Produção Nacional
Revisado por pares
A double edged sword: Schistosoma mansoni Sm29 regulates both Th1 and Th2 responses in inflammatory mucosal diseases
2016; Elsevier BV; Volume: 9; Issue: 6 Linguagem: Inglês
10.1038/mi.2016.69
ISSN1935-3456
AutoresSérgio C. Oliveira, Bárbara C. Figueiredo, Luciana Santos Cardoso, Edgar M. Carvalho,
Tópico(s)Parasite Biology and Host Interactions
ResumoParasitic helminths develop the capability to live for decades in the human host. Besides that, parasites acquire the ability to modulate human immune responses, what has always called the attention of many scientists worldwide. Among these helminths is Schistosoma mansoni, one of the main agents of schistosomiasis, which lives for years within human blood vessels. Schistosomiasis is the most important human helminthic infection in terms of global morbidity and mortality,1van der Werf MJ Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa.Acta Trop. 2003; 86 (12745133): 125-13910.1016/S0001-706X(03)00029-9Crossref PubMed Scopus (708) Google Scholar representing a major public health problem in endemic countries, debilitating infected people due to abdominal pain, portal hypertension, and hepatic and intestinal fibrosis in chronically infected patients.1van der Werf MJ Quantification of clinical morbidity associated with schistosome infection in sub-Saharan Africa.Acta Trop. 2003; 86 (12745133): 125-13910.1016/S0001-706X(03)00029-9Crossref PubMed Scopus (708) Google Scholar, 2Steinmann P. Keiser J. Bos R. Tanner M. Utzinger J. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk.Lancet Infect. Dis. 2006; 6 (16790382): 411-42510.1016/S1473-3099(06)70521-7Abstract Full Text Full Text PDF PubMed Scopus (1565) Google Scholar On the other hand, evidence reveals that S. mansoni and other helminths downregulate inflammatory responses in immune-mediated mucosal diseases.3Bafica AM Changes in T-cell and monocyte phenotypes in vitro by schistosoma mansoni antigens in cutaneous leishmaniasis patients.J. Parasitol. Res. 2012; 2012 (23209879): 52030810.1155/2012/520308Crossref PubMed Scopus (7) Google Scholar, 4Bafica AM Schistosoma mansoni antigens alter the cytokine response in vitro during cutaneous leishmaniasis.Mem. Inst. Oswaldo Cruz. 2011; 106 (1:CAS:528:DC%2BC3sXhs1ejtb4%3D, 22124559): 856-86310.1590/S0074-02762011000700012Crossref PubMed Scopus (13) Google Scholar, 5Cardoso LS Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation.Clin. Exp. Immunol. 2010; 160 (1:CAS:528:DC%2BC3cXms1yjtb4%3D, 20132231): 266-27410.1111/j.1365-2249.2009.04084.xCrossref PubMed Scopus (61) Google Scholar, 6Lima LM Schistosoma antigens downmodulate the in vitro inflammatory response in individuals infected with human T cell lymphotropic virus type 1.Neuroimmunomodulation. 2013; 20 (1:CAS:528:DC%2BC3sXhtVWhtb%2FK, 23752304): 233-23810.1159/000348700Crossref PubMed Scopus (12) Google Scholar Fortunately, the control of the host inflammatory response appears not to be strictly dependent on parasite infection, but can be extended to pathogen-derived antigens,3Bafica AM Changes in T-cell and monocyte phenotypes in vitro by schistosoma mansoni antigens in cutaneous leishmaniasis patients.J. Parasitol. Res. 2012; 2012 (23209879): 52030810.1155/2012/520308Crossref PubMed Scopus (7) Google Scholar, 5Cardoso LS Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation.Clin. Exp. Immunol. 2010; 160 (1:CAS:528:DC%2BC3cXms1yjtb4%3D, 20132231): 266-27410.1111/j.1365-2249.2009.04084.xCrossref PubMed Scopus (61) Google Scholar, 6Lima LM Schistosoma antigens downmodulate the in vitro inflammatory response in individuals infected with human T cell lymphotropic virus type 1.Neuroimmunomodulation. 2013; 20 (1:CAS:528:DC%2BC3sXhtVWhtb%2FK, 23752304): 233-23810.1159/000348700Crossref PubMed Scopus (12) Google Scholar, 7Pacifico LG Schistosoma mansoni antigens modulate experimental allergic asthma in a murine model: a major role for CD4+ CD25+ Foxp3+ T cells independent of interleukin-10.Infect. Immun. 2009; 77 (1:CAS:528:DC%2BD1MXhs1Sju7c%3D, 18824533): 98-10710.1128/IAI.00783-07Crossref PubMed Scopus (94) Google Scholar suggesting that some S. mansoni molecules are useful weapons to control inflammation. Among helminths that regulate inflammation, S. mansoni appears to induce particularly strong downmodulation of inflammatory responses.8Pearce EJ MacDonald AS The immunobiology of schistosomiasis.Nat. Rev. Immunol. 2002; 2 (1:CAS:528:DC%2BD38XkvFKksrc%3D, 12094224): 499-51110.1038/nri843Crossref PubMed Scopus (896) Google ScholarS. mansoni acute phase of infection is characterized by a strong T-helper (Th)1 inflammatory response, which is regulated by interleukin (IL)-10 production and evolves to a parasite antigen-driven Th2 response.8Pearce EJ MacDonald AS The immunobiology of schistosomiasis.Nat. Rev. Immunol. 2002; 2 (1:CAS:528:DC%2BD38XkvFKksrc%3D, 12094224): 499-51110.1038/nri843Crossref PubMed Scopus (896) Google Scholar, 9Montenegro SM Cytokine production in acute versus chronic human Schistosomiasis mansoni: the cross-regulatory role of interferon-gamma and interleukin-10 in the responses of peripheral blood mononuclear cells and splenocytes to parasite antigens.J. Infect. Dis. 1999; 179 (1:CAS:528:DyaK1MXjvFelt7k%3D, 10228073): 1502-151410.1086/314748Crossref PubMed Scopus (93) Google Scholar IL-10 is able to inhibit the production of proinflammatory mediators such as interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and nitric oxide (NO).8Pearce EJ MacDonald AS The immunobiology of schistosomiasis.Nat. Rev. Immunol. 2002; 2 (1:CAS:528:DC%2BD38XkvFKksrc%3D, 12094224): 499-51110.1038/nri843Crossref PubMed Scopus (896) Google Scholar Particular functions mediated by this cytokine are the inhibition of T cells, inhibition of dendritic cell (DC) differentiation, activation of macrophages, and regulation of the Th1- and Th2-type cytokines.10Hoffmann KF Cheever AW Wynn TA IL-10 and the dangers of immune polarization: excessive type 1 and type 2 cytokine responses induce distinct forms of lethal immunopathology in murine schistosomiasis.J. Immunol. 2000; 164 (1:CAS:528:DC%2BD3cXktFWltLw%3D, 10843696): 6406-641610.4049/jimmunol.164.12.6406Crossref PubMed Scopus (366) Google Scholar Some S. mansoni proteins have the ability to increase the production of IL-10 in vitro and in vivo. Among them, Sm29 (Genbank acession number AAC98911.1) has been studied as a potential immunoregulatory molecule.3Bafica AM Changes in T-cell and monocyte phenotypes in vitro by schistosoma mansoni antigens in cutaneous leishmaniasis patients.J. Parasitol. Res. 2012; 2012 (23209879): 52030810.1155/2012/520308Crossref PubMed Scopus (7) Google Scholar, 4Bafica AM Schistosoma mansoni antigens alter the cytokine response in vitro during cutaneous leishmaniasis.Mem. Inst. Oswaldo Cruz. 2011; 106 (1:CAS:528:DC%2BC3sXhs1ejtb4%3D, 22124559): 856-86310.1590/S0074-02762011000700012Crossref PubMed Scopus (13) Google Scholar, 5Cardoso LS Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation.Clin. Exp. Immunol. 2010; 160 (1:CAS:528:DC%2BC3cXms1yjtb4%3D, 20132231): 266-27410.1111/j.1365-2249.2009.04084.xCrossref PubMed Scopus (61) Google Scholar, 11Cardoso FC Schistosoma mansoni tegument protein Sm29 is able to induce a Th1-type of immune response and protection against parasite infection.PLoS Negl. Trop. Dis. 2008; 2 (18827884): e30810.1371/journal.pntd.0000308Crossref PubMed Scopus (147) Google Scholar Sm29 is a membrane-bound glycoprotein found on S. mansoni tegument that seems to be important in the surface biology of this parasite.11Cardoso FC Schistosoma mansoni tegument protein Sm29 is able to induce a Th1-type of immune response and protection against parasite infection.PLoS Negl. Trop. Dis. 2008; 2 (18827884): e30810.1371/journal.pntd.0000308Crossref PubMed Scopus (147) Google Scholar Sm29 amino acid sequence shows homology to some unknown S. japonicum proteins: SJCHGC03008, SJCHGC05668, SJCHGC05578, and SJCHGC02532 (53, 53, 49, and 37% identity, respectively). Besides S. japonicum proteins, Sm29 shows no similarity to any other protein deposited in databases.12Cardoso FC Pinho JM Azevedo V. Oliveira SC Identification of a new Schistosoma mansoni membrane-bound protein through bioinformatic analysis.Genet. Mol. Res. 2006; 5 (1:CAS:528:DC%2BD28XhtFGitb7O, 17183472): 609-618PubMed Google Scholar On stimulation with Sm29 in vitro, increased IL-10 production was observed in both splenocytes of Sm29-vaccinated mice and in peripheral blood mononuclear cell (PBMC) of S. mansoni-infected individuals.11Cardoso FC Schistosoma mansoni tegument protein Sm29 is able to induce a Th1-type of immune response and protection against parasite infection.PLoS Negl. Trop. Dis. 2008; 2 (18827884): e30810.1371/journal.pntd.0000308Crossref PubMed Scopus (147) Google Scholar This report aims to discuss the available evidence regarding Sm29 importance as a potential therapeutic agent against two important mucosal inflammatory diseases: leishmaniasis and asthma. Leishmaniasis is a public health problem in at least 88 countries, in which ∼350 million people are at risk, and 1.5 million cases emerge per year.13Desjeux P. The increase in risk factors for leishmaniasis worldwide.Trans. R. Soc. Trop. Med. Hyg. 2001; 95 (1:STN:280:DC%2BD3MvksFyisw%3D%3D, 11490989): 239-24310.1016/S0035-9203(01)90223-8Abstract Full Text PDF PubMed Scopus (788) Google Scholar Cutaneous leishmaniasis (CL) is the most common clinical manifestation of leishmaniasis, causing several skin lesions that can be destructive and disfiguring, and that occasionally advance to involve the mucosa.14Jones TC Epidemiology of American cutaneous leishmaniasis due to Leishmania braziliensis braziliensis.J. Infect. Dis. 1987; 156 (1:STN:280:DyaL2s3lt1Chsg%3D%3D, 3598227): 73-8310.1093/infdis/156.1.73Crossref PubMed Scopus (187) Google Scholar Early in the establishment of infection in skin and lymphoid organs, Leishmania parasites have multiple effects on macrophage and DC functions, inhibiting host innate anti-microbial defenses and impairing their capacity to initiate Th1 cell immunity.15Peters N. Sacks D. Immune privilege in sites of chronic infection: Leishmania and regulatory T cells.Immunol. Rev. 2006; 213 (1:CAS:528:DC%2BD28XhtF2lsrbF, 16972903): 159-17910.1111/j.1600-065X.2006.00432.xCrossref PubMed Scopus (112) Google Scholar The Th1-type immune response is crucial in leishmania infection control, by releasing IFN-γ necessary for activation of macrophages, leading to NO-mediated killing of the intracellular parasite.15Peters N. Sacks D. Immune privilege in sites of chronic infection: Leishmania and regulatory T cells.Immunol. Rev. 2006; 213 (1:CAS:528:DC%2BD28XhtF2lsrbF, 16972903): 159-17910.1111/j.1600-065X.2006.00432.xCrossref PubMed Scopus (112) Google Scholar Nevertheless, considerable evidence suggests that the excessive inflammation triggered by Th1 cytokine release is implicated in the pathogenesis of leishmaniasis. High levels of TNF-α and IFN-γ are associated with increase in lesion size in cutaneous leishmaniasis.16Bacellar O. Up-regulation of Th1-type responses in mucosal leishmaniasis patients.Infect. Immun. 2002; 70 (1:CAS:528:DC%2BD38XptVyitbc%3D, 12438348): 6734-674010.1128/IAI.70.12.6734-6740.2002Crossref PubMed Scopus (269) Google Scholar Moreover, patients positive for leismaniasis without clinical manifestations (subclinical individuals) shown low IFN-γ production and an equilibrium between IFN-γ and IL-10 production.15Peters N. Sacks D. Immune privilege in sites of chronic infection: Leishmania and regulatory T cells.Immunol. Rev. 2006; 213 (1:CAS:528:DC%2BD28XhtF2lsrbF, 16972903): 159-17910.1111/j.1600-065X.2006.00432.xCrossref PubMed Scopus (112) Google Scholar Current evidence supports an interaction between helminths and a co-Leishmania infection.17O'Neal SE Influence of helminth infections on the clinical course of and immune response to Leishmania braziliensis cutaneous leishmaniasis.J. Infect. Dis. 2007; 195 (17152018): 142-14810.1086/509808Crossref PubMed Scopus (53) Google Scholar Patients with CL and infected with helminths have smaller skin lesions and increased IL-5 compared with those with no helminth co-infection.17O'Neal SE Influence of helminth infections on the clinical course of and immune response to Leishmania braziliensis cutaneous leishmaniasis.J. Infect. Dis. 2007; 195 (17152018): 142-14810.1086/509808Crossref PubMed Scopus (53) Google Scholar In another study conducted by our research group with leishmaniasis patients, PBMC cultures were stimulated with Leishmania soluble antigen (SLA) and then, exposed or not to S. mansoni antigen Sm29. We observed reduction in IFN-γ and TNF-α production and increased levels of IL-10 and IL-5 in Sm29-treated cells.4Bafica AM Schistosoma mansoni antigens alter the cytokine response in vitro during cutaneous leishmaniasis.Mem. Inst. Oswaldo Cruz. 2011; 106 (1:CAS:528:DC%2BC3sXhs1ejtb4%3D, 22124559): 856-86310.1590/S0074-02762011000700012Crossref PubMed Scopus (13) Google Scholar This cytokine profile change coincides with an enhanced CD4+ T cell frequency detected in CL patients. Therefore, Sm29 used in this study downregulated the in vitro proinflammatory responses induced by SLA in a group of CL patients. Together with Th1 immune response, monocytes and macrophages are key cells to control Leishmania sp. infection but also can lead to immunopathology. In another study with a different cohort, we observed that Sm29 caused a decrease in HLA-DR expression in monocytes from cutaneous leishmaniasis patients after SLA stimulation which may interfere with antigen presentation during infection, reducing the magnitude of the immune response.3Bafica AM Changes in T-cell and monocyte phenotypes in vitro by schistosoma mansoni antigens in cutaneous leishmaniasis patients.J. Parasitol. Res. 2012; 2012 (23209879): 52030810.1155/2012/520308Crossref PubMed Scopus (7) Google Scholar However, the effect of MHC class II expression in regulation of inflammatory responses in CL patients requires further investigation. As DCs are critical to orchestrate the initial immune response during leishmaniasis, we tested the ability of Sm29 to modify DCs activation profile. We observed that Sm29 led to an increase in the frequency of DCs expressing IL-10 and IL-10 receptor (IL-10R) in patients with CL.18Lopes DM Dendritic cell profile induced by Schistosoma mansoni antigen in cutaneous leishmaniasis patients.BioMed Res. Int. 2014; 2014 (4182898, 25309922): 743069Crossref PubMed Scopus (4) Google Scholar IL-10 may act in the control of cell-mediated lesion development in leishmaniasis. In mucosal leishmaniasis (ML) there is a lack of IL-10 response, in part explained by the downregulation of the IL-10R.19Faria DR Decreased in situ expression of interleukin-10 receptor is correlated with the exacerbated inflammatory and cytotoxic responses observed in mucosal leishmaniasis.Infect. Immun. 2005; 73 (1:CAS:528:DC%2BD2MXhtlersbjF, 16299275): 7853-785910.1128/IAI.73.12.7853-7859.2005Crossref PubMed Scopus (154) Google Scholar These authors demonstrated that impaired expression of IL-10R in lesions from ML patients was associated with the exacerbated immune response observed in this clinical form of disease. The potential mechanisms used by Sm29 to regulate inflammatory responses during human leishmaniasis are summarized in Figure 1. In addition to the regulatory effect of Sm29 on Th1 responses, this antigen was also reported to modulate inflammatory Th2 immune responses involved in allergic disorders. Asthma is a chronic inflammatory disorder in the airways that affects as many as 300 million people worldwide, with a predicted increase in asthmatic patients living in urban areas.20Marks, G., Pearce, N., Strachan, D. & Asher, I. Global Burden of Disease Due to Asthma 2014 edn, Vol. The Global Asthma Report 2014, 16–21 (The Global Asthma Network, Auckland, New Zealand, 2014).Google Scholar Genetic factors contribute to the development of asthma, although the environmental factors are also surely important in this disease and is the main cause of high prevalence, especially in developed countries.20Marks, G., Pearce, N., Strachan, D. & Asher, I. Global Burden of Disease Due to Asthma 2014 edn, Vol. The Global Asthma Report 2014, 16–21 (The Global Asthma Network, Auckland, New Zealand, 2014).Google Scholar In asthmatic individuals, exposure to certain allergens triggers a dysregulated Th2-mediated immune response, with the secretion of characteristic cytokines, such as IL-4, IL-5 and IL-13, and also IgE antibodies.21Cho SH Stanciu LA Holgate ST Johnston SL Increased interleukin-4, interleukin-5, and interferon-gamma in airway CD4+ and CD8+ T cells in atopic asthma.Am. J. Respir. Crit. Care Med. 2005; 171 (15502111): 224-23010.1164/rccm.200310-1416OCCrossref PubMed Scopus (197) Google Scholar, 22Olin JT Wechsler ME Asthma: pathogenesis and novel drugs for treatment.BMJ. 2014; 349 (25420994): g551710.1136/bmj.g5517Crossref PubMed Scopus (169) Google Scholar IL-10 together with regulatory T cells, participate in balancing Th2-type inflammation, leading to suppression of the allergic response and asthma resolution.23Robinson DS Larche M. Durham SR Tregs and allergic disease.J. Clin. Invest. 2004; 114 (1:CAS:528:DC%2BD2cXpvFOqs7g%3D, 15545986): 1389-139710.1172/JCI200423595Crossref PubMed Scopus (266) Google Scholar Chronic helminth infections are characterized by skewing towards Th2 and regulatory immune responses. This regulatory network is thought to also temper responses to non-helminth antigens, like allergens, possibly leading to lower prevalence of allergies in subjects that are chronically infected with helminths.24Smits HH Microbes and asthma: opportunities for intervention.J. Allergy Clin. Immunol. 2016; 137 (26947981): 690-69710.1016/j.jaci.2016.01.004Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar The hygiene hypothesis postulates that decreased exposure to certain infectious agents is associated with changes in the immune system which predispose subjects to allergy.25Yazdanbakhsh M. Kremsner PG van Ree R. Allergy, parasites, and the hygiene hypothesis.Science. 2002; 296 (1:CAS:528:DC%2BD38XjtFamsLw%3D, 11964470): 490-49410.1126/science.296.5567.490Crossref PubMed Scopus (1195) Google Scholar Although there is a reduced IL-10 production in asthma patients,26Borish L. Aarons A. Rumbyrt J. Cvietusa P. Negri J. Wenzel S. Interleukin-10 regulation in normal subjects and patients with asthma.J. Allergy Clin. Immunol. 1996; 97 (1:STN:280:DyaK283ktlOjuw%3D%3D, 8648025): 1288-129610.1016/S0091-6749(96)70197-5Abstract Full Text Full Text PDF PubMed Scopus (442) Google Scholar during chronic schistosomiasis, IL-10 production is crucial in the regulation of granuloma around parasites' eggs deposited in the host's liver.8Pearce EJ MacDonald AS The immunobiology of schistosomiasis.Nat. Rev. Immunol. 2002; 2 (1:CAS:528:DC%2BD38XkvFKksrc%3D, 12094224): 499-51110.1038/nri843Crossref PubMed Scopus (896) Google Scholar IL-10 production that occurs during long-term helminth infections are inversely correlated with allergy. A pioneering study performed in Brazil revealed that S. mansoni-infected asthmatic patients from a rural area presented a milder course of asthma when compared with non-infected asthmatic subjects living in rural or urban areas with the same socio-economic conditions.27Medeiros Jr., M. Schistosoma mansoni infection is associated with a reduced course of asthma.J. Allergy Clin. Immunol. 2003; 111 (12743556): 947-95110.1067/mai.2003.1381Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar Further, asthmatic patients infected with S. mansoni were investigated for IL-10 production. The authors observed that PBMCs from these patients produced higher levels of allergen-specific IL-10 when compared with non-infected asthmatic cells.28Araujo MI Hoppe BS Medeiros Jr., M. Carvalho EM Schistosoma mansoni infection modulates the immune response against allergic and auto-immune diseases.Mem. Inst. Oswaldo Cruz. 2004; 99 (1:CAS:528:DC%2BD2cXosFyqtL4%3D, 15486631): 27-3210.1590/S0074-02762004000900005Crossref PubMed Google Scholar In another study, the expression of CTLA-4 was also significantly higher in lymphocytes of S. mansoni-infected asthmatic patients when compared to non-infected ones.29Oliveira RR Schistosoma mansoni infection alters co-stimulatory molecule expression and cell activation in asthma.Microb. Infect./Inst. Pasteur. 2009; 11 (1:CAS:528:DC%2BD1MXivVWgsLk%3D): 223-22910.1016/j.micinf.2008.11.017Crossref PubMed Scopus (21) Google Scholar CLTA-4 has an important role in inflammatory asthma modulation through the reduction of IL-4 and IL-5 secretion, and controlling Th2 immune responses.30Tsuyuki S. Tsuyuki J. Einsle K. Kopf M. Coyle AJ Costimulation through B7-2 (CD86) is required for the induction of a lung mucosal T helper cell 2 (TH2) immune response and altered airway responsiveness.J. Exp. Med. 1997; 185 (1:CAS:528:DyaK2sXjtVOisbo%3D, 9151904): 1671-167910.1084/jem.185.9.1671Crossref PubMed Scopus (219) Google Scholar A study performed by our group using laboratory animals demonstrated that mice infected with S. mansoni or exposed to parasite's eggs became more resistant to experimental OVA (OVA)-induced allergic airway inflammation (AAI). AAI protection was associated with increased frequency of CD4+ CD25+ Foxp3+ T cells independent of IL-10 activity, which is consistent with the hypothesis that parasite-induced regulatory T cells (Tregs) can down-modulate Th2 allergic inflammation via cell–cell contact-dependent mechanisms. Proteins secreted or localized on the surface of S. mansoni, that are in intimate contact with host tissues, may be more effective in triggering immunoregulatory processes. Among them is Sm29, which was used in immunization of mice before AAI induction with OVA. Immunization with Sm29 reduces the number of inflammatory cells in the lungs and the OVA-specific IgE levels. Sm29 immunized mice also presented a higher percentage of regulatory T cells, that lead to a consistent reduction in peribronchial airway inflammation and improved asthma resolution. It is also possible that IL-10 induced by Sm29 inhibits mast cell migration and activation interfering with allergic responses as previously demonstrated.31Kim HS Interleukin-10-producing CD5+ B cells inhibit mast cells during immunoglobulin E-mediated allergic responses.Sci. Signal. 2015; 8 (25783157): ra2810.1126/scisignal.2005861Crossref PubMed Scopus (24) Google Scholar However, further studies are required to confirm the modulatory effect of Sm29 in allergic asthma in humans. The potential mechanisms used by Sm29 to modulate experimental AAI are shown in Figure 2. Evidences presented here demonstrate that S. mansoni antigens seem to be protective against leishmaniasis and asthma. Although not the focus of this commentary, it has also been found that Sm29 can modulate Th1 responses induced by human T cell lymphotropic virus type 1 (HTLV-1) infection, which is the causal agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).6Lima LM Schistosoma antigens downmodulate the in vitro inflammatory response in individuals infected with human T cell lymphotropic virus type 1.Neuroimmunomodulation. 2013; 20 (1:CAS:528:DC%2BC3sXhtVWhtb%2FK, 23752304): 233-23810.1159/000348700Crossref PubMed Scopus (12) Google Scholar This regulatory effect was associated with increased levels of IL-10 induced by this antigen. Other studies, using S. mansoni infection or schistosome antigens have demonstrated that this parasite seems to also protect against the development of autoimmune diseases, such as diabetes32Zaccone P. The S. mansoni glycoprotein omega-1 induces Foxp3 expression in NOD mouse CD4(+) T cells.Eur. J. Immunol. 2011; 41 (1:CAS:528:DC%2BC3MXhtVOktbnE, 21710488): 2709-271810.1002/eji.201141429Crossref PubMed Scopus (76) Google Scholar, 33Bhargava P. Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and insulin resistance through direct and indirect control of metabolic pathways.Nat. Med. 2012; 18 (1:CAS:528:DC%2BC38XhsFOmtrfP, 23104131): 1665-167210.1038/nm.2962Crossref PubMed Scopus (94) Google Scholar, 34Hussaarts L. Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice.FASEB J. 2015; 29 (1:CAS:528:DC%2BC2MXhslSqtbnF, 25852044): 3027-303910.1096/fj.14-266239Crossref PubMed Scopus (132) Google Scholar, 35Zaccone P. Burton O. Miller N. Jones FM Dunne DW Cooke A. Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention in NOD mice.Eur. J. Immunol. 2009; 39 (1:CAS:528:DC%2BD1MXltlamu7k%3D, 19291704): 1098-110710.1002/eji.200838871Crossref PubMed Scopus (160) Google Scholar and inflammatory bowel diseases (IBDs).36Heylen M. Worm proteins of Schistosoma mansoni reduce the severity of experimental chronic colitis in mice by suppressing colonic proinflammatory immune responses.PLoS One. 2014; 9 (25313594): e11000210.1371/journal.pone.0110002Crossref PubMed Scopus (28) Google Scholar, 37Heylen M. Treatment with egg antigens of Schistosoma mansoni ameliorates experimental colitis in mice through a colonic T-cell-dependent mechanism.Inflamm. Bowel Dis. 2015; 21 (25437821): 48-5910.1097/MIB.0000000000000246Crossref PubMed Scopus (19) Google Scholar, 38Hasby EA Hasby Saad MA Shohieb Z. El Noby K. FoxP3+ T regulatory cells and immunomodulation after Schistosoma mansoni egg antigen immunization in experimental model of inflammatory bowel disease.Cell Immunol. 2015; 295 (1:CAS:528:DC%2BC2MXjslyguro%3D, 25766778): 67-7610.1016/j.cellimm.2015.02.013Crossref PubMed Scopus (28) Google ScholarS. mansoni infection results in long-lasting prevention of diabetes and IBDs characterized by a string Th2 response.34Hussaarts L. Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice.FASEB J. 2015; 29 (1:CAS:528:DC%2BC2MXhslSqtbnF, 25852044): 3027-303910.1096/fj.14-266239Crossref PubMed Scopus (132) Google Scholar, 36Heylen M. Worm proteins of Schistosoma mansoni reduce the severity of experimental chronic colitis in mice by suppressing colonic proinflammatory immune responses.PLoS One. 2014; 9 (25313594): e11000210.1371/journal.pone.0110002Crossref PubMed Scopus (28) Google ScholarS. mansoni protection appears to stem largely from a shift to non-pathological Th2 response, although there is also evidence for the generation of immunosuppressive regulatory cells (Treg).35Zaccone P. Burton O. Miller N. Jones FM Dunne DW Cooke A. Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention in NOD mice.Eur. J. Immunol. 2009; 39 (1:CAS:528:DC%2BD1MXltlamu7k%3D, 19291704): 1098-110710.1002/eji.200838871Crossref PubMed Scopus (160) Google Scholar, 38Hasby EA Hasby Saad MA Shohieb Z. El Noby K. FoxP3+ T regulatory cells and immunomodulation after Schistosoma mansoni egg antigen immunization in experimental model of inflammatory bowel disease.Cell Immunol. 2015; 295 (1:CAS:528:DC%2BC2MXjslyguro%3D, 25766778): 67-7610.1016/j.cellimm.2015.02.013Crossref PubMed Scopus (28) Google Scholar So far, we have not tested Sm29 ability to modulate autoimmune diseases. However, the capacity of Sm29 to induce IL-10 production and expansion of Treg cells might influence the outcome of autoimmune conditions. The mechanisms by which whole parasite, helminth extracts, or defined schistosome products modulate the immune responses and inhibit inflammatory diseases are summarized in Table 1.Table 1Schistosome antigens involved in modulation of inflammatory diseasesAntigenModelPutative mechanisms of protectionReferencesLeishmaniasisSm29PBMC of CL patientsDecreases IFN-γ and TNF-α production and induces IL-10 and IL-5Increases IL-10 and IL-10 receptor expression in DCs3Bafica AM Changes in T-cell and monocyte phenotypes in vitro by schistosoma mansoni antigens in cutaneous leishmaniasis patients.J. Parasitol. Res. 2012; 2012 (23209879): 52030810.1155/2012/520308Crossref PubMed Scopus (7) Google Scholar, 4Bafica AM Schistosoma mansoni antigens alter the cytokine response in vitro during cutaneous leishmaniasis.Mem. Inst. Oswaldo Cruz. 2011; 106 (1:CAS:528:DC%2BC3sXhs1ejtb4%3D, 22124559): 856-86310.1590/S0074-02762011000700012Crossref PubMed Scopus (13) Google Scholar, 18Lopes DM Dendritic cell profile induced by Schistosoma mansoni antigen in cutaneous leishmaniasis patients.BioMed Res. Int. 2014; 2014 (4182898, 25309922): 743069Crossref PubMed Scopus (4) Google Scholar SmTSP-2PBMCs of CL patientsDecreases IFN-γ and TNF-α production and increases IL-5Induces the expression of CTLA-4 on CD4+ T cells and the frequency of CD4+FoxP3+ T cells3Bafica AM Changes in T-cell and monocyte phenotypes in vitro by schistosoma mansoni antigens in cutaneous leishmaniasis patients.J. Parasitol. Res. 2012; 2012 (23209879): 52030810.1155/2012/520308Crossref PubMed Scopus (7) Google Scholar, 4Bafica AM Schistosoma mansoni antigens alter the cytokine response in vitro during cutaneous leishmaniasis.Mem. Inst. Oswaldo Cruz. 2011; 106 (1:CAS:528:DC%2BC3sXhs1ejtb4%3D, 22124559): 856-86310.1590/S0074-02762011000700012Crossref PubMed Scopus (13) Google Scholar PIIIPBMCs of CL patientsDecreases IFN-γ and TNF-α production and induces IL-5Induces the expression of CTLA-4 on CD4+ T cells and the frequency of CD4+FoxP3+ T cells3Bafica AM Changes in T-cell and monocyte phenotypes in vitro by schistosoma mansoni antigens in cutaneous leishmaniasis patients.J. Parasitol. Res. 2012; 2012 (23209879): 52030810.1155/2012/520308Crossref PubMed Scopus (7) Google Scholar, 4Bafica AM Schistosoma mansoni antigens alter the cytokine response in vitro during cutaneous leishmaniasis.Mem. Inst. Oswaldo Cruz. 2011; 106 (1:CAS:528:DC%2BC3sXhs1ejtb4%3D, 22124559): 856-86310.1590/S0074-02762011000700012Crossref PubMed Scopus (13) Google Scholar S. mansoni infectionLeishmania and Schistosoma-coinfected patientsReduces the lesion sizeInduces high levels of IL-5 and IgE17O'Neal SE Influence of helminth infections on the clinical course of and immune response to Leishmania braziliensis cutaneous leishmaniasis.J. Infect. Dis. 2007; 195 (17152018): 142-14810.1086/509808Crossref PubMed Scopus (53) Google ScholarAsthma Sm29Murine model of OVA-induced airway inflammationReduces peribronchial airway inflammation and improves asthma resolutionDecreases OVA-specific IgE levels and increases frequency of CD4+FoxP3+ T cells5Cardoso LS Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation.Clin. Exp. Immunol. 2010; 160 (1:CAS:528:DC%2BC3cXms1yjtb4%3D, 20132231): 266-27410.1111/j.1365-2249.2009.04084.xCrossref PubMed Scopus (61) Google Scholar Sm22.6Murine model of OVA-induced airway inflammationPBMCs of asthmatic S. mansoni-infected patientsDecreases OVA-specific IgE levels and EPO in lung tissue and increases frequency of CD4+FoxP3+ T cellsInduces IL-10 production by PBMCs of asthmatic patients infected with S. mansoni5Cardoso LS Schistosoma mansoni antigens modulate the allergic response in a murine model of ovalbumin-induced airway inflammation.Clin. Exp. Immunol. 2010; 160 (1:CAS:528:DC%2BC3cXms1yjtb4%3D, 20132231): 266-27410.1111/j.1365-2249.2009.04084.xCrossref PubMed Scopus (61) Google Scholar, 41Cardoso LS Schistosoma mansoni antigen-driven interleukin-10 production in infected asthmatic individuals.Mem. Inst. Oswaldo. Cruz. 2006; 101 (1:CAS:528:DC%2BD28Xht1ertb%2FN, 17308794): 339-34310.1590/S0074-02762006000900055Crossref PubMed Scopus (23) Google Scholar SjP40Murine model of OVA-induced airway inflammationInduces Th1 responses42Ren J. Novel T-cell epitopes on Schistosoma japonicum SjP40 protein and their preventive effect on allergic asthma in mice.Eur. J. Immunol. 2016; 46 (1:CAS:528:DC%2BC28XmsFejsbw%3D, 26840774): 1203-121310.1002/eji.201545775Crossref PubMed Scopus (15) Google Scholar SEAMurine model of OVA-induced airway inflammationReduces eosinophils in BAL and Th2 cytokinesIncreases frequency of CD4+FoxP3+ T cells and IL-10 production7Pacifico LG Schistosoma mansoni antigens modulate experimental allergic asthma in a murine model: a major role for CD4+ CD25+ Foxp3+ T cells independent of interleukin-10.Infect. Immun. 2009; 77 (1:CAS:528:DC%2BD1MXhs1Sju7c%3D, 18824533): 98-10710.1128/IAI.00783-07Crossref PubMed Scopus (94) Google Scholar S. mansoni infectionSchistosoma-infected asthmatic patientsMilder course of asthma27Medeiros Jr., M. Schistosoma mansoni infection is associated with a reduced course of asthma.J. Allergy Clin. Immunol. 2003; 111 (12743556): 947-95110.1067/mai.2003.1381Abstract Full Text Full Text PDF PubMed Scopus (142) Google ScholarPBMCs of asthmatic S. mansoni-infected patientsMonocytes and CD4+CD25+ T cells produce IL-10Increases CTLA-4 and CD40L expression in CD4+ T cells28Araujo MI Hoppe BS Medeiros Jr., M. Carvalho EM Schistosoma mansoni infection modulates the immune response against allergic and auto-immune diseases.Mem. Inst. Oswaldo Cruz. 2004; 99 (1:CAS:528:DC%2BD2cXosFyqtL4%3D, 15486631): 27-3210.1590/S0074-02762004000900005Crossref PubMed Google Scholar, 29Oliveira RR Schistosoma mansoni infection alters co-stimulatory molecule expression and cell activation in asthma.Microb. Infect./Inst. Pasteur. 2009; 11 (1:CAS:528:DC%2BD1MXivVWgsLk%3D): 223-22910.1016/j.micinf.2008.11.017Crossref PubMed Scopus (21) Google ScholarHTLV-1 Sm29PBMCs of HTLV-1 infected patientsIncreases IL-10 levels and reduces IFN-γ6Lima LM Schistosoma antigens downmodulate the in vitro inflammatory response in individuals infected with human T cell lymphotropic virus type 1.Neuroimmunomodulation. 2013; 20 (1:CAS:528:DC%2BC3sXhtVWhtb%2FK, 23752304): 233-23810.1159/000348700Crossref PubMed Scopus (12) Google Scholar SmTSP-2PBMCs of HTLV-1 infected patientsIncreases IL-10 levels and reduces IFN-γ6Lima LM Schistosoma antigens downmodulate the in vitro inflammatory response in individuals infected with human T cell lymphotropic virus type 1.Neuroimmunomodulation. 2013; 20 (1:CAS:528:DC%2BC3sXhtVWhtb%2FK, 23752304): 233-23810.1159/000348700Crossref PubMed Scopus (12) Google ScholarInflammatory bowel diseases (IBDs) SWAPAdoptive transfer T cell modelReduces IFN-γ and IL-17A production and increases IL-4 levels in the colon36Heylen M. Worm proteins of Schistosoma mansoni reduce the severity of experimental chronic colitis in mice by suppressing colonic proinflammatory immune responses.PLoS One. 2014; 9 (25313594): e11000210.1371/journal.pone.0110002Crossref PubMed Scopus (28) Google Scholar SEAAdoptive transfer T cell modelDownregulates IL-17A-producing cells and upregulates IL-4-production in the colon37Heylen M. Treatment with egg antigens of Schistosoma mansoni ameliorates experimental colitis in mice through a colonic T-cell-dependent mechanism.Inflamm. Bowel Dis. 2015; 21 (25437821): 48-5910.1097/MIB.0000000000000246Crossref PubMed Scopus (19) Google Scholar SEADSS-induced colitisIncreases Th2 cytokines and CD4+FoxP3+T (regs) cells38Hasby EA Hasby Saad MA Shohieb Z. El Noby K. FoxP3+ T regulatory cells and immunomodulation after Schistosoma mansoni egg antigen immunization in experimental model of inflammatory bowel disease.Cell Immunol. 2015; 295 (1:CAS:528:DC%2BC2MXjslyguro%3D, 25766778): 67-7610.1016/j.cellimm.2015.02.013Crossref PubMed Scopus (28) Google Scholar SjcystatinTNBS-induced colitisReduces IFN-γ and increases IL-4, IL-13, IL-10 and TGF-β in colon tissues43Wang S. Therapeutic potential of recombinant cystatin from Schistosoma japonicum in TNBS-induced experimental colitis of mice.Parasit. Vectors. 2016; 9 (26728323): 610.1186/s13071-015-1288-1Crossref PubMed Scopus (60) Google ScholarType 1 diabetes (T1D) Omega-1Non-obese diabetic (NOD) miceCD4+FoxP3+T (regs) cells inducing factor32Zaccone P. The S. mansoni glycoprotein omega-1 induces Foxp3 expression in NOD mouse CD4(+) T cells.Eur. J. Immunol. 2011; 41 (1:CAS:528:DC%2BC3MXhtVOktbnE, 21710488): 2709-271810.1002/eji.201141429Crossref PubMed Scopus (76) Google Scholar LNFPIIIInsulin sensitivity in diet-induced obese miceInduces IL-10 production by macrophages and dendritic cells33Bhargava P. Immunomodulatory glycan LNFPIII alleviates hepatosteatosis and insulin resistance through direct and indirect control of metabolic pathways.Nat. Med. 2012; 18 (1:CAS:528:DC%2BC38XhsFOmtrfP, 23104131): 1665-167210.1038/nm.2962Crossref PubMed Scopus (94) Google Scholar S. mansoni infection and SEAInsulin sensitivity in diet-induced obese miceInduces M2 macrophage activation and shift to Th2 responses34Hussaarts L. Chronic helminth infection and helminth-derived egg antigens promote adipose tissue M2 macrophages and improve insulin sensitivity in obese mice.FASEB J. 2015; 29 (1:CAS:528:DC%2BC2MXhslSqtbnF, 25852044): 3027-303910.1096/fj.14-266239Crossref PubMed Scopus (132) Google Scholar SEANon-obese diabetic (NOD) miceInduces Th2 and Treg cells expansion35Zaccone P. Burton O. Miller N. Jones FM Dunne DW Cooke A. Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention in NOD mice.Eur. J. Immunol. 2009; 39 (1:CAS:528:DC%2BD1MXltlamu7k%3D, 19291704): 1098-110710.1002/eji.200838871Crossref PubMed Scopus (160) Google ScholarAbbreviations: BAL, bronchoalveolar lavage fluid; OVA, ovalbumin; PIII, a fraction of S. mansoni soluble adult worm antigen (SWAP) obtained by anionic chromatography (FPLC); SEA, S. mansoni soluble egg antigens; SWAP, S. mansoni soluble worm proteins; TSP, tetraspanin. Open table in a new tab Abbreviations: BAL, bronchoalveolar lavage fluid; OVA, ovalbumin; PIII, a fraction of S. mansoni soluble adult worm antigen (SWAP) obtained by anionic chromatography (FPLC); SEA, S. mansoni soluble egg antigens; SWAP, S. mansoni soluble worm proteins; TSP, tetraspanin. Helminth infections affect the host immune system at several levels and the regulatory effects of the parasite and its secretions may not be restricted to the sites of infestation, but may extend to distal mucosal sites.39Mishra PK Palma M. Bleich D. Loke P. Gause WC Systemic impact of intestinal helminth infections.Mucosal Immunol. 2014; 7 (1:CAS:528:DC%2BC2cXmtlWjsbw%3D, 24736234): 753-76210.1038/mi.2014.23Crossref PubMed Scopus (78) Google Scholar For these reasons, the identification of one or more products with therapeutic potential, from all the genes that a single helminth can express, is a challenging task.40Raine T. Zaccone P. Dunne DW Cooke A. Can helminth antigens be exploited therapeutically to downregulate pathological Th1 responses?.Curr. Opin. Investig. Drugs. 2004; 5 (1:CAS:528:DC%2BD2cXhtFWqtrnL, 15573869): 1184-1191PubMed Google Scholar The possibility of specific molecules from helminth parasites having potent modulatory effect may be an important resource for the development of future immunotherapies to control inflammatory diseases. Here, we focused on Sm29 function as an immunoregulatory molecule and reported studies in which this protein was able to control inflammatory mucosal diseases with both Th1 and Th2 immune response profiles. Promising results have been obtained by Sm29 treatment of cells from Leishmania infected patients in vitro and also by Sm29 treatment of OVA-induced AAI mice. In summary, Sm29 protein acts like a double edged sword affecting both Th1 and Th2 branches of inflammatory mediated-diseases by IL-10 production and Treg cells expansion. Future studies should focus on better understanding of the mechanisms by which Sm29 regulates inflammatory reactions in autoimmune diseases. The Sm29 molecule is a potential therapeutic agent in the resolution of mucosal inflammation, possibly helping patients to improve their conditions without paying the price of becoming infected with noxious pathogens. Our group is now working with regulatory agencies in Brazil to produce Sm29 in good manufacturing practices conditions to a begin phase 1 clinical trial using this molecule. This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq/Helmintíases, #470561/2014-9) and Fundação do Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG/PPSUS, #03535-13). PowerPoint slides Download .ppt (.25 MB) Help with ppt files PowerPoint slide for Fig. 1 Download .ppt (.26 MB) Help with ppt files PowerPoint slide for Fig. 2
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