Immunodeficiency 14

A number sign (#) is used with this entry because of evidence that immunodeficiency-14 (IMD14) is caused by heterozygous mutation in the PIK3CD gene (602839) on chromosome 1p36.

Description

Immunodeficiency-14 is an autosomal dominant primary immunodeficiency characterized by onset of recurrent sinopulmonary and other infections in early childhood. Laboratory studies show defects in both B- and T-cell populations, with an inability to control infection with Epstein Barr-virus (EBV) and cytomegalovirus (CMV). Patient CD8+ T cells are skewed toward differentiation and senescence. Many patients develop lymphadenopathy, mucosal lymphoid aggregates, and/or increased serum IgM. There is also an increased susceptibility to B-cell lymphomas (summary by Lucas et al., 2014).

Clinical Features

Jou et al. (2006) reported a Taiwanese boy of Chinese descent with primary B-cell immunodeficiency. He had had hypogammaglobulinemia and recurrent sinopulmonary infections since 7 months of age. He was an only child, and there was no family history of a similar disorder.

Angulo et al. (2013) identified 17 patients from 7 families with a primary immunodeficiency characterized by recurrent respiratory infections and progressive airway damage. Whereas the immunologic phenotype was largely consistent between patients, the clinical presentation and disease course were variable. All patients had recurrent respiratory and ear infections caused by H. influenzae and S. pneumoniae. Twelve of 16 (75%) had CT evidence of bronchiectasis or mosaic attenuation airway disease. Ninety-one percent had low or intermittently low serum IgG2 levels and 82% had high or intermittently high serum IgM levels. All had low levels of antibodies to S. pneumoniae and 80% had low levels of antibodies to H. influenzae type B. Ten of 17 had splenomegaly before the onset of recurrent infections. Seven of 17 (41%) had cellulitis or abscess formation. Four of 17 (24%) had infection by the herpesvirus group (HSV, CMV, VZV, and EBV). Only 1 was reported to have a marginal zone lymphoma. Twelve of 17 had decreased circulating T cells (total CD3+) and/or CD4+ and/or CD8+ T cells. Twelve of 17 also had decreased circulating B cells (total CD19+). Fourteen of 16 patients (88%) had increased circulating transitional B cells (CD19+CD38+IgM+). Half the patients had decreased circulating class-switched memory B cells (CD19+CD27+IgD-).

Lucas et al. (2014) reported 9 patients from 7 unrelated families with IMD14. All presented in childhood with recurrent sinopulmonary infections and EBV viremia, and most had chronic CMV infection. Two patients developed EBV-positive lymphoma. Other features included lymphadenopathy and mucosal lymphoid aggregates. Laboratory studies showed decreased numbers of CD4+ T cells with increased numbers of CD8+ effector T cells. T-cell mitogen responses in vitro were poor. There was a deficiency of memory CD27+ B cells and enrichment of immature transitional B cells. Most patients had hypogammaglobulinemia and 4 had increased IgM, indicating impaired class-switched immunoglobulin isotypes.

Crank et al. (2014) reported 3 patients from 2 unrelated families with IMD14. Each had had recurrent infections since childhood associated with increased serum IgM but with low levels of other antibodies. CD4+ T cells were decreased. All 3 patients had a history of lymphadenopathy and also developed non-EBV B-cell lymphomas.

Inheritance

The transmission pattern of IMD14 in the families reported by Lucas et al. (2014) was consistent with autosomal dominant inheritance.

Molecular Genetics

In a Taiwanese boy of Chinese descent with primary B-cell immunodeficiency, Jou et al. (2006) identified a heterozygous missense mutation in the PIK3CD gene (E1021K; 602839.0001). Functional studies of the variant were not performed. The PIK3CD gene was chosen for study because Pik3cd-null mice show a B-cell immunodeficiency; the patient was the only one of 15 probands with immunodeficiency who was found to carry a pathogenic PIK3CD mutation.

Angulo et al. (2013) used exome sequencing to search for causative mutations in 35 primary immunodeficiency (PID) patients from the United Kingdom who suffered from recurrent infections and had a family history of susceptibility to infections. They identified 3 patients from 1 family and 1 patient from another family who had the same heterozygous E1021K mutation in the PIK3CD gene. Sanger sequencing confirmed the presence of this mutation in the families. Angulo et al. (2013) then screened for the mutation in 3,346 healthy subjects from around the world and did not identify it. Subsequently, DNA samples from an additional heterogeneous cohort of 134 PID patients from the United Kingdom and Ireland were screened, and 5 further patients from 3 unrelated families had the same mutation. Since 1 of these patients had been diagnosed with hyper-IgM syndrome (see 308230), the authors studied an additional 15 hyper-IgM patients from 13 French families who had undergone exome sequencing. In that group, Angulo et al. (2013) found 3 patients from 2 unrelated families with the E1021K mutation, indicating that this mutation may cause a typical hyper-IgM syndrome. In 1 family (P8) the mutation occurred as a de novo event. No shared haplotypes were found among the other families, suggesting that this mutation is recurring rather than a founder effect. Prior to genetic analysis, patients from families A to G were not considered to have the same disease etiology.

In 14 patients from 7 unrelated families with IMD14, Lucas et al. (2014) identified 3 different heterozygous gain-of-function mutations in the PIK3CD gene (602839.0001-602839.0003). The mutations were found by whole-exome sequencing and targeted Sanger sequencing. Studies of patient-derived cells and control cells showed that the mutations caused increased phosphorylation of AKT (164730) compared to wildtype PIK3CD, consistent with a gain of function. Patient CD8+ T cells had an effector memory phenotype and were more activated compared to controls, suggesting that a large proportion of these cells are in a terminally differentiated state with a corresponding low proliferative capacity. Patient T cells showed hyperphosphorylation of the downstream mTOR (601231) signaling pathway, which resulted in increased glucose usage in the cells and predisposition to differentiation and senescence. Treatment of 1 patient with rapamycin, which inhibits mTOR, resulted in a reduction in CD8+ T cells to normal numbers and an increase in naive T cells.

In 3 patients from 2 unrelated families with IMD14 manifest as hyper IgM and B-cell lymphoma, Crank et al. (2014) identified 2 heterozygous gain-of-function mutations in the PIK3CD gene (602839.0001 and 602839.0004).

Pathogenesis

Angulo et al. (2013) showed that the E1021K mutation in PIK3CD enhanced membrane association and kinase activity of p110-delta. Patient-derived lymphocytes had increased levels of phosphatidylinositol 3,4,5-trisphosphate and phosphorylated AKT protein and were prone to activation-induced cell death. Selective p110-delta inhibitors reduced the activity of the mutant enzyme in vitro, suggesting a therapeutic approach for patients with APDS.

Animal Model

Okkenhaug et al. (2002) generated mice expressing a catalytically inactive form of Pik3cd (asp910 to ala). They observed impaired signaling and attenuated immune responses by antigen receptors of B and T cells from these mice. The presence of Pik3ca (171834) and Pik3cb (602925) did not compensate for Pik3cd in immune function. The mutant mice also developed inflammatory bowel disease.