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

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SCHOOL OF MEDICINE
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Tan, Enrica E. K.
Hopkins, Richard A.
Lim, Chrissie K.
Jamuar, Saumya S.
Ong, Christina
Thoon, Koh C.
Koh, Mark J. A.
Shin, Eun Mong
Lian, Derrick W. Q.
Weerasooriya, Madhushanee

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Abstract

Although IKK-beta has previously been shown as a negative regulator of IL-1 beta secretion in mice, this role has not been proven in humans. Genetic studies of NF-kappa B signaling in humans with inherited diseases of the immune system have not demonstrated the relevance of the NF-kappa B pathway in suppressing IL-1 beta 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 I kappa B alpha variant that severely repressed NF-kappa B activation and downstream cytokine production. Paradoxically, IL-1 beta 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-1 beta 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-1 beta release from stimulated leukocytes. Additional therapeutic blockade of IL-1 ameliorated liver damage, while decreasing neutrophil activation and associated IL-1 beta secretion. Our studies reveal a previously unrecognized role of human I kappa B alpha as an essential regulator of canonical NF-kappa B 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-kappa B inhibition.

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AMER SOC CLINICAL INVESTIGATION INC

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Medicine, Medicine, experimental

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JOURNAL of CLINICAL INVESTIGATION

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DOI

10.1172/JCI98882

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