B cells from patients with common variable panhypogammaglobulinemia are intrinsically unable to mature to high-rate antibody-secreting cells at the normal pace even in the presence of normal interacting T cells and monocytes. However, they are able to perform certain early and intermediate activation events normally, so failure to become activated appears not to be their problem. Anticipating that identifying the defective step in B cells from different patients will reveal much about normal B cell activation, we propose to exploit recently described alternative modes of activating B cells with factors or reagents that act with or after surface Ig crosslinking to promote progression to DNA-synthesis or antibody secretion. These experiments should distinguish patients with defective differentiation from patients with defective proliferation. A potentially important new approach is to analyze how cytochalasins, which prevent actin assembly into microfilaments, promote advancement to DNA synthesis, and whether they can do so in patients whose normal mechanisms are blocked. Finally, using a variety of assays for early biochemical and cell surface events in activation, we will discover whether the differentiation factor interferon beta 2, the high and low molecular weight B cell growth factors, and anti-CDw40, utilize any of the known signal transduction pathways or stimulate intermediate events, so we can also determine how far their signals progress in defective B cells. This approach has the dual objective of elucidating normal B cell differentiation and proliferation signals at the biochemical level, and also understanding the physiology of the defective B cells, eventually leading to new strategies for regulation of antibody production.
