Background and Aims

The NF-κB family of transcription factors are essential for immune function. Mutations in NFKB1 and NFKB2 are the most prevalent monogenic causes of Common Variable Immunodeficiency (CVID). NF-κB activity is regulated by the IκB family of inhibitor proteins, including 3 atypical nuclear IκBs (Bcl-3, IκBζ, and IκBNS) that bind to NF-κB dimers at target gene promoters to provide additional regulation. Disruption of any one of these interactions may thus have significant impact on immune responses.

We identified biallelic loss-of-function mutations in NFKBID (encoding IκBNS) in 3 unrelated patients with antibody deficiency complicated by significant immune dysregulation. Two adult patients were identified (Royal Melbourne Hospital, Australia; Vall d’Hebron Hospital, Barcelona, Spain) and one child (Royal Children’s Hospital, Australia).

Aims:

1. Characterise the clinical spectrum of NFKBID-deficiency

2. Determine the cellular and regulatory consequences of NFKBID-deficiency

Methods

Comprehensive clinical and immunological characterisation of 3 patients was performed. IκBNS null leukocyte cell lines were generated (Jurkat, THP-1, Bjab) by CRISPR/Cas9 editing, representing key immune cell lineages with specific point mutations introduced, and NF-κB activity assessed.

Results

Both adult IκBNS-deficient patients developed a progressive dysregulatory immune phenotype with shared clinical features of severe dermatitis, autoimmune cytopenia and recurrent respiratory infections We identified defects in NFκB signalling both upstream and downstream of IκBNS, suggesting atypical IκB inhibitors also regulate expression and function of classical IκBs and underlie severe disease in patients.

Conclusions

Mutations in NFKBID represent a new inborn error of immunity due to aberrant NF-κB signalling and disruption of classical IκB inhibiror proteins.