Immunodeficiency, Common Variable, 3

A number sign (#) is used with this entry because of evidence that this form of common variable immunodeficiency, referred to here as CVID3, is caused by homozygous or compound heterozygous mutation in the CD19 gene (107265) on chromosome 16p11.2.

For a general description and a discussion of genetic heterogeneity of common variable immunodeficiency, see CVID1 (607594).

Van Zelm et al. (2006) evaluated 4 patients from 2 unrelated families who had increased susceptibility to infection, hypogammaglobulinemia, and normal numbers of mature B cells in blood, indicating a B-cell antibody-deficient immunodeficiency disorder. The disorder was consistent with a clinical diagnosis of common variable immunodeficiency syndrome. One family included 3 Colombian sibs examined at 35, 33, and 49 years of age, respectively. All 3 sibs had had otitis media, sinusitis, and pharyngitis during childhood. In addition, 1 had had 4 bouts of pneumonia between the ages of 18 and 35 years; he had received diagnoses of bacterial conjunctivitis and chronic gastritis (Helicobacter pylori infection). The proband of the other family was a Turkish girl, born of consanguineous parents, with a history of recurrent bronchiolitis and bronchopneumonia starting at 1 year of age and meningitis starting at 8 years of age. A diagnosis of postinfectious glomerulonephritis was made at the age of 10 years, at which time she was found to have hypogammaglobulinemia.

Artac et al. (2010) identified a Turkish patient with CVID3 who was related to the patient reported by van Zelm et al. (2006). Both patients came from a very large consanguineous kindred. Artac et al. (2010) identified and examined 30 members of this kindred who were carriers of a heterozygous truncating mutation in the CD19 gene (107265.0001) and found that none had clinical signs of immunodeficiency. Flow cytometric analysis of carrier lymphocytes found no significant difference in B-cell, T-cell, or NK-cell subset numbers between carriers and noncarriers. CD19 and CD21 (120650) expression levels on B lymphocytes were significantly decreased in carriers compared to noncarriers, and some carriers had decreased proportions of transitional and CD5+ B cells. Somatic hypermutation was not significantly affected in carriers. The findings suggested that carriers of CVID3 mutations may have alterations in the naive B-cell department, but they do not have clinical signs of immunodeficiency or evidence of autoimmune phenomena.

Kanegane et al. (2007) reported a Japanese boy with CVID3 characterized by recurrent infections, including pyelonephritis and gastritis beginning around age 5 years. Laboratory studies showed hypogammaglobulinemia and no antibody response to prior vaccinations. He also had mild thrombocytopenia. Patient B cells showed lack of CD19 membrane expression, as well as decreased expression of CD21. The patient also had a decrease in Ig class-switched memory B cells compared to controls. However, in vitro studies indicated that the remaining memory B cells were capable of somatic hypermutation, could undergo proliferation upon stimulation, and could produce normal levels of IgM.

Van Zelm et al. (2011) reported a 6-year-old Moroccan boy, born of consanguineous parents, with CVID3. He had a history of recurrent respiratory bacterial infections and septicemia associated with hypogammaglobulinemia. He had poor antibody response to vaccination, and responded well to immunoglobulin therapy. T-cell and NK cell function were normal. Flow cytometric analysis showed decreased numbers of memory B cells and absence of CD19 expression on B cells.

Vince et al. (2011) reported a 31-year-old woman, born of consanguineous Moroccan parents, with CVID3 and a somewhat unusual phenotype. She had clinical evidence of immunodeficiency, such as recurrent respiratory infections, but the major complication was progressive IgA nephropathy and glomerulonephritis resulting in end-stage renal disease. Laboratory studies showed that she had protective levels of antibodies to vaccinations, had selective IgG1 deficiency, and normal levels of IgD-CD27+ switched memory and IgD+CD27- naive B cells. Most of the B cells lacked expression of CD19.

In all 4 patients reported by van Zelm et al. (2006), laboratory studies showed decreased levels of CD21 (120650), but normal levels of CD81 (186845) and CD225 (IFITM1; 604456). The composition of the precursor B-cell compartment in bone marrow and the total number of B cells in blood were normal. However, the number of CD27-positive (186711) memory B cells and CD5-positive (153340) B cells were decreased. Secondary follicles in lymphoid tissues were small to normal in size and had a normal cellular composition. The few B cells that showed molecular signs of switching from one immunoglobulin class to another contained V(H)-C(alpha) and V(H)-C(gamma) transcripts with somatic mutations. The response of the patients' B cells to in vitro stimulation through the B-cell receptor was impaired, and in all 4 patients, the antibody response to rabies vaccination was poor.

Using flow cytometric analysis, van Zelm et al. (2014) found reduced numbers of all memory B-cell subsets except CD27-negative/IgA-positive B cells in both CD19-deficient patients and CD40L (CD40LG; 300386)-deficient patients compared with controls. Analysis of transcripts after class switching demonstrated that patient transcripts had fewer somatic mutations and reduced usage of IgG2 and IgA2 subclasses. There was also a deficiency in selection strength of mutations for antigen binding in patients compared with controls, whereas selection to maintain superantigen binding was normal. Selection against the autoreactive properties of immunoglobulins was impaired in patients. Somatic hypermutation analysis revealed decreased AICDA (605257) and UNG (191525) activity in CD40L deficiency, but increased UNG activity and decreased mismatch repair in CD19 deficiency. Van Zelm et al. (2014) concluded that both the B-cell antigen receptor and CD40 signaling pathways are required for selection of immunoglobulin reactivity, but that they differentially mediate DNA repair pathways during somatic hypermutation and thereby together shape the mature B-cell repertoire.

The transmission pattern of CVID3 in the family reported by van Zelm et al. (2011) was consistent with autosomal recessive inheritance.

In 4 patients with common variable immunodeficiency, van Zelm et al. (2006) identified homozygous truncating mutations in the CD19 gene (107265.0001 and 107265.0002). Levels of CD19 were undetectable in 1 patient and substantially reduced in the other 3. Based on laboratory studies, van Zelm et al. (2006) concluded that mutation of the CD19 gene causes a type of hypogammaglobulinemia in which the response of mature B cells to antigenic stimulation is defective. On the basis of the crucial role of CD19 in signaling by the B-cell receptor on antigen recognition, van Zelm et al. (2006) thought it likely that defects in other members of the CD19 complex (CD21, CD81, and CD225) may also lead to antibody deficiency in humans.

In a Japanese boy with CVID3, Kanegane et al. (2007) identified a heterozygous splice site mutation in the CD19 gene that was inherited from his mother and resulted in a truncated protein (107265.0003). The other allele carried a 68.5-kb deletion including the ATP2A1 (108730), CD19, and NFATC2IP (614525) genes. Paternal DNA was not available to determine whether the large deletion was inherited or occurred de novo.

In a 6-year-old Moroccan boy, born of consanguineous parents, with CVID3 and absence of CD19 on his B cells, van Zelm et al. (2011) identified a homozygous missense mutation in the CD19 gene (W52C; 107265.0004). The substitution occurred at a conserved residue in the D1 extracellular immunoglobulin superfamily constant domain. Each unaffected parent was heterozygous for the mutation. Western blot analysis of patient cells showed decreased amounts of intracellular protein compared to controls, and the mutant protein was smaller, suggesting abnormal processing and immature glycosylation. Patient B cells showed delayed calcium influx from the endoplasmic reticulum to the cytoplasm upon stimulation, consistent with a signaling defect. The few remaining memory B cells from the patient showed greatly reduced somatic hypermutation compared to controls. A tryptophan at position 52 is present in all variable domains in immunoglobulin and T-cell receptors, and was not mutated in 117 Ig class-switched transcripts of B cells. Expression of wildtype CD19 in patient cells restored the expression of CD19 on the surface of B cells. The findings indicated that the W52 residue is critical for proper folding and stability of the immunoglobulin superfamily domain.

In 2 unrelated patients with CVID3, Vince et al. (2011) identified 2 different homozygous truncating mutations in the CD19 gene (107265.0005 and 107265.0006).