Absence of Memory B Cells in Patients with Common Variable Immunodeficiency

The molecular basis of common variable immunodeficiency (CVID) is unknown. To assess humoral immunity in CVID, we selected 24 patients with early or late onset of disease. X-linked agammaglobulinemia (XLA), X-linked hyper-IgM syndrome (XHIM), and non-XHIM were excluded based on clinical phenotype, assessment of the immune response, presence of Brutonʹs tyrosine kinase (Btk) in monocytes or platelets, and normal expression of CD40 ligand by activated T cells. The number of circulating B cells was within the normal range or reduced. IgD− CD27+ memory B cells were markedly reduced or absent in all 24 patients and IgD+ CD27+ B cells were diminished in 8 patients. Circulating B cells from all 6 patients examined, including CVID patients with IgD+ CD27+ cells, failed to undergo somatic hypermutation in immunoglobulin-variable (V)-region genes, similar to cord blood B cells. B cells from CVID patients produced IgM and IgG, but not IgA upon the engagement of Ig receptor and CD40 in the presence of IL-2 and IL-10. B cells from all but 5 patients secreted IgE when stimulated by CD40 crosslinking in the presence of IL-4. The observation of defective memory B cells with abnormal cell marker expression and function demonstrates that naive CVID B cells including those expressing IgD+ CD27+, in analogy to cord blood and hyper-IgM syndrome B cells, may be responsible for their failure to differentiate into plasma cells and to produce high-affinity antibodies of different isotypes.