Tolerization of mice to Schistosoma mansoni egg antigens causes elevated type 1 and diminished type 2 cytokine responses and increased mortality in acute infection

The granuloma that surrounds the Schistosoma mansoni egg is the cause of pa thology in murine schistosomiasis, and its formation is driven by egg Ag-st imulated type 1 and type 2 cytokines. To determine the role of egg-driven i mmune responses during schistosome infection we rendered CBA/Ca mice unresp onsive to schistosome eggs by combined cyclophosphamide treatment and thyme ctomy. In the early acute stages of schistosome infection, egg-tolerized mi ce suffered high mortalities. Granuloma size and deposition of collagen in the liver were significantly reduced in egg-tolerized mice. Similarly, limi ted 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 micro vesicular steatosis, Elevated plasma transaminase levels confirmed the dama ge to hepatocytes. Infected egg-tolerized mice had impaired proliferation r esponses to egg Ag but intact responses to worm Ag. Tolerized mice had dimi nished Ab responses to egg Ag and had a type I cytokine isotype pattern to worm Ag, with elevated IgG2a and diminished IgG1 and IgE. Egg-tolerized mic e failed to dean-regulate type 1 cytokines that are normally elicited durin g early schistosome infection. Hepatic granuloma cells from egg-tolerized m ice were also type 1 cytokine dominated, with elevated frequencies of Tc1/T h1 and reduced Tc2/Th2 cells. This study demonstrates that mice tolerized t o schistosome eggs have elevated type I cytokine responses with diminished type 2 responses and reduced anti-egg Ab during schistosome infection, and these effects are detrimental to the host.