The eggs of the parasitic trematode Schistosoma mansoni are powerful inducers of a T helper type 2 (Th2) immune response and immunoglobulin E (IgE) production. S. mansoni egg extract (SmEA) stimulates human basophils to rapidly release large amounts of interleukin (IL)-4, the key promoter of a Th2 response. Here we show purification and sequence of the IL-4-inducing principle of S. mansoni eggs (IPSE). Stimulation studies with human basophils using SmEA fractions and natural and recombinant IPSE as well as neutralization and immunodepletion studies using antibodies to recombinant IPSE demonstrate that IPSE is the bioactive principle in SmEA leading to activation of basophils and to expression of IL-4 and IL-13. Regarding the mechanism of action, blot analysis showed that IPSE is an IgE-binding factor, suggesting that it becomes effective via crosslinking receptor-bound IgE on basophils. Immunohistology revealed that IPSE is enriched in and secreted from the subshell area of the schistosome egg. We conclude from these data that IPSE may be an important parasitederived component for skewing the immune response toward Th2.Infection with the parasitic trematode Schistosoma mansoni leads to a pronounced Th2 1 response and to elevated IgE production both in humans and in experimental animals. The definition of parasite-derived products capable of skewing the immune response toward Th2 would not only enhance our understanding of the defense mechanisms involved in helminth infections but may also lead to new insights into the pathogenesis of immediate-type hypersensitivity diseases such as asthma. However, in contrast to our increasing understanding of how pathogen-derived products can initiate Th1-type immune responses, there is so far little detailed knowledge about the nature of the parasite-derived molecule(s) and the underlying mechanisms that trigger and/or amplify a Th2-type reaction. In S. mansoni infection, a critical role in inducing a polarized Th2 response is played by the egg stage of the parasite (1), since a Th2 response and IgE production are only observed after egg deposition or following injection of schistosome eggs (2) or extracts thereof (3) into naive animals. By contrast, the initial larval (schistosomula) and adult worm stages rather induce a response skewed to Th1.It is now firmly established, both in vivo and in vitro, that the cytokine profile present during an immune reaction is an important element in directing the response to Th1 or Th2 and that IL-4 is the key cytokine responsible for biasing the immune reaction toward a Th2 phenotype (4 -7). In the human system, basophils are a prominent source of IL-4 and IL-13; these cells secrete large amounts of IL-4 and IL-13 in response to IgE-receptor cross-linking or activation by a combination of IL-3 and C5a (8, 9). Indeed, human basophils can be viewed as "innate Th2-type" effector cells, since IL-4 and IL-13 are expressed in a very restricted manner without production of any of the cytokines involved in Th1-type immune responses. We therefore ...

Dietary lectins, present in beans and other edible plant products, pose a potential threat to consumers due to their capacity to induce histamine release from basophils. In this study, we analyzed the capacity of 16 common, in particular dietary, lectins to induce human basophils to secrete IL-4 and IL-13, the key promoters of Th2 responses and IgE synthesis. Several of the lectins, especially concanavalin A, lentil lectin, phytohemagglutinin, Pisum sativum agglutinin and Sambucus nigra agglutinin, triggered basophils to release IL-4 at concentrations of up to 1 ng/10(6) basophils. Lectins with high IL-4-inducing capacity also stimulated the release of IL-13 and histamine. Lectin-induced IL-4 and IL-13 release reached a maximum after 4-6 h and more than 18 h, respectively. Affinoblotting revealed that lectins with the capacity to induce mediator release bind to IgE, suggesting IgE binding as initial step of signal generation. In conclusion, several dietary lectins can trigger human basophils to release IL-4 and IL-13. Since lectins can enter the circulation after oral uptake, they might play a role in inducing the so-called early IL-4 required to switch the immune response towards a Th2 response and type I allergy.

The etiology of IgE–mediated allergies is complex and, thus far, not completely understood. A common feature, however, is the overproduction of IgE–inducing cytokines, e.g. interleukin–4(IL–4), compared to IgE–antagonistic cytokines, such as interferon–γ or IL–12. IgE–inducing cytokines are produced by T helper type 2 (Th2) cells. The differentiation of naive T cells towards the Th2 phenotype seems to be crucially dependent upon the particular cytokines present in the early stages of an immune response. Concerning the factors driving Th2 differentiation, the so–called 'early IL–4’ seems to play an important role, although there is some controversy over the degree of its requirement and its cellular source. We have recently demonstrated that basophils might be such a source, since they rapidly release IL–4 upon antigen–specific or nonantigen–specific stimuli, such as certain lectins. This makes lectins interesting candidates for inducing a Th2 response and IgE–mediated allergy in unsensitized individuals.

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We have recently shown that soluble extracts from Schistosoma mansoni eggs (SmEA) triggered basophils from nonsensitized donors to rapidly release interleukin (IL)-4. Assuming that this mechanism might play a role in vivo in biasing the immune response towards a Th2 phenotype, we determined basic properties of the IL-4-inducing activity contained in SmEA. Sensitivity to pepsin digestion indicated protein nature. Binding to and specific elution from Concanavalin A-sepharose suggested that this protein contains mannose residues, thus being a glycoprotein. The IL-4-inducing activity was stable for 30 min at room temperature towards shifting the pH between 3 and 10. When incubated at 100 degrees C, it was stable at pH 3, but less stable at neutral and alkaline pH. Electroelution from an SDS-PAGE gel indicated an apparent molecular weight of the IL-4-inducing activity between 31 and 66 kDa. Although binding to purified human immunoglobulin E (IgE) and activating basophils IgE-dependently, SmEA appears to activate basophils in a non-antigen-specific way, since the cells were purified from noninfected donors. Because the IL-4-inducing activity was found to be released from eggs, it could be an important factor in the environment of the eggs skewing the immune response towards the Th2 phenotype.