title: Tolerization of mice to Schistosoma mansoni egg antigens causes elevated type 1 and diminished type 2 cytokine responses and increased mortality in acute infection.
abstract: The granuloma that surrounds the Schistosoma mansoni egg is the cause of pathology in murine schistosomiasis, and its formation is driven by egg Ag-stimulated type 1 and type 2 cytokines. To determine the role of egg-driven immune responses during schistosome infection we rendered CBA/Ca mice unresponsive to schistosome eggs by combined cyclophosphamide treatment and thymectomy. In the early acute stages of schistosome infection, egg-tolerized mice suffered high mortalities. Granuloma size and deposition of collagen in the liver were significantly reduced in egg-tolerized mice. Similarly, limited granuloma responses were detected in the intestines of these mice, and this was associated with a >90% reduction in egg excretion. Histologically, egg-tolerized mice had exacerbated hepatocyte damage, with extensive microvesicular steatosis. Elevated plasma transaminase levels confirmed the damage to hepatocytes. Infected egg-tolerized mice had impaired proliferation responses to egg Ag but intact responses to worm Ag. Tolerized mice had diminished Ab responses to egg Ag and had a type 1 cytokine isotype pattern to worm Ag, with elevated IgG2a and diminished IgG1 and IgE. Egg-tolerized mice failed to down-regulate type 1 cytokines that are normally elicited during early schistosome infection. Hepatic granuloma cells from egg-tolerized mice were also type 1 cytokine dominated, with elevated frequencies of Tc1/Th1 and reduced Tc2/Th2 cells. This study demonstrates that mice tolerized to schistosome eggs have elevated type 1 cytokine responses with diminished type 2 responses and reduced anti-egg Ab during schistosome infection, and these effects are detrimental to the host.
authors: Department of Pathology, University of Cambridge, United Kingdom. pgf@mole.bio.cam.ac.uk
authors: P G
authors: PG
authors: Fallon
authors: D W
authors: DW
authors: Dunne
mesh_terms: D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis*; D015536:Down-Regulation / Q000276:immunology; D005260:Female; D006099:Granuloma / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007111:Immunity, Cellular; D007136:Immunoglobulins / Q000096:biosynthesis; D008109:Liver Diseases, Parasitic / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D010063:Ovum / Q000276:immunology*; D012550:Schistosoma mansoni / Q000276:immunology*; D012555:Schistosomiasis mansoni / Q000276:immunology* / Q000401:mortality / Q000469:parasitology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism*; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism*
chemical_list: D000947:Antigens, Helminth; D016207:Cytokines; D007136:Immunoglobulins