Enhanced B cell survival in familial macroglobulinaemia is associated withincreased expression of Bcl-2

A family with three cases of macroglobulinaemia of undetermined significanc e (MGUS), and one case each of immunoblastic lymphoma, Waldentrom's macrogl obulinaemia and multiple myeloma was first described 20 years ago. We have previously identified 10 out of 35 healthy family members tested whose lymp hocytes produced abnormally high amounts of immunoglobulins in culture. In the present study lymphocyte subpopulations of these hyper-responders have been further characterized and lymphocyte reactivity and survival in vitro, have been studied. No differences were detected in the proportions of rest ing B lymphocytes (CD19(+)) co-expressing CD5, CD10, CD11b, or CD38, and th e CD4/CD8 ratio of T cells was normal before and after stimulation with pok eweed mitogen (PWM). The initial rate of response in terms of immunoglobuli n production was not increased, but immunoglobulin levels continued to rise during the second week of culture whereas the production peaked at 8 days in control cultures. This was associated with significantly greater surviva l of lymphocytes and at 14 days surviving B cells could only be identified in samples from hyper-responders. A lymph node removed because of tuberculo sis from a family member 23 years before the diagnosis of multiple myeloma showed very marked Bcl-2 expression in a B cell follicle. This was not seen in a tuberculous lymph node from an unrelated subject. Stimulated cultures from three hyper-responders tested demonstrated significantly higher reten tion of Bcl-2 in B cells compared with one family control and six unrelated controls. We conclude that the increased production of immunoglobulins pre viously observed in this family with an inherited tendency for benign and m alignant B cell proliferation is the result of enhanced B cell survival, wh ich is associated with increased expression of Bcl-2 following stimulation.