The regulation of IgG subclass production in man: low serum IgG4 in inherited deficiencies of the classical pathway of C3 activation.

Human serum IgG subclasses have been measured by a sensitive enzyme-linked immunoassay in 52 subjects with severe genetic deficiency of a complement component. The mean serum IgG4 in 4 subjects with C3 deficiency was 8.2 micrograms/ml and in 14 subjects with C1-4 deficiency was 27.9 micrograms/ml. These means are severely depressed compared with the mean normal IgG4 of 292 micrograms/ml. IgG4 levels in C5-9 deficiency (175 micrograms/ml) and C1INH deficiency (179 micrograms/ml) did not differ significantly from normal. Serum IgG2 was reduced significantly, but far less severely than IgG4, in C3 and in some cases of C1-4 deficiency. IgG1 and IgG3 levels were within the normal range in all complement-deficient groups. Age differences between the groups do not explain the very low levels of IgG4 in C1-4 and C3 deficiency. These data suggest that serum IgG4 synthesis is dependent on an intact classical, but not alternative, pathway for activation of C3 and that IgG4-committed B cells require a complement-dependent maturation pathway not required by B cells committed to other IgG isotypes. IgG4 antibody responses are associated with secondary responses to T-dependent antigens. The possibility that IgG4 may be the product of a memory B cell which has been through a stage of differentiation in a germinal centre is discussed.