Novel mutations in a Japanese patient with CD19 deficiency

Abstract

Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by recurrent bacterial infections, hypogammaglobulinemia and low to normal numbers of circulating B cells. Mutations in the ICOS, TACI and CD19 genes have recently been identified in o10% of CVID patients. We, herein, describe two novel CD19 gene disruptions in an 8-year-old Japanese boy, who had been clinically diagnosed as having CVID at the age of 5 years. Flow-cytometric analysis demonstrated absence of CD19 and reduced CD21 expression on CD20-postive peripheral blood B cells. Mutation analysis of CD19 revealed a mutation in the splice acceptor site of intron 5 (IVS5-1G4T) of the maternal allele, resulting in skipping of exon 6, and a truncated protein product. The paternal allele was disrupted by a gross deletion encompassing at least the ATP2A1, CD19 and NFATC2IP genes. The patient had a small number of IgD À CD27 þ memory B cells, in which somatic mutation were detected. His B cells showed substantial proliferation upon stimulation, but reduced IgG and IgA production in vitro. These findings extend the mutation spectrum of the CD19 deficiency to four, and confirm the homogeneity of the CD19 deficiency as a unique type of CVID.

B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele

“…Our observations of reduced CD19 and CD21 membrane expression in 30 carriers of a CD19 gene mutation confirm and strengthen earlier observations. 5,6 The 2.4-fold reduction of CD19 in carriers clearly showed that two functional alleles are required for normal CD19 membrane expression levels on B cells, and that the loss of one allele cannot be compensated for by the remaining functional allele. Furthermore, the 1.3-fold decrease in CD21 membrane expression in carriers shows the tight relation between CD19 and CD21 on mature B cells.…”

“…23,24 In fact, several CD19-deficient patients have high levels of autoantibodies either with or without an autoimmune disease. 5,6,25 Because only five CD19-deficient patients have been described so far, it cannot be concluded whether loss of CD19 is associated with increased autoimmunity. BCR-mediated signaling and Toll-like receptor-mediated signaling in precursor B cells are important for the removal of autoreactive B-cell receptors, as patients with genetic defects in BTK or MyD88 have been shown to have increased number of B cells carrying autoreactive BCRs.…”

“…Also, autoreactive antibodies have been found in CD19-deficient patients. 5,6 To study whether defective CD19 alleles are associated with autoreactive antibody production, we measured anti-nuclear IgG antibodies in both CD19-deficient patients and 96 family members. Despite reduced total serum IgG levels, CD19-deficient patient, ID037, had high titers of anti-nuclear antibodies (ANAs; 1/640) measured at multiple time points, which were specific for SS-A.…”

“…2,3 In about 90% of patients diagnosed with agammaglobulinemia and about 75% of cases with a Hyper-IgM syndrome, the underlying genetic defect has been identified. 2 Whereas mutations have been described in patients diagnosed with CVID, [4][5][6][7][8][9][10][11][12] in over 90% of these patients no associated genetic defect has been found. In fact, in most CVID patients a complex genetic trade rather than a single affected gene is likely to contribute to development of the disease.…”

“…5,6 CD19 forms a complex with CD21, CD81 and CD225, and functions to lower the threshold for B-cell antigen receptor (BCR) signaling following antigen engagement. 13 Consequently, CD19-deficient and CD81-deficient patients were found to be defective in BCR stimulation and showed poor responses to vaccination.…”