Posttreatment changes in cytokines induced by Schistosoma mansoni egg and worm antigens: dissociation of immunity- and morbidity-associated type 2 responses

Abstract

Background: Human type 2 cytokine responsiveness to schistosome antigens increases after treatment; due either to removal of the immunosuppressive effects of active infection or immunological boosting by antigens released from dying parasites. We determined the responsiveness to Schistosoma mansoni over a 2-year period, when reinfection was restricted by interrupting transmission.

Methods: The proinflammatory and type 2 responses of Kenyan schoolchildren were measured before, and 1 year and 2 years posttreatment in whole blood cultures stimulated with soluble egg antigen (SEA) or soluble worm antigen (SWA). The site of S. mansoni transmission was molluscicided throughout.

Results: Pretreatment proinflammatory responses to SEA were high but reduced 1 and 2 years posttreatment, whereas type 2 responses were low pretreatment and increased 1 and 2 years posttreatment. Type 2 responses to SWA were high pretreatment and increased at 1 year, with no further increases at 2 years posttreatment. Children infected at follow-up had lower SEA, but not SWA, posttreatment type 2 responsiveness. Increases at 1 year in type 2 SWA, but not SEA, responsiveness correlated with pretreatment egg counts.

Conclusions: Removal of immunosuppressive effects of active infection increases SEA type 2 responsiveness; long-term SWA type 2 responsiveness is due to treatment-induced immunological boosting. Dissociation of type 2 responses potentially protects against severe egg-associated immunopathology during infection, while allowing worm-antigen derived immunity to develop.

Keywords: Schistosoma mansoni; cytokine; human; immunity; immunopathology; praziquantel.

Figure 1.

Cohort recruitment and follow-up. Shown is the treatment efficacy at 5 weeks, and the success of follow-up and prevalence (P) of Schistosoma mansoni at 1 year and 2 years posttreatment. ^aThree individuals successfully followed up at 1 and 2 years posttreatment did not provide stool samples at 5 weeks. ^bPrevalence based on 39 individuals and ^c30 individuals, due to missing parasitological data among those followed up immunologically at 2 years posttreatment.

Figure 2.

Cytokine production in whole blood cultures stimulated with Schistosoma mansoni antigens and the mitogen phytohemagglutin (PHA). The levels of cytokines and the chemokine CCL5 were measured in pretreatment whole blood culture supernatants left unstimulated (Med), or stimulated with soluble egg antigen (SEA), soluble worm antigen (SWA), or with the mitogen PHA. The boxes show the medians and interquartile ranges of the cytokine levels, with whiskers representing up to 1.5 times the interquartile range. Circles represent outlying data points. Nonsignificant (ns) comparisons using paired Wilcoxon tests are indicated. All other comparisons remained significant after correction for multiple testing by Simes-modified Bonferroni method. Abbreviations: IFN-γ, interferon gamma; IL, interleukin; TNF-α, tumor necrosis factor alpha.

Figure 3.

Longitudinal cytokine production in whole blood cultures stimulated with Schistosoma mansoni soluble egg antigen (SEA). Shown are the levels of cytokines and the chemokine CCL5 measured in whole blood cultures stimulated with SEA pretreatment, 1 year posttreatment, and 2 years posttreatment. Nonsignificant (ns) comparisons using paired Wilcoxon tests are indicated. All other longitudinal comparisons remained significant after correction for multiple testing by Simes-modified Bonferroni method. Abbreviations: IFN-γ, interferon gamma; IL, interleukin; TNF-α, tumor necrosis factor alpha.

Figure 4.

Longitudinal type 2 cytokine production in whole blood cultures stimulated with Schistosoma mansoni soluble worm antigen (SWA). Shown are the levels of type 2 cytokines measured in whole blood cultures stimulated with SWA pretreatment, 1 year posttreatment, and 2 years posttreatment. Nonsignificant (ns) comparisons using paired Wilcoxon tests are indicated. All other longitudinal comparisons remained significant after correction for multiple testing by Simes-modified Bonferroni method. Abbreviation: IL, interleukin.

Figure 5.

Posttreatment type 2 cytokine production in whole blood cultures stimulated with schistosome antigens in children positive and negative for Schistosoma mansoni infection. Shown are the levels of type 2 cytokines measured in whole blood cultures stimulated with either soluble egg antigen (SEA) or soluble worm antigen (SWA), 1 year and 2 years posttreatment for schistosomiasis, for children who did (1 year posttreatment [n = 32], 2 years posttreatment [n = 42]) and did not have detectable infections (1 year posttreatment [n = 46] and 2 years posttreament [n = 31]) at those time points. Nonsignificant (ns) comparisons using Mann–Whitney tests are indicated. All other comparisons remained significant after correction for multiple testing by Simes-modified Bonferroni method. Abbreviations: –ve, negative; +ve, positive; IL, interleukin.