We are developing quantitative functional assays for B lymphocyte responses to study cells from patients with sporadic, presumably polygenic cases of the most prevalent primary immunodeficiency, Common Variable Immunodeficiency (CVID). We hypothesised that such quantitative methods will reveal the underlying functional causes for many cases of CVID, and that the sum of multiple small changes in cellular functions are responsible for an antibody deficit when combined in an immunodeficient individual. As such, we have established standardised quantitative assays to measure the human naïve and memory B cell response to both T-dependent (CD40L+IL-21) and T-independent (anti-Ig+CpG) stimuli. These assays include measurement of division, death, differentiation and isotype switching, to reveal the innate programming of the B-lymphocyte in response to these conditions. In establishing these assays we have determined that human B lymphocytes regulate survival, independently of division rate, and the number of divisions undergone (division destiny), as previously noted for mouse cells. These quantitative assays provide a sensitive measure of the ‘health’ of B cells, and are being applied to test responses in antibody deficient individuals, to reveal the underlying functional deficits in B-cell regulation.