Dominant-Negative Nfkbia Mutation Promotes Il-1 Beta Production Causing Hepatic Disease With Severe Immunodeficiency

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.