Immunodeficiency 15a

A number sign (#) is used with this entry because of evidence that immunodeficiency 15A is caused by heterozygous missense mutation in the IKBKB gene (603258) on chromosome 8p11.

Homozygous mutation in IKBKB results in the more severe immunodeficiency IMD15B (615592).

Description

Immunodeficiency 15A is an autosomal dominant primary immunodeficiency disorder characterized by relatively late onset of recurrent respiratory tract infections and lymphopenia, combined with immune activation of both CD4+ and CD8+ T cells. One patient presented with inflammatory disease and possible ectodermal defect.

Clinical Features

Cardinez et al. (2018) reported 2 families in which the probands presented with immune dysregulation, combined T and B cell deficiency, inflammation, and epithelial defects. The first proband was an adult woman who presented with recurrent respiratory tract infections, severe and atypical eczema, dental abnormalities consistent with ectodermal dysplasia (without conical teeth), hidradenitis suppurativa and subcutaneous abscesses, mucocutaneous candidiasis, and premature cataracts. The 2 parents of the woman were alive and had no evidence of immune deficiency or dysregulation. She had 2 children, aged 2 years and 5 years, who both suffered from recurrent otitis media and sinusitis but had no inflammation or ectodermal dysplasia. Initial cellular analysis of peripheral blood mononuclear cells isolated from the proband and both children revealed lymphopenias. One child and the proband exhibited T cell deficiency, and the other child exhibited a reduction in total lymphocytes for age. Lymphopenia was a fixed phenotype in the proband, with no significant change over at least 7 years of observation. In addition, she had mild hypogammaglobulinemia and defective specific antibody responses to pneumococcal vaccination. The second proband was a 33-year-old male from an unrelated and geographically remote family who had a history of recurrent respiratory infections, otitis media, and tonsillitis since childhood. He was noted to have hypogammaglobulinemia at age 18 years and subcutaneous abscesses at age 28 years. Further investigations revealed bronchiectasis and hepatosplenomegaly. Probands of both kindreds exhibited deficiencies of CD4+ and CD8+ T cells, with a significant reduction in naive T cells in both compartments. Both had a significant increase in circulating follicular helper T cells as well as a significant deficiency of memory B cells. Transitional B cells were numerically normal but were universally CD21(hi)/CD10+. There was increased activation of naive CD4+ T cells from one proband. There was also a significant increase in circulating regulatory T cells in the first, but not the second, proband.

Molecular Genetics

In probands from 2 unrelated families with an immune deficiency with combined T and B cell deficiency as well as immune activation of both CD4+ and CD8+ T cells (IMD15A), Cardinez et al. (2018) identified the same de novo missense mutation in the IKBKB gene (V203I; 603258.0003). This mutation changes the highly conserved valine at position 203, which is conserved to at least Drosophila melanogaster and is located within the active site of IKK2 on the second lobe of the kinase domain, which phosphorylates the N-terminal region of IKB-alpha (NFKBIA; 164008) and leads to activation of NF-kappa-B (see 164011). The mutant protein was predicted to assume an unstable conformation, while maintaining its kinase activity, but disrupting the tetrameric interaction of IKK2.

Animal Model

Cardinez et al. (2018) engineered a G-to-A transition in codon 203 of mouse Ikbkb using CRISPER/CAS9. The mutant allele was propagated, and heterozygous and homozygous mice were born at expected Mendelian ratios. Analysis of isolated splenocytes revealed constitutive IKBA phosphorylation, with evidence of a gene dose effect: phosphorylation was greater in cells with homozygous mutation compared with heterozygotes, both at baseline and for at least 120 minutes after stimulation. This result, taken together with transfection results, and analysis of cells from the proband, confirmed that the V203I mutation confers gain of function on IKK2. These findings were consistent with previously reported results for the same mutation identified as a somatic mutation in patients with central nervous system B cell lymphoma, where gain of function was demonstrated biochemically (Fukumura et al., 2016).