IgG1 Is Pathogenic in Leishmania mexicana Infection

There are >2 million new cases of leishmaniasis annually, and no effective vaccine has been developed to prevent infection. In murine infection, Leishmania mexicana, which lives intracellularly in host macrophages, has developed pathways to hijack host IgG to induce a suppressive IL-10 response through Fc gamma Rs, the cell-surface receptors for IgG. To guide vaccine development away from detrimental Ab responses, which can accompany attempts to induce cell-mediated immunity, it is crucial to know which isotypes of IgG are pathogenic in this infection. We found that IgG1 and IgG2a/c induce IL-10 from macrophages in vitro equally well but through different Fc gamma R subtypes: IgG1 through Fc gamma RIII and IgG2a/c through Fc gamma RI primarily, but also through Fc gamma RIII. In sharp contrast, mice lacking IgG1 develop earlier and stronger IgG2a/c, IgG3, and IgM responses to L. mexicana infection and yet are more resistant to the infection. Thus, IgG1, but not IgG2a/c or IgG3, is pathogenic in vivo, in agreement with prior studies indicating that Fc gamma RIII is required for chronic disease. This calls into question the assumption that macrophages, which should secrete IL-10 in response to IgG1 and IgG2a/c immune complexes, are the most important source of IL-10 generated by IgG-Fc gamma R engagement in L. mexicana infection. Further investigations are required to better determine the cell type responsible for this immunosuppressive Fc gamma RIII-induced IL-10 pathway and whether IgG2a/c is protective. The Journal of Immunology, 2010, 185: 6939-6946.