Exacerbated egg-induced immunopathology in murine Schistosoma mansoni infection is primarily mediated by IL-17 and restrained by IFN-γ.

In schistosomiasis, the severity of CD4+ T-cell-mediated hepatic granulomatous inflammation against parasite eggs varies considerably in humans and among mouse strains. In C57BL/6 mice, pronounced exacerbation of immunopathology induced by immunization with schistosome egg Ag in CFA (SEA/CFA) substantially recapitulates the natural high pathology seen in CBA mice; both are associated with a significant elevation of Th17- and Th1-cell-derived proinflammatory cytokines. We now investigated the relative contribution of the effector cytokines IL-17 and IFN-γ in pathology development of 7 wk-infected, SEA/CFA-immunized, IL-17−/−, IFN-γ−/−, and IL-17/IFN-γ−/− mice. In IL-17−/− mice there was significant reduction of immunopathology despite increased levels of IFN-γ, whereas in IFN-γ−/− mice, markedly exacerbated immunopathology correlated with an increase in IL-17. In IL-17/IFN-γ−/− mice, complete resistance to SEA/CFA-induced disease exacerbation was associated with a reduction in IL-23p19, IL-1β, CXCL1 and iNOS, and with an increase in IL-5, IL-10 and Relmα. IL-17 and IFN-γ were derived from distinct CD4+ T cells in which production of each cytokine was suppressed by the other. Our results indicate that severe immunopathology in murine schistosomiasis is mainly driven by IL-17 and regulated by IFN-γ; however, in the absence of IL-17, IFN-γ is capable of exerting a limited, yet significant, pathogenic function.