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A detrimental role for IgG and FcgammaR in Leishmania mexicana infection

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Abstract

The intracellular protozoan parasite Leishmania causes leishmaniasis, which is the second biggest killer worldwide among parasitic diseases, after malaria. As drug therapy for leishmaniasis is toxic and resistance is growing, a vaccine is an important weapon against this disease. Unfortunately, no effective vaccine exists for any human parasitic infection. Worse yet, nearly all effective vaccines whose mechanisms are known work through the induction of protective antibodies. Leishmania mexicana causes primarily chronic cutaneous disease. Not only are antibodies not effective at killing Leishmania, as it hides inside the parasitophorous vacuole of the host cell, but new research indicates that IgG antibodies may be crucial in suppressing the host immune response by generating an immunosuppressive interleukin-10 response. IL-10 is able to decrease the needed Th1-generated IFN-γ and downregulates production of nitric oxide, a required effector mechanism of parasite killing. We have been studying the pathways that the host uses to partially control L. mexicana infection, which include STAT4, IFN-γ, and inducible nitric oxide synthase, but found that the IL-12 pathway is suppressed by IL-10. We are now studying the mechanisms by which IgG, bound to parasites, can induce IL-10 through FcγR ligation and how this suppresses a healing immune response. We are examining which IgG isotypes bind to which FcγRs and whether macrophages are the necessary source of IL-10 for chronic disease. Elucidation of these mechanisms may help us to design vaccines that will not induce antibody-mediated immunosuppressive IL-10 responses.

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Acknowledgments

The work was begun by the author in the lab of Dr. Phillip Scott and continued by Dr. Buxbaum in his own independent lab. We would like to thank Dr. Bolaji Thomas for his in vitro work on macrophages, and Andrea Rosso and Dr. Niansheng Chu for technical help with other aspects of the research. This work was supported by the University of Pennsylvania, by NIH (K08-AI01805), and by a Merit Review Award from the Department of Veterans Affairs.

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  1. Division of Infectious Diseases, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Laurence U. Buxbaum

  2. Veterans Affairs Medical Center of Philadelphia, 3900 Woodland Ave., Res 151, Philadelphia, PA, 19104, USA

    Laurence U. Buxbaum

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Correspondence to Laurence U. Buxbaum.

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Buxbaum, L.U. A detrimental role for IgG and FcgammaR in Leishmania mexicana infection. Immunol Res 42, 197–209 (2008). https://doi.org/10.1007/s12026-008-8074-5

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