Immunodeficiency 32b

A number sign (#) is used with this entry because of evidence that immunodeficiency-32B (IMD32B) is caused by homozygous or compound heterozygous mutation in the IRF8 gene (601565) on chromosome 16q24.

Immunodeficiency-32A (IMD32A; 614893), an autosomal dominant disorder, is allelic.

Description

Immunodeficiency-32B is an autosomal recessive primary immunodeficiency characterized by recurrent infections resulting from variable defects in immune cell development or function, including monocytes, dendritic cells, and natural killer (NK) cells. Patients have particular susceptibility to viral disease (summary by Mace et al., 2017).

Clinical Features

Fleisher et al. (1982) reported a family in which 3 sibs had an immunodeficiency syndrome characterized by susceptibility to Epstein-Barr virus (EBV). One patient was a 16-year-old boy with a history of recurrent sinusitis, otitis, and pneumonia, followed by progressive bronchiectasis; he developed infectious mononucleosis at age 16 and died on the 26th day of illness from 'uncontrollable hemorrhage and multiple organ failure.' A sister with a history of recurrent pneumonia and bronchiectasis developed infectious mononucleosis at age 17 but recovered. A brother with a history of recurrent infections including pneumonia but no bronchiectasis developed infectious mononucleosis at age 22 but recovered after a severe illness. Another brother developed infectious mononucleosis at age 21 and recovered completely in 2 months; he had not had recurrent infections. The patients produced a full spectrum of antibodies to EBV, but NK cell activity was markedly deficient compared to controls. Mace et al. (2017) provided follow-up of the family reported by Fleisher et al. (1982). Only 1 affected sib was still alive; he had recurrent respiratory infections, but no bronchiectasis or lymphadenopathy, and T- and B-cell counts were consistently normal. The patient had decreased NK cells and a subtle decrease in dendritic cells.

Joncas et al. (1984) described father and daughter with chronic infection by EBV. Infection with EBV persisted for 4 years in the daughter and at least 3 years, perhaps 10 years, in the father. Both had persistent splenomegaly and occasional bouts of unexplained fever. The mother and a son were healthy. A deficiency of natural killer-cell activity was recognized in this family.

Hambleton et al. (2011) reported a female infant who presented at 10 weeks of age with failure to thrive, oral candidiasis, and early-onset disseminated BCG disease. The authors noted florid myeloproliferation. The infant had a profound deficit of tissue dendritic cells and blood dendritic cells and monocytes, along with a variable deficit of tissue macrophages and normal numbers of Langerhans cells. She gradually improved with antimycobacterial and antibacterial therapy. However, at the age of 6 months, she exhibited respiratory failure and fever and deteriorated further, and only rhinovirus was present in respiratory secretions. The infant underwent hematopoietic stem cell transplantation and was well 12 months posttransplantation, with minimal medication and moderate developmental delay. The child was born of healthy unrelated parents of Irish ancestry and had a healthy older sib. All 4 family members received BCG, which only resulted in illness in the proband. Hambleton et al. (2011) stated that this patient had normal numbers of B cells and NK cells, but Mace et al. (2017) stated that she had decreased numbers of NK cells with an expanded CD56-bright population, indicating aberrant generation of terminally mature subsets of NK cells.

Inheritance

The transmission pattern of IMD32B in the family reported by Fleisher et al. (1982) was consistent with autosomal recessive inheritance.

Molecular Genetics

In the only surviving sib from the family reported by Fleisher et al. (1982) with IMD32B, Mace et al. (2017) identified compound heterozygous missense mutations in the IRF8 gene (A201V, 601565.0003 and P224L, 601565.0004). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Studies of patient B cells showed normal IRF8 expression and nuclear localization. The patient had decreased numbers of NK cells and significantly decreased NK cell cytotoxic function. Detailed analysis of patient NK cells showed increased CD56-bright cells and decreased CD56-dim cells compared to controls, indicating a defect in terminal differentiation of NK cells. Gene expression analysis showed dysregulation of multiple genes involved in NK-cell maturation and function.

In the Irish infant with autosomal recessive monocyte and dendritic cell deficiency, myeloproliferation, and susceptibility to severe opportunistic infections consistent with IMD32B, Hambleton et al. (2011) identified a homozygous lys108-to-glu (K108E; 601565.0001) mutation in the DNA-binding domain of IRF8. In transfected mouse macrophages, the mutant protein bound poorly to IL12B (161561) and NOS2 (163730) promoters, probably due to prevention of hydrogen bond formation. The infant's healthy parents, who were heterozygous for K108E, and an unaffected sib, who lacked the K108E allele, had normal peripheral blood mononuclear cell and dendritic cell numbers. The K108E mutation was not present in 454 unrelated individuals with susceptibility to mycobacterial disease (see 209950).

Animal Model

Mace et al. (2017) found that Irf8-null mice had splenomegaly, lymphocytosis, and an increase in the subset of immature NK cells compared to controls, suggesting an impairment in terminal differentiation of NK cells.