI98882
Abstrakt:	Although 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.
Databáze:	MEDLINE
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