Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection.

Epidermal Langerhans cells (LCs) play a key role in immune defense mechanisms and in numerous immunological disorders. In this report, we show that percutaneous infection of C57BL/6 mice with the helminth parasite Schistosoma mansoni leads to the activation of LCs but, surprisingly, to their retention in the epidermis. Moreover, using an experimental model of LC migration induced by tumor necrosis factor (TNF)-alpha, we show that parasites transiently impair the departure of LCs from the epidermis and their subsequent accumulation as dendritic cells in the draining lymph nodes. The inhibitory effect is mediated by soluble lipophilic factors released by the parasites and not by host-derived antiinflammatory cytokines, such as interleukin-10. We find that prostaglandin (PG)D2, but not the other major eicosanoids produced by the parasites, specifically impedes the TNF-alpha-triggered migration of LCs through the adenylate cyclase-coupled PGD2 receptor (DP receptor). Moreover, the potent DP receptor antagonist BW A868C restores LC migration in infected mice. Finally, in a model of contact allergen-induced LC migration, we show that activation of the DP receptor not only inhibits LC emigration but also dramatically reduces the contact hypersensitivity responses after challenge. Taken together, we propose that the inhibition of LC migration could represent an additional stratagem for the schistosomes to escape the host immune system and that PGD2 may play a key role in the control of cutaneous immune responses.

Cutaneous interleukin-7 transgenic mice display a propitious environment to Schistosoma mansoni infection.

Interleukin (IL)-7 is produced early in Schistosoma mansoni-infected human and murine skin and was recently shown to favour parasite development. In the present work, we investigated the participation of keratinocyte-derived IL-7 in this process. Keratinocytes are the predominant cellular constituents of the epidermis and the first tissue encountered by the parasite when it infects the vertebrate host. We therefore infected IL-7 cutaneous transgenic mice and compared several parasitological and immunological parameters to those of infected littermate controls. In transgenic mice, an increased number of total adult worms was observed while egg number and female fecundity remained unchanged. Additionally, transgenic animals displayed a more intensive hepatic fibrosis. In parallel, infected IL-7 transgenic animals showed a dominant Th2-type humoral response towards egg antigens. The results presented here confirm and reinforce the key role play by IL-7 in S. mansoni-vertebrate host interplay, beginning with keratinocyte-derived IL-7.

Infection of mice lacking interleukin-7 (IL-7) reveals an unexpected role for IL-7 in the development of the parasite Schistosoma mansoni.

A single intradermal administration of recombinant interleukin-7 (IL-7) has been shown to aggravate the course of murine schistosomiasis, to favor the development of Th2-associated antibodies specific for the parasite, and to alter migration kinetics and/or migratory route of the parasite within its vertebrate host. Here we show that after infection of IL-7-deficient mice with Schistosoma mansoni, the predominant parasite-specific humoral response follows a Th1 pattern, and the development of the parasite is greatly impaired. In IL-7-deficient mice, increased numbers of larvae reach the lungs and fewer larvae reach the liver, compared to control mice. In the absence of IL-7, female worms show an altered fecundity, leading to decreased numbers of eggs trapped in the tissues and to an amelioration of the pathology of the infected host. The most striking observation is the blockade of parasite growth in an IL-7-defective environment, leading to dwarf male and female worms. The results of this study have important implications for the role of IL-7 in the host-parasite relationship and show how parasites can disable or evade the host immune response.

Dermal endothelial cells and keratinocytes produce IL-7 in vivo after human Schistosoma mansoni percutaneous infection.

The parasite Schistosoma mansoni infects its definitive mammalian host through an obligatory cutaneous penetration. In this work, we studied early immune response following migration of larvae through human skin, the first immunocompetent organ encountered by the parasite. For this purpose we used an experimental model of severe combined immunodeficient mice engrafted with human skin and injected with autologous PBL. Six days after percutaneous infection, we observed an infiltration of lymphocytes within the human skin, predominantly composed of CD4+ T cells. Moreover, among the cytokines potentially present in the infected skin, immunohistochemistry analysis revealed an in vivo expression of IL-7 in the epidermal layers and strikingly at the level of vascular endothelium. Using an in vitro coculture system, we showed that the S. mansoni larvae directly trigger IL-7 production by human dermal microvascular endothelial cells but not by keratinocytes. Finally, measurements of IL-7 concentrations in plasma of 187 S. mansoni-infected individuals showed that the youngest, which are also the most infected, displayed the highest IL-7 levels. Together, these findings describe dermal endothelial cells as a novel source of IL-7, a cytokine particularly important in schistosomiasis.

Infection of B-cell-deficient mice by the parasite Schistosoma mansoni: demonstration of the participation of B cells in granuloma modulation.

The contribution of B lymphocytes to immunity towards the parasite Schistosoma mansoni has been investigated in a mouse strain rendered genetically B-cell deficient (the muMT mouse). These studies demonstrated that T cells primed in vivo in B-cell-deficient mice proliferate less efficiently in vitro in response to parasite antigenic extracts except at 10 weeks of infection. In addition, analysis of the cytokine profiles (IL-2, IL-4, IL-5 and IFN-gamma), investigated using RT-PCR, showed that spleens of muMT animals displayed a predominant Th1-like profile compared to control, B-cell-intact infected mice. This showed that B cells, either per se or through their secretions, are involved in the in vivo generation and/or maximal expansion of Th2-type T lymphocytes during the course of murine S. mansoni infection. Interestingly, the data showed that B-cell-deficient mice display an increased hepatic fibrosis at 10 weeks postinfection (p.i.), whereas they behaved like infected controls, with regard to the other assessed parasitological parameters (e.g. worm burden estimation). This demonstrated that even if B lymphocytes are not essential for the development of the general immune response towards S. mansoni in the mouse, they may nevertheless be involved in the correct immunoregulation of the granulomatous reaction around the eggs.

Interleukin-7 in the skin of Schistosoma mansoni-infected mice is associated with a decrease in interferon-gamma production and leads to an aggravation of the disease.

The effect of recombinant interleukin-7 (rIL-7) on the course of murine schistosomiasis and the development of the accompanying immune response were investigated. We demonstrated that IL-7 expression could be detected in the skin of infected mice from 1 to 21 days following infection. We here report that intradermal injection of exogenous human IL-7, prior to the penetration of the parasite into the skin, leads to a more severe liver pathology and an increased number of surviving adult parasites. In addition, injection of rIL-7 alters parasite migration (estimation of burdens of young larvae in lungs and liver). Administration of rIL-7 led to a decrease of IL-12 and interferon-gamma-(IFN-gamma) specific messengers RNA in skin and, more markedly, in skin-draining lymph nodes. The number of B220 expressing cells was increased, and T-cell number was reduced, in IL-7-treated infected mice. In addition, levels of IFN-gamma and IL-4 in sera were significantly reduced, whereas there was a shift from a Th1 to a Th2 type associated humoral response towards the egg antigens. Our experimental observation illustrate that the exogenous administration of rIL-7 affects both the development of the host's immune response and the behaviour of the parasite within the infected host. The early and specific production of IL-7 in the host skin, following infection with Schistosoma mansoni, raises fascinating questions concerning the relationships between the parasite and its host at the very beginning of their interaction.