Periportal fibrosis in human Schistosoma mansoni infection is associated with low IL-10, low IFN-gamma, high TNF-alpha, or low RANTES, depending on age and gender.

Schistosoma mansoni infection is highly endemic in parts of Uganda, and periportal fibrosis is common in communities along the shore of Lake Albert. In this study, we have identified cellular immune responses associated with fibrosis. A cohort of 199 individuals aged 6-50, resident in the village for at least 10 years or since birth, were examined for evidence of periportal fibrosis by ultrasound using the Niamey protocol. Whole-blood samples were assayed for levels of nine cellular immune molecules (IL-3, IL-4, IL-5, IL-10, IL-13, TNF-alpha, IFN-gamma, IL-1beta, and RANTES) in the absence of in vitro Ag stimulation, and after stimulation with egg and worm Ags. A lack of Ag specificity allowed the number of variables in the analysis to be reduced by factor analysis. The resulting factor scores were then entered into a risk analysis using a classification tree algorithm. Children, adult males, and adult females had different factors associated with fibrosis. Most cases of fibrosis in children (eight of nine) were associated with low (<47th percentile) IL-10 factor scores. Adult females at lowest risk had relatively high IFN-gamma factor scores (>83rd percentile), whereas those at highest risk had a combination of intermediate (32nd to 83rd percentile) IFN-gamma and relatively high (>60th percentile) TNF-alpha factor scores. Adult males at lowest risk of fibrosis had moderate TNF-alpha factor scores (55th to 82nd percentile), and a high risk was associated with either high TNF-alpha factor scores (>82nd percentile), or intermediate TNF-alpha combined with low RANTES factor scores (<58th percentile). These results demonstrate that periportal fibrosis is associated with cytokine production profiles that vary with both age and gender.

Cytokine production in whole blood cultures from a fishing community in an area of high endemicity for Schistosoma mansoni in Uganda: the differential effect of parasite worm and egg antigens.

The human host is continuously exposed to the egg and the adult worm developmental stages of Schistosoma mansoni during chronic infections with the parasite. To assess the cytokine responses induced by these different costimulating stages and how they are influenced by host age and infection intensity, whole blood samples from a cross-sectional cohort of 226 members of a Ugandan fishing community who had been resident in an area with high transmission of S. mansoni for the previous 10 years or from birth were stimulated with S. mansoni egg antigen (SEA) or worm antigen (SWA). SWA-specific gamma interferon (IFN-gamma) production increased with age, and the levels of SWA- and SEA-specific interleukin 3 (IL-3) were weakly correlated with schistosome infection intensity. The production of most cytokines was little affected by age or infection intensity but was either SEA or SWA specific. One hundred thirty-two members of the cohort coproduced IL-5 and IL-13 specifically in response to SWA, whereas only 15 produced these cytokines, and at much lower levels, in response to SEA. IL-10, IL-4, and IFN-gamma were also produced in response to SWA, whereas the response to SEA consisted almost exclusively of IL-10. Our results suggest that, in contrast to what has been described for the murine model of S. mansoni and during acute human infections, chronic intense exposure to and infection with S. mansoni in this cohort resulted in very low levels of response to SEA in vitro in the presence of a vigorous and mixed Th1-Th2 response to SWA.

The relationship between age, sex, egg-count and specific antibody responses against Schistosoma mansoni antigens in a Ugandan fishing community.

In schistosomiasis endemic areas, antibody isotype responses against Schistosoma mansoni antigens vary with host age, sex and duration or intensity of infection, and are associated with susceptibility or resistance to infection. Identifying the quality and quantity of these responses is important to our understanding of the host-parasite relationship; however, the various host and parasite factors have a strong tendency to confound each other. We investigated the relationships and interactions between age, sex, faecal egg-counts and specific antibody isotype (IgA, IgG1, IgG2, IgG3, IgG4, IgE, IgM) responses to S. mansoni worm (SWA) and egg (SEA) antigens, amongst 380 individuals aged 5-59 from a fishing community from Uganda. This community was characterized by high levels of exposure, and high infection intensities, with higher infection intensities in males than in females. Multivariate anova was conducted with interaction terms between the three categorized explanatory variables. Most anti-SWA responses increased with age, whereas anti-SEA responses tended to decline with age, especially after puberty. IgG1-SWA, IgG4-SWA, IgG4-SEA, IgE-SWA responses increased with egg count, whereas IgG2-SEA decreased with egg count. IgG1-SWA, IgG4-SWA, IgE-SWA and IgG4-SEA responses were independently higher in males, whereas IgG2-SEA responses were independently higher in females. The significant effects of sex on isotype responses to adult worm antigens may be partly because of different levels of cumulative exposure. IgG4-SEA and IgG4-SWA were both strongly correlated with egg count. Patterns of IgE-SWA responses were qualitatively different to IgG4 responses, suggesting independent pathways of regulation.