We challenge the theory that the CD40-CD40
ligand is the only explanation for X-linked immunodeficiency in patients with hyper-
immunoglobulin M (
IgM) syndrome (
HIGM1), and we demonstrate an intrinsic defect in the patients' B cells. Patients with
HIGM1 have a defective
CD40 ligand on their activated T-helper cells; therefore, they cannot receive signals for isotype switching when the cells are activated by T cell-dependent
antigens. We activated mononuclear cells from three patients with
HIGM1 and from three healthy blood donors with T cell-independent
mitogens and studied their proliferative responses and Ig secretion. Normal murine plasma membrane fragments were implanted into peripheral blood mononuclear cells, and the cells were activated with Staphylococcus aureus Cowan I,
pokeweed mitogen, and
lipopolysaccharide. This implantation significantly augmented the proliferative responses to the
mitogens in two patients. However, it augmented
IGM secretion in response to B-cell
mitogens in only one patient. No
IgG or
IgA response could be detected in the implanted mononuclear cells that originated from patients with
HIGM1, unlike implanted mononuclear cells from healthy donors, which responded by
IgM,
IgG, and
IgA antibody secretion following their stimulation with B-cell
mitogens. The data suggest that the B cells of patients with
HIGM1 possess an additional defect which prevents
Ig isotype switching in response to T cell-independent
mitogens. This defect is not located in the membrane receptors or within the membrane
enzymes.