Immunodeficiency-15 (IMD15) 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 ... Immunodeficiency-15 (IMD15) 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).
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 ... 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.
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 ... 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).