Combined immunodeficiency with autoimmunity caused by a homozygous missense mutation in inhibitor of nuclear factor κB kinase alpha (IKKα)

Inhibitor of nuclear factor kappa B kinase alpha (IKK alpha) is critical for p100/NF-kappa B2 phosphorylation and processing into p52 and activation of the noncanonical NF-kappa B pathway. A patient with recurrent infections, skeletal abnormalities, absent secondary lymphoid structures, reduced B cell numbers, hypogammaglobulinemia, and lymphocytic infiltration of intestine and liver was found to have a homozygous p.Y580C mutation in the helix-loop-helix domain of IKK alpha. The mutation preserves IKK alpha kinase activity but abolishes the interaction of IKK alpha with its activator NF-kappa B-inducing kinase and impairs lymphotoxin-beta-driven p100/NF-kappa B2 processing and VCAM1 expression. Homozygous IKK alpha(Y580C/Y580C) mutant mice phenocopy the patient findings; lack marginal zone B cells, germinal centers, and antigen-specific T cell response to cutaneous immunization; have impaired Il17a expression; and are susceptible to cutaneous Staphylococcus aureus infection. In addition, these mice demonstrate a severe reduction in medullary thymic epithelial cells, impaired thymocyte negative selection, a restricted TCRV beta repertoire, a selective expansion of potentially autoreactive T cell clones, a decreased frequency of regulatory T cells, and infiltration of liver, pancreas, and lung by activated T cells coinciding with organ damage. Hence, this study identifies IKK alpha deficiency as a previously undescribed cause of primary immunodeficiency with associated autoimmunity.

Automated summary

The Y580C mutation in the helix-loop-helix domain of IKK alpha causes functional abnormalities, severely affecting immune system function, leading to primary immunodeficiency and autoimmune diseases in patients and mice.