Antibody enhanced intracellular killing of Leishmania amazonensis: the role of soluble immune complexes and their effect on autophagy

Leishmania amazonensis is an intracellular protozoal parasite that causes cutaneous leishmaniasis in humans and other mammalian hosts. This disease affects people within tropical and subtropical countries. Generally a Th1 cell-mediated host immune response is thought to be important for the clearance of the parasite. However, throughout this work we have shown that a productive B cell response is important for the clearance of the parasite through the production of IgG2a isotype antibodies. These antibodies can form small soluble immune complexes that can stimulate the FcγR leading to the production of superoxide. Superoxide and nitric oxide are required to kill intracellular L. amazonenesis parasites. Our studies have also shown that macrophages can be activated to produce these required immune factors if they are stimulated with soluble immune complexes, IFN-γ, and Leishmania antigen (tripartite activation). We have also found that these three factors can lead to the upregulation of the autophagy pathway for the clearance of the parasite. These soluble immune complexes can be replaced by novel recombinant proteins that have similar morphology to murine IgG2a Fc. These Fc constructs have the ability to recapitulate killing of the parasite and superoxide production seen with tripartite activation. All of these factors are important for the development of a possible immunomodulating therapy that could be used to treat patients infected with this chronic, debilitating disease.