Failure of B cells in common variable immunodeficiency to transit from proliferation to differentiation is associated with altered B cell surface-molecule display

B cells from patients with common variable immunodeficiency (CVI) were investigated as to their surface-molecule display and their functional ability to transit through defined in vitro developmental stages. Patients' B cells were analyzed by dual color-flow cytometry and found to have an abnormal surface-molecule display characterized by depressed Leu 8 and CD21 expression. Membrane immunoglobulin (mu, delta, and light chain) were normally displayed. The lack of Leu 8 and CD21 expression did not represent the normal loss of these antigens from B cells with activation because the cells did not demonstrate enhanced display of activation markers, nor did they demonstrate enhanced display of early B cell molecules, such as common acute lymphocytic leukemia antigen or CD5. Small resting B cells from the patients were isolated and tested for their ability to respond functionally to a series of activation, proliferation, and differentiation signals. B cells from 14 of 17 patients failed to transit from proliferation to differentiation with increased immunoglobulin production when B cells were stimulated with T cell replacing factor ± phorbol myristate acetate. Cells of one patient failed to proliferate, whereas B cells from the remaining two patients with CVI did not undergo activation (size change and RNA synthesis) when they were exposed to antimu antibody or low-dose phorbol myristate acetate. These studies demonstrate that most patients with CVI have B cells displaying an altered-surface phenotype that is associated with a specific functional defect in transiting from cell proliferation to differentiation and immunoglobulin production.