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

J Clin Invest. 2020 Nov 2;130(11):5817-5832. doi: 10.1172/JCI98882.

Abstract

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.

Keywords: Immunology; Immunotherapy; Inflammation.

MeSH terms

  • Allografts
  • Animals
  • Female
  • Genes, Dominant*
  • HEK293 Cells
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Interleukin-1beta* / genetics
  • Interleukin-1beta* / immunology
  • Liver Diseases* / genetics
  • Liver Diseases* / immunology
  • Liver Diseases* / therapy
  • Male
  • Mice
  • Mutation*
  • NF-KappaB Inhibitor alpha* / genetics
  • NF-KappaB Inhibitor alpha* / immunology
  • Neutropenia / genetics
  • Neutropenia / immunology
  • Neutropenia / therapy
  • Severe Combined Immunodeficiency* / genetics
  • Severe Combined Immunodeficiency* / immunology
  • Severe Combined Immunodeficiency* / therapy
  • Signal Transduction / genetics
  • Signal Transduction / immunology

Substances

  • IL1B protein, human
  • IL1B protein, mouse
  • Interleukin-1beta
  • NFKBIA protein, human
  • Nfkbia protein, mouse
  • NF-KappaB Inhibitor alpha