Immunodeficiency 15b

A number sign (#) is used with this entry because of evidence that immunodeficiency-15B (IMD15B) is caused by homozygous mutation in the IKBKB gene (603258) on chromosome 8p11.

Heterozygous mutation in IKBKB results in IMD15A (618204), a less severe immunodeficiency with later onset.

Description

Immunodeficiency-15B (IMD15B) is an autosomal recessive primary immunodeficiency disorder characterized by onset in infancy of life-threatening bacterial, fungal, and viral infections and failure to thrive. Laboratory studies show hypo- or agammaglobulinemia with relatively normal numbers of B and T cells. However, functional studies show impaired differentiation and activation of immune cells (summary by Pannicke et al., 2013).

Clinical Features

Pannicke et al. (2013) reported 4 patients of Northern Cree ancestry from the Manitoba and Saskatchewan regions of Canada who presented shortly after birth with a clinical phenotype consistent with severe combined immunodeficiency (SCID). No close family connection among these patients was known. The patients presented within the first months of life with numerous bacterial, fungal, and viral infections, including candidiasis, pneumonia, bacteremia and sepsis, meningitis, and osteomyelitis. Multiple and variable organisms were isolated from the patients, including E. coli, Mycobacterium avium, Listeria monocytogenes, pneumococcus, Serratia marcescens, and Klebsiella. Other features included chronic diarrhea and failure to thrive. Two patients died in infancy. One patient underwent successful bone marrow transplant and another had successful cord blood transplant. An affected sib of 1 patient died at age 14 months. Postmortem examination of 1 patient showed small spleen, small thymus, and lack of lymph nodes in the neck and mesentery; some lymphoid aggregates were devoid of germinal centers. Laboratory studies showed hypogammaglobulinemia or agammaglobulinemia in all patients, with normal numbers of B cells in all except 1. All had normal T-cell counts, and 3 had decreased NK cells. Early lymphocyte development was normal, but subsequent differentiation and proliferation of these cells was deficient. None of the patients had evidence of liver damage.

Nielsen et al. (2014) reported a female infant, born of consanguineous Turkish parents, with severe immunodeficiency resulting in death at age 14 months. After uneventful vaccination with BCG, she presented at age 5 months with fungal pneumonia (Pneumocystis jirovecii). Immunologic workup showed increased serum IgM, absence of isotype-switched memory B cells, and low numbers of CD45R0+ memory T cells. At age 9 months, she presented with systemic infection by Mycobacterium bovis. Despite intense treatment, she died of cardiac arrest.

Inheritance

The transmission pattern of IMD15B in the families reported by Pannicke et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 4 patients of Cree ancestry with primary immunodeficiency, Pannicke et al. (2013) identified a homozygous truncating mutation in the IKBKB gene (c.1292dupG; 603258.0001), resulting in complete loss of protein function. The mutation was found by homozygosity mapping followed by sequencing of the genes within the candidate region on chromosome 8p. Functional and gene expression studies of patient fibroblasts showed variable effects on receptor activation and NFKB signaling involved in immunity. There was impaired phosphorylation of NFKBIA (164008) in response to stimulation with TNFA (191160) and flagellin, which acts through TLR5 (603031), but only a marginally impaired response to IL1B (147720). IL6 (147620) response to TNFA was normal, but it was reduced in response to lipopolysaccharide, with acts through TLR4 (603030). These studies showed selective dependence of the regulation of NFKB target genes on IKBKB function. Patient peripheral blood B and T cells were almost exclusively of the naive type, and B, T, and NK cells showed poor differentiation or mitogenic responses under certain conditions. These findings were consistent with the role of IKBKB in transmitting signals by various surface receptors. Pannicke et al. (2013) noted that the phenotype in these patients with null mutations in IKBKB is not as severe as that in the null mouse model, which is lethal (Li et al., 1999).

In a Turkish infant, born of consanguineous parents, with fatal IMD15B, Nielsen et al. (2014) identified a homozygous truncating mutation in the IKBKB gene (R272X; 603258.0002). The mutation was found by whole-exome sequencing. Western blot analysis of patient cells showed a complete lack of the IKBKB protein, although IKKA (CHUK; 600664) and NEMO (IKBKG; 300248) levels were similar to control. Stimulation of patient T cells failed to result in phosphorylation of p65 (NFKB3; 164014), and patient T cells failed to proliferate in response to stimulation. The findings indicated that IKBKB is critical for activation of T cells and differentiation of B cells.