Soluble egg antigens of the parasitic helminth Schistosoma mansoni (S. mansoni egg antigen [SEA]) induce strong Th2 responses both in vitro and in vivo. However, the specific molecules that prime the development of Th2 responses have not been identified. We report that omega-1, a glycoprotein which is secreted from S. mansoni eggs and present in SEA, is capable of conditioning human monocyte-derived dendritic cells in vitro to drive T helper 2 (Th2) polarization with similar characteristics as whole SEA. Furthermore, using IL-4 dual reporter mice, we show that both natural and recombinant omega-1 alone are sufficient to generate Th2 responses in vivo, even in the absence of IL-4R signaling. Finally, omega-1–depleted SEA displays an impaired capacity for Th2 priming in vitro, but not in vivo, suggesting the existence of additional factors within SEA that can compensate for the omega-1–mediated effects. Collectively, we identify omega-1, a single component of SEA, as a potent inducer of Th2 responses.

Schistosome ribonuclease Omega-1 primes DCs to generate Th2 responses by binding and internalization by the mannose receptor and by subsequently impairing protein synthesis.

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 ...

During infection with the helminth parasite Schistosoma mansoni, the deposition of eggs coincides with the onset of IL-4 production and Th2 development. Although IL-4 is known as a potent inducer of Th2 differentiation, the mechanism by which schistosome eggs induce IL-4 production is not clear. In this study, we demonstrate that the S. mansoni egg Ag (SmEA) induces IgE-dependent IL-4 production by basophils derived from Heligmosomoides polygyrus-infected or OVA/alum-immunized mice in the absence of pathogen-specific IgE. The effect is mediated by the secretory glycoprotein IPSE/alpha-1, because IPSE/alpha-1-depleted SmEA no longer induces cytokine production. Conversely, recombinant IPSE/alpha-1 is sufficient to induce IL-4 production. Importantly, the injection of SmEA or recombinant IPSE/alpha-1 into H. polygyrus-infected 4get/KN2 IL-4 reporter mice rapidly induces the dose-dependent IL-4 production by basophils in the liver, a major site of egg deposition. Thus, IPSE/alpha-1 induces basophils to produce IL-4 even in the absence of Ag-specific IgE.

Recent studies have shown that human basophils, like mast cells, generate interleukin (IL)-4 following immunological activation and may thus participate in late-phase allergic and inflammatory processes. Here, we report the capacity of human basophils to release IL-13 within 24 h following stimulation with anti-IgE. Additionally, in 14 out of 31 experiments, we observed that basophils rapidly release performed IL-4 within 5-10 min, as well as newly generated IL-4, which was released 4 h following stimulation of the cells with anti-IgE. In contrast to the biphasic release of IL-4 from the cells, no preformed IL-13 was detected at earlier times (5-30 min). Preformed IL-4 and IL-4 and IL-13 generated de novo were also released after stimulation of the cells with IL-3; an enhanced production of these cytokines was observed using a combination of IL-3 and anti-IgE. We conclude from these data that, by releasing performed IL-4 and IL-4 and IL-13 generated de novo, human basophils may be centrally involved in the orchestration of allergic inflammation by providing a trigger to IL-4-mediated T helper 2 lymphocyte activation, B cell IgE switching, and increased vascular adhesion molecule expression.