Since parasite opsonization by antibodies is unlikely in this system we hypothesized that non-specific soluble ICs could recapitulate this antibody-FcRc-common chain dependent NADPH oxidase activation. In testing this hypothesis we show that non-specific IgG2a soluble ICs, with IFN-c and parasite antigen activate infected macrophages to kill L. amazonensis in a NADPH oxidase dependent process. Together with our previous studies these results support a model of L. amazonensis intracellular killing that is dependent, in part, on antibody-mediated activation of NADPH oxidase post-infection. Furthermore we can promote this mechanism of parasite killing using non-specific immune complexes in the co-culture system. In experimental murine leishmaniasis antibodies are known to be associated with a non-productive immune response. Antibodies promote increased lesion size and parasite numbers during ineffective immunity towards L. major, L. mexicana and L. amazonensis. High antibody titers after natural infection in humans and dogs are frequently associated with an uncontrolled infection. Immunopathology, such as glomerulonephritis, is often associated with high levels of antibodies. There are only a few reports that indicate antibodies can have a positive outcome during Leishmania infection. Woelbing et al demonstrated that antibodies produced during productive immunity against L. major increased the efficiency of the immune response. Recent studies have implicated Leishmania-specific B cells in enhancing T cellmediated immunity during human disease. Our laboratory has published that B cells and their IgG2a antibodies are required for killing L. amazonensis in our in vitro cross-protection assay. We have also shown that after L. amazonensis infection C3H mice have a poor IgG2a response, whereas the same mice have a robust IgG2a response after L. major infection. One simple interpretation is that the B cell response reflects the ability of the immune system to either promote or exacerbate Leishmania infection. During ineffective immunity against Leishmania the B cell response promotes disease by limiting classical macrophage activation and promoting IL-10-mediated immunoregulation, whereas we propose that during effective immunity the B cell response associated with Th1 immunity can support healing, in part, by promoting NADPH oxidase-mediated superoxide production. During L. major infection this pathway is not required and the B cell response is dispensable. In contrast, L. amazonensis is resistant to the effects of nitric oxide alone and in our assay, B cells, and more specifically their production of antibodies, are required to promote superoxide production. In our system, we demonstrate a novel mechanism whereby non-specific antibodies can trigger pathogen killing. This mechanism does require additional PI-103 PI3K inhibitor factors for activation. The requirement for IFN- c is consistent with CD4+ Th1 cell-mediated immunity and IFN- c.