| Granulomatous inflammation is key to the pathogenesis of many infectious diseases, including hepatic schistosomiasis. Granulomas forming around schistosome eggs trapped in the liver were thought to be induced primarily, if not exclusively, by egg antigens. In the studies detailed in this dissertation, I now show that adult worms, which migrate to the liver prior to the production of eggs, prime local immune responses key to granuloma formation. When parasite eggs are injected into livers of naive animals, only a minimal, nongranulomatous, inflammatory response results. However, if eggs are injected into livers of mice presensitized with single-sex adults, granuloma formation is restored. Granuloma formation is also restored if mice are presensitized with adult homogenates or eggs themselves. These sensitization studies suggest that antigen(s) are shared between adult and egg stages of the schistosome life cycle and that immune priming by these antigen(s) is necessary for hepatic granuloma formation. TNF-alpha may mediate part of the immune priming necessary for granuloma development since injection of purified TNF-alpha alone restores formation of granulomas in the livers of naive mice injected with eggs. If mice presensitized by single-sex infection are treated with a soluble TNF receptor prior to egg injection, granuloma formation is no longer rescued. In natural infections, both the degree of liver pathology and the extent of egg laying by adult females are directly proportional to plasma levels of TNF-alpha as determined by ELISA. Models of infection that isolate the effects of worms from those of eggs confirm that each of these life cycle stages induces a unique pattern of cytokine expression as determined by RT PCR. Hepatic induction of TNF-alpha mRNA is a reaction to adults, not eggs, and a crude fractionation of adult proteins stimulates TNF-alpha secretion from a cultured macrophage cell line. Kupffer cells appear to be the major cellular sources of adult worm-induced TNF-alpha protein prior to egg production as determined by immunohistochemistry and in situ hybridization. Once egg deposition begins, TNF-alpha protein is additionally expressed by recruited macrophages located at the periphery of the enlarging granuloma. |
