Variability in B cell maturation and differentiation in X-linked agammaglobulinemia

Among seven males with X-linked agammaglobulinemia in an extended pedigree, serum immunoglobulins and antibodies were extremely low in all but one who had a normal IgA (78 mg/dl) and tetanus antibodies (1:19,683). Following bacteriophage phi X 174 immunizations, the oldest failed to clear phage and had no primary or secondary antibody responses. The youngest had normal phage clearance, low primary and secondary antibody responses, and no amplification or switching to IgG. The other four affected had normal or slightly delayed phage clearance, low primary and secondary responses, but some amplification and switching from IgM to IgG which increased with age. Normal percentages of surface immunoglobulin positive cells were present in the two youngest patients, but all seven affected had very low percentages of cells reacting with monoclonal antibodies to B cell surface antigens. Immunoglobulin production by cultured blood B cells was very low and not increased by pokeweed mitogen. However, a majority of Epstein-Barr virus (EBV)-transformed lymphoblastoid cells derived from the blood of four of the patients bore IgD and IgM and reacted with all of the monoclonal antibodies to B cell antigens. Culture supernatants from those lines contained significant quantities of IgM and lesser amounts of IgG and IgA. The studies presented here provide further support for the hypothesis that the primary abnormality in X-linked agammaglobulinemia affects B cells at more than one stage of development rather than just at the level of the pre-B cell.