Control of infection with Leishmania major in susceptible BALB/c mice lacking the common gamma-chain for FcR is associated with reduced production of IL-10 and TGF-beta by parasitized cells.
Previous studies have shown that the in vitro ligation of FcgammaRs with IgG-opsonized Leishmania amastigotes promotes IL-10 production by macrophages. In addition, infection of either BALB/c mice lacking the common gamma-chain of Fc receptors (FcgammaR(-/-)) or mice genetically altered to lack circulating Ab (J(H)D) with Leishmania pifanoi results in reduced and delayed lesion development and a deficit in the recruitment of inflammatory cells into infected lesions. We show in this study that FcgammaR(-/-) mice can control infection with Leishmania major and totally resolve cutaneous lesions. The ability to eventually control infection is not associated with a reduction in lesion inflammation or a reduction in the ability of Leishmania to parasitize cells through week 6 of infection. The immune response in healing FcgammaR(-/-) mice is associated with a reduction in numbers of cells producing Th2-type cytokines, including IL-4 and IL-10, but not an increase in numbers of IFN-gamma-producing cells characteristic of a dominant Th1-type response. Instead, we observe a reduction in levels of IL-10 and TGF-beta within infected lesions, including reduced levels of these cytokines within parasitized macrophages. Together, these results suggest that uptake of opsonized parasites via FcgammaRs may be a strong in vivo stimulus for the production of anti-inflammatory cytokines that play a role in susceptibility to infection.
Padigel
Udaikumar M
UM
Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Farrell
Jay P
JP
D000818:Animals; D000913:Antibodies, Protozoan / Q000096:biosynthesis / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005260:Female; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate / Q000235:genetics; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000097:blood; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000172:deficiency / Q000378:metabolism; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics; D017452:Receptors, IgG / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000913:Antibodies, Protozoan; D016207:Cytokines; D007074:Immunoglobulin G; D021122:Protein Subunits; D017452:Receptors, IgG; D016212:Transforming Growth Factor beta; D016753:Interleukin-10