Schistosomiasis and the Immune Response

Our laboratory studies the immunopathology and immunopathogenesis of infection with schistosome helminths. In humans, schistosomiasis is a major parasitic disease affecting over 200 million people throughout tropical areas of the world. Morbidity in schistosomiasis results as a consequence of a host CD4 T lymphocyte-mediated granulomatous and fibrosing inflammation against the parasite’s eggs, which in the case of Schistosoma mansoni, takes place in the liver and intestines. There is typically considerable variation of the severity of disease, both in the human patient population, as well as among mouse strains in an experimental mouse model.

The intensity of egg-induced immunopathology is determined by the predominance of a net pro- vs. anti-inflammatory host cytokine environment orchestrated by CD4 T cells specific for schistosome egg antigens. We recently found that the novel subset of T cells producing interleukin (IL)-17 (Th17 cells) is a major force that drives severe inflammation. Current efforts are directed at determining the mechsnisms responsible for the preferential development of Th-17 cells in certain mouse strains, such as CBA, which are genetically prone to high pathology. These studies focus on analyzing parasite interactions with antigen presenting cells that prime and activate the pathogenic Th17 cells.

 

 

The illustration depicts some important aspects of schistosome - host interaction. Snails are the intermediate hosts of the parasite while people are the permanent hosts. Adult schistosomes residing the the portal-mesenteric venous system release eggs, and a CD4 T cell-mediated immune response to schistosome egg antigens (SEA) results in granulomatous inflammation and fibrosis, the main pathology in schistosomiasis.

A related line of research concerns the identification and characterization of the schistosome egg antigens that sensitize host CD4 T cells mediating immunopathology. We have found that the major Sm-p40 egg antigen, specifically its immunodominant epitope peptide 234-246 (Sm-p40234-236), is a main target of the T cell response in high pathology CBA mice. This response is based on T cells with a remarkably restricted TCR configuration predominantly using Vα 11.3 β 8 Using a transgenic mouse expressing this TCR, we expect to elucidate to what degree this skewed T cell population contributes to the immmunopathology.

Additional emphasis in the lab is placed on understanding the genetic basis of disease heterogeneity in schistosomiasis. Based on past studies suggesting the existence of genetic intervals controlling the size of egg granulomas, we currently use F2 cohorts and targeted backcrosses to further pinpoint loci associated with enhanced immunopathology and IL17 production.

Our efforts attempt to understand the innate and adaptive immunopathogenic mechanisms operating in genetically diverse host populations that develop dissimilar forms of schistosomiasis. The overall goal is to design strategies for prevention and/or amelioration of severe diseaese.