ABSTRACT
The role of the third component of complement (C3) during schistosome infection was investigated using mice deficient in C3. While no effect was observed 8 wk after infection on worm development or liver pathology, Ag-specific Th2-associated cytokine production (IL-13, IL-5, IL-6, and IL-10) was significantly reduced, and IFN-gamma production was enhanced in the absence of C3. IgG1 and IgE, but not IgG2a or IgM, Ab responses were also significantly impaired in infected C3(-/-) mice, suggesting that C3 may play a role in IL-4-mediated Th2 response enhancement during schistosome infection. Furthermore, C3-deficient mice could not effectively clear adult worms after praziquantel (PZQ) treatment and suffered increased morbidity due to the overproduction of proinflammatory mediators following drug administration. However, the ischemic liver damage that normally accompanies PZQ administration in infected wild-type mice was substantially reduced in treated C3-deficient mice, probably due to the absence of dead or dying worms in the livers of these animals. Together these results indicate that C3 enhances Th2 responses during schistosome infection, potentiates PZQ-mediated parasite clearance, and reduces chemotherapy-induced proinflammatory mediator production.
Subject(s)
Anthelmintics/therapeutic use , Complement C3/deficiency , Complement C3/genetics , Schistosomiasis mansoni/drug therapy , Schistosomiasis mansoni/immunology , Th2 Cells/immunology , Th2 Cells/metabolism , Animals , Antigens, Helminth/immunology , Cells, Cultured , Complement C3/physiology , Cytokines/biosynthesis , Cytokines/blood , Immune Tolerance/genetics , Inflammation Mediators/blood , Liver Diseases, Parasitic/drug therapy , Liver Diseases, Parasitic/genetics , Liver Diseases, Parasitic/immunology , Liver Diseases, Parasitic/pathology , Mice , Mice, Inbred C57BL , Mice, Knockout , Morbidity , Praziquantel/therapeutic use , Schistosoma mansoni/drug effects , Schistosoma mansoni/growth & development , Schistosoma mansoni/immunology , Schistosomiasis mansoni/genetics , Schistosomiasis mansoni/pathology , Th1 Cells/drug effects , Th1 Cells/immunology , Th1 Cells/metabolism , Th1 Cells/parasitology , Th2 Cells/drug effects , Th2 Cells/parasitologyABSTRACT
The role of CD40/CD154 interaction during infection has primarily focused on pathogens that drive inflammatory Th1 responses. In this study, we show that CD40/CD154 interaction is a fundamental requirement for Th2 response development to the parasitic helminth Schistosoma mansoni. Compared with infected wild-type mice, greatly reduced levels of Th2-associated cytokines were measured both in vitro and in vivo, and no IgE or IgG1 was detected in infected CD154(-/-) mice. In the absence of an overt Th2 response, no exaggerated Th1 response was mounted by CD154(-/-) mice. Infected CD154(-/-) mice suffered severe morbidity and mortality, even though parasitemias in wild-type and CD154(-/-) mice did not differ significantly. These data indicate that CD40/CD154 interaction is required to allow development of a Th2-dominated immune response to S. mansoni and support the view that failure to develop such a response can have fatal consequences.
