Immunomodulation

The profile of human (and rodent) immune responses to schistosome infection is well documented. Exposure of an unsensitised host to normal S. mansoni cercariae provokes only a minimal response. However, after approximately 5 weeks, the onset of egg deposition in the gut (and liver) tissues initiates an acute phase of reactivity by peripheral blood mononuclear cells (PBMC) to schistosome antigens. This peaks around 8 weeks, and then begins to modulate so that by 15 weeks the infection has entered the chronic phase, characterised by relatively unresponsive PBMCs. The acute-to-chronic transition is paralleled by the pattern of granulomatous hypersensitivity to the tissue eggs. In the acute phase the circumoval granulomas are large and florid whilst by the chronic phase they are collagenous and more tightly condensed. Some humans continue to be reactive to the eggs, mounting a response that leads over a number of years, to periportal fibrosis and the chain reaction of pathological events in the liver and portal tract that can be fatal.

The mechanisms of immune modulation are still not fully understood although great progress has been made in dissecting the response to eggs, as a model of granulomatous hypersensitivity (e.g. Wynn TA, 2003, Ann. Rev. Immunol. 21:425-56). We have demonstrated that transition from the acute to chronic phase of schistosome infection in mice is crucially dependent on production of the cytokine IL-10 (Sadler et al., 2003), but other factors must also play a role in maintaining the chronic unresponsive state. We are currently using proteomics to characterise the antigens secreted by schistosome eggs. The proteins constitute a relatively simple mixture that originates in the sub-shell envelope, not the miracidium, and one of their biological roles is to facilitate egg passage to the gut lumen (Ashton et al., 2001). The secretions contain at least two protease activities and are highly immunoreactive; the functions of both native and recombinant proteins are being evaluated by in vivo and in vitro assays.

The images below show sections of the livers of either wild-type (WT) or IL-10 knockout (KO) mice either 8 or 15 weeks after infection. The granulomas around embolised eggs are smaller at week 15 in the wild-type, showing that down regulation has occurred, but remain large in the knockouts.

WT Week 8

KO Week 8

WT Week 15

KO Week 15