IgE production in human helminth infection. Reciprocal interrelationship between IL-4 and IFN-gamma

To determine whether there is a reciprocal relationship between IL-4 and IFN-gamma production in persons with parasite-induced elevations in serum IgE, PBMC were obtained from helminth-infected individuals with a broad range of serum IgE levels that fell into two distinct groups--extremely elevated (HI; n = 9; range, 4,129 to 18,400 ng/ml) or elevated (EL; n = 6; range, 403 to 1,018 ng/ml), relative to control subjects (NL; n = 7; range, 4 to 159 ng/ml). PBMC were stimulated in vitro, with Ag or mitogens, and IL-4 and IFN-gamma were measured by ELISA in culture supernatants. Helminth Ag- (but not tetanus toxoid) stimulated IL-4 production in eight of nine HI (range, 49 to 150 pg/ml) but was undetectable in either EL or NL (p < 0.01). In contrast, PBMC from EL produced significant levels of IFN-gamma to helminth Ag (GM = 358 pg/ml) compared with HI (GM = 89 pg/ml; p = 0.02) and NL (GM = 9 pg/ml; p < 0.001). Tetanus toxoid induced comparable levels of IFN-gamma among the three groups. Mitogen-driven IL-4 production was ninefold greater in HI [geometric mean (GM) = 913 pg/ml] versus EL (GM = 111 pg/ml; p < 0.01) and NL (GM = 193 pg/ml; p < 0.001) and correlated with serum IgE levels (r = 0.8; p < 0.01). Mitogen-driven IFN-gamma synthesis was equivalent among the groups. Although parasite Ag-driven IL-4 secreting CD4+ cells were detected (by ELISPOT) among infected subjects with both high and low serum IgE levels, the number of IL-4 exceeded that of IFN-gamma-secreting cells among individuals with elevated serum IgE levels, whereas the opposite relationship existed among subjects with normal serum IgE. In a subpopulation of infected individuals (n = 4), parasite-Ag added to PBMC cultures induced polyclonal IgE that was directly associated with the parasite-Ag-driven IL-4 production and inversely related to IFN-gamma synthesis in PBMC supernatants from parallel cultures. Furthermore, neutralizing anti-IFN-gamma antibody augmented both parasite-driven IL-4 synthesis and IgE production in vitro (n = 4). The data indicate that helminth-induced serum IgE levels are directly related to an increased capacity by PBMC to produce IL-4 and inversely associated to IFN-gamma production. It further supports the concept that IL-4 and IFN-gamma reciprocally regulate IgE in vivo.