Antibody Responses During Infection with Leishmania spp.
Miles, Suzanne Adell
Mosser, David M
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Classically activated macrophages produce high levels of IL-12 and moderate levels of IL-10. When IgG immune complexes ligate the Fc gamma receptors on activated macrophages, they shut off IL-12 synthesis and increase IL-10 production. These macrophages are termed 'type II' activated macrophages. The anti-inflammatory responses of type II activated macrophages could be harmful to the host when an inflammatory response is critical to pathogen clearance. The clearance of intracellular pathogens, such as Leishmania spp., relies upon an inflammatory response. Inflammatory cytokines lead to classical macrophage activation, which is critical to the destruction and clearance of phagocytosed parasites. Without a robust inflammatory response, Leishmania parasites are free to replicate within macrophages, leading to disease pathology. Based on this knowledge, it was hypothesized that IgG coated Leishmania amastigotes would ligate Fc gamma receptors on host macrophages and induce the production of IL-10. Therefore, the role of IgG in mediating host defense to Leishmania was examined. For these studies, JH mice, which lack IgG and are on the Leishmania major susceptible BALB/c background, were used. We show that IgG not only fails to provide protection against this intracellular pathogen, but it actually contributes to disease progression. JH mice were more resistant to disease than control BALB/c mice, and reconstitution with anti-L. major antisera resulted in increased disease, with larger lesions and higher numbers of parasites. Antibody administration correlated with an increase in IL-10 production in lesions, however, this IgG mediated exacerbation of disease could be reversed by simultaneously treating with anti-L. major antisera and a monoclonal antibody against the IL-10 receptor. The anti-L. major IgG profiles of resistant C57BL/6 mice and susceptible BALB/c mice were examined. BALB/c mice exhibited higher levels of IgG, in both circulating titers and on the surfaces of amastigotes, than C57BL/6 mice. The differences in the anti-L. major IgG titers between resistant and susceptible strains provide evidence of the integral role of IgG during leishmaniasis. These studies demonstrate that IgG can cause a novel form of immune enhancement due to its ability to induce IL-10 production from macrophages.