NF-κB pathway variants in Iranian patients with inborn errors of immunity

Clinical and immunological manifestations associated with genetic alterations are crucial for understanding inborn errors of immunity (IEI). This study aims to characterize the clinical and immunological profiles and provide the molecular features of IEI patients from the Iranian population with IEI who harbor rare variants in the nuclear factor kappa B (NF-κB) pathway.

Peripheral blood mononuclear cells (PBMCs) were used for immunophenotyping of B and T lymphocyte subsets via flow cytometry and for assessing T cell proliferation. Immunoblotting was performed to evaluate the expression levels of NF-κB proteins.

This multi-center study enrolled 16 patients with mutations in the NFKB1, NFKB2, IKBKB, and IKBKG genes. NFKB1 and NFKB2 mutations were heterozygous, while IKBKB mutations were homozygous, and the IKBKG mutation was hemizygous. Patients exhibited hypogammaglobulinemia and switched memory B cell abnormalities. Immunoblotting revealed decreased NF-κB1 protein expression in most cases. Similarly, NFKB2 mutations led to lower protein expression in unstimulated PBMCs, with mild to strong reductions after stimulation, though some cases showed no significant changes.

This study identifies novel IEI cases associated with NF-κB pathway defects. Further comprehensive evaluation and functional analysis of these mutations are warranted to confirm their impact on disease manifestation.