Immature B cells in fetal development and immunodeficiency: studies of IgM, IgG, IgA and IgD production in vitro using Epstein-Barr virus activation.

Epstein-Barr virus has been used as a B cell mitogen to explore the parallels between the B cells found in patients with hypogammaglobulinemia and the immature B cells in fetal tissues. Peripheral blood lymphocytes from 29 cases of late onset hypogammaglobulinemia (common variable immunodeficiency) and from 10 cases of X-linked hypogammaglobulinemia were depleted of T lymphocytes and stimulated with virus in vitro. Immunoglobulin production was measured over a 4-week culture period using inhibition radioimmunoassays for IgM, IgG, IgA and IgD. The results were compared with those seen with fetal liver cells, cord blood lymphocytes and adult lymphocytes. Virus-stimulated cells from fetal sources produced small amounts of IgG and IgA relative to IgM, the ratio of IgM to IgG in the second week being in all cases greater than 10. Similar patterns were seen in 25/29 cases of late onset hypogammaglobulinemia, and in the eight cases of X-linked hypogammaglobulinemia that responded in vitro. In contrast, the ratio of IgM to IgG was always less than 8 in cultures of normal adult peripheral blood or bone marrow lymphocytes, and also in cultures from four cases of hypogammaglobulinemia known independently to have abnormal circulating suppressor cells. Eight cases of selective IgA deficiency showed reduced IgA production; six of these showed a normal ratio of IgM to IgG production. Thus, the B lymphocytes which circulate in many patients with hypogammaglobulinemia are functionally immature.