Cross-reactive, natural IgG recognizing L. major promote parasite internalization by dendritic cells and promote protective immunity

In cutaneous leishmaniasis, infection of dendritic cells (DC) is essential for generation of T cell-dependent protective immunity. DC acquires Leishmania major through Fc receptor (FcR)-mediated uptake of complexes comprising antibodies bound to parasites. We now assessed the development of the initial B cell and DC response to the parasite itself and if natural IgG play a role. L. major parasites display large numbers of phospholipids on their surface. Parasites were opsonized with normal mouse serum (NMS), or serum containing anti-phospholipid IgG (PL). We found that L. major bound to PL which significantly enhanced parasite phagocytosis by DC as compared to NMS. Similar results were obtained with cross-reactive human PL antibodies using myeloid primary human DC. In addition, mice infected with PL-opsonized parasites showed significantly improved disease outcome compared to mice infected with NMS-opsonized parasites. Finally, IgMi mice, which produce membrane-bound IgM only and no secreted antibodies, displayed increased susceptibility to infection as compared to wild types. Interestingly, once NMS was administered to IgMi mice, their phenotype was normalized to that of wild types. Upon incubation with IgG-opsonized parasite (IgG derived from infected mice or using PL antibodies), also the IgMi mice were able to show superior immunity. Our findings suggest that natural cross-reactive antibodies (e.g., anti-PL Ab) in NMS bind to pathogens to facilitate phagocytosis, which leads to induction of protective immunity via preferential DC infection. Prior L. major-specific B cell-priming does not seem to be absolutely required to facilitate clearance of this important human pathogen in vivo. Key messages We found that anti-phospholipid (anti-PL) antibodies enhance phagocytosis of L. major by DCs. We also found that normal mouse sera have natural antibodies that can imitate PL specific antibodies. Using different genetically modified mice, we found that these antibodies can be IgG, not only IgM