The Potential Role of Schistosome-Associated Factors as Therapeutic Modulators of the Immune System

The parasites and eggs of helminths, including schistosomes, are associated with factors that can modulate the nature and outcomes of host immune responses, particularly enhancing type 2 immunity and impairing the effects of type 1 and type 17 immunity. The main species of schistosomes that cause infection in humans are capable of generating a microenvironment that allows survival of the parasite by evasion of the immune response. Schistosome infections are associated with beneficial effects on chronic immune disorders, including allergies, autoimmune diseases, and alloimmune responses.

ABSTRACT

The parasites and eggs of helminths, including schistosomes, are associated with factors that can modulate the nature and outcomes of host immune responses, particularly enhancing type 2 immunity and impairing the effects of type 1 and type 17 immunity. The main species of schistosomes that cause infection in humans are capable of generating a microenvironment that allows survival of the parasite by evasion of the immune response. Schistosome infections are associated with beneficial effects on chronic immune disorders, including allergies, autoimmune diseases, and alloimmune responses. Recently, there has been increasing research interest in the role of schistosomes in immunoregulation during human infection, and the mechanisms underlying these roles continue to be investigated. Further studies may identify potential opportunities to develop new treatments for immune disease. In this review, we provide an update on the advances in our understanding of schistosome-associated modulation of the cells of the innate and adaptive immune systems as well as the potential role of schistosome-associated factors as therapeutic modulators of immune disorders, including allergies, autoimmune diseases, and transplant immunopathology. We also discuss potential opportunities for targeting schistosome-induced immunoregulation for future translation to the clinical setting.

INTRODUCTION

Schistosomiasis remains a challenging global health problem, affecting more than 200 million people around the world and accounting for 1.496 million years lost due to disability (YLD) worldwide and 11,700 deaths per year (1–3). This kind of parasite disease is caused by parasitic worms of the genus Schistosoma. Schistosoma mansoni, Schistosoma haematobium, and Schistosoma japonicum are the main schistosome species capable of infecting human beings. Schistosomiasis results from exposure to the cercariae in contaminated water. The cercariae grow into adult worms within the human host and live in the veins, where they mate and produce eggs. A distinctive feature of schistosomiasis is the ability of both schistosomes and eggs to achieve long-term survival within their human host. Thus, their evasion of host immunity reflects their ability to manipulate the immune system of the host to survive.

It is well established that chemical messenger cross talk occurs between certain parasites and their specific hosts, including those found in humans (4–8). The use of common signaling molecules in this relationship has been documented (5, 9–11). Interestingly, many of these molecules are associated with host immunosuppression, enhancing the parasitic life span, and thus survival, in the host (4–13). It is also noted that successful parasites tend not to cause the demise of their hosts, and messenger molecules conserved across parasites may be an important reason. Furthermore, various nonparasitic invertebrates also synthesize the same molecules in order to modulate their own immune responsiveness (6–8, 12, 13). This illustrates the concept that these communicating molecules arose first in simple animals and then were conserved during evolution (6, 12, 13). We speculate that parasitic organisms may simply have found a novel function for their messenger molecules to support their lifestyle in a new environment, which exhibits similar molecular processes because of their significance in all animal survival processes (4, 12). Previously, studies suggested that the evolutionary conservation of these messengers from “primitive” animals is due to the molecules biosynthesis pathways, which contain numerous stereospecific events that stabilize a communication mechanism across phyla (4, 12). Thus, conformational matching appears to present the mechanism for similar, if not identical, conservation of messenger and structural molecules. Importantly, this suggests that examining parasite-induced immunosuppression in the host, whereby the parasite escapes immune surveillance, may reveal novel “naturally” occurring processes that will be useful for addressing immune disorders, including allergies, autoimmune disorders, and transplant immunopathology.

Studies have shown that during long-term infection, the schistosome has properties that can activate or inhibit host immune cells (14–16). There has been interest in understanding the regulatory immune responses mediated by the schistosome and its eggs with the aim of developing immunological strategies to control or eliminate the schistosome. However, recent studies have also shown that there are beneficial effects of schistosomiasis in those with allergic and autoimmune diseases and following organ transplantation (14–16). Preclinical studies have shown that chronic schistosomiasis is associated with reduced responses to allergens (17, 18). The strong type 2 helper T cell (Th2) response stimulated by the schistosome is capable of suppressing Th1/Th17-mediated disease, including autoimmune disease (19, 20). The schistosome and its eggs induce the secretion of anti-inflammatory cytokines and promote the generation of regulatory T cells (Tregs) and regulatory B cells (Bregs), leading to the generation of immune tolerance. In particular, the role of the schistosome egg-derived excretory-secretory products (ESPs), as part of the schistosome-associated ESP proteome, has generated research interest in the immunoregulatory mechanisms involved and the potential for modulating the immune response in chronic inflammation and autoimmune diseases (18, 21).

This review aims to provide an update on the potential role of schistosome-associated factors as therapeutic modulators of the immune system. We also discuss the modulation of the cells of the innate and adaptive immune systems, the potential therapeutic areas of allergic and autoimmune disease, and potential roles for ESPs in transplant immunopathology. We conclude by highlighting the potential to therapeutically manipulate schistosome and schistosome-derived products in treatment of human diseases.

SCHISTOSOME AND EGG ESPs: THE RATIONALE

Immune responses to schistosome infections depend on the effects of innate and adaptive immune cells reacting to schistosome and eggs ESPs. Modulation of the immune system may occur through the release of mediators by schistosomes but also molecules secreted by eggs (Table 1). Recent studies have shown that ESPs act as immune mediators to regulate immunological activities. ESPs include molecules that are well identified and characterized, but also some that remain unclear. Recent advances in genomics, transcriptomics, and proteomics have improved our understanding of the complexity and heterogeneity of schistosome ESP mediators by identifying the individual components and defining their roles in modifying immune cells (21–24). These immunomodulators include not only proteins but also glycans, lipids, nucleic acids, and microRNAs (miRNAs) (21, 25, 26). Thus, exosomes or extracellular vesicles of schistosome are also involved in regulating immune cells, in particular, miRNA (27, 28). Also, other components, such as metabolites and small molecules, are involved in schistosome-mediated immunomodulation.

TABLE 1.

Schistosome-derived products with immunomodulatory activity^a

Immune cells	Schistosome-derived product(s)	Immunomodulatory effect	Reference(s)
Macrophages	S. japonicum SEA	Promotes M2 macrophage polarization via STAT6 and PI3K pathways but does not inhibit M1 activation	36–42
	Sj-CP1412	Enhances M2 polarization, characterized by increased CD206, Arg1, and IL-10, depending on its RNase activity	38
	S. mansoni omega-1	Enhances TLR2-mediated secretion of IL-1β	39
	S. mansoni LPC	Drives M2 macrophage differentiation and triggers M2 macrophage profile and upregulated arginase 1, Chi3l3, and TGF-β	43
	Sm16	Inhibits the generation of M1 macrophages induced by LPS or IFN-γ; delays antigen processing by macrophages	45
	Sj16	Impairs LPS-induced activation of macrophages; inhibits proliferation, phagocytosis, and cell migration in vitro; increases the level of IL-10	41
	Exosomes and extracellular vesicles	Stimulates M1 macrophage polarization or induces a mixture of M1 and M2 macrophages	26–28
Dendritic cells	S. mansoni omega-1	Primes DCs for Th2 polarization and stimulates an anti-inflammatory response in DCs	29, 30, 55, 56
	S. mansoni LNFPIII	Impairs the migration of DCs; drives DC maturation with a Th2-promoting phenotype	34, 49, 50
	S. japonicum CP1412	Suppresses LPS-induced DC maturation	38
	Sj16	Inhibits LPS-mediated DC maturation; increases expression of IL-10 and contributes to induction of Tregs	32–34, 51
	Sj-C	Reduces the expression of MHC-II and suppresses and inhibits MHC-II-restricted antigen presentation	54
	Sm29	Stimulates maturation and activation of DCs	52
	Schistosomal lysophosphatidylserine	Activates TLR2 and primes DCs to stimulate the generation of IL-10-producing Tregs	53
Neutrophils	SmKI-1	Impairs neutrophil migration and function	57
ILC2	S. mansoni omega-1	Increases ILC2 and Th2 cytokines	60
T cells	S. mansoni omega-1	Induces Th2 cytokines; promotes generation of Tregs	29, 30, 39, 55, 70
	Sj-CP1412	Enhances Th2 responses; promotes differentiation of Tregs	38
	Sj-C	Enhances Th2 responses; induces increased Tregs	54
	LNFPIII	Promotes Th2 polarization by stimulating the maturation of Th2-promoting DCs	42
	Sj16	Promotes the differentiation of Tregs	34
B cells	IPSE/α-1 derived from S. mansoni	Induces Bregs	72

^aDCs, dendritic cells; IPSE, immune-polarizing side effects; LPC, lysophosphatidylcholine; LNFPIII, lacto-N-fucopentaose III; SEA, soluble egg antigen; Sj-C, cysteine protease inhibitor from S. japonicum.

Schistosome-derived products interact with the host immune system through a variety of mechanisms, including strong Th2 responses, depending on the specific molecules involved. Schistosome infection activates immune responses by stimulating damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Meanwhile, schistosomes have a potential role in suppressing the initiation of immune responses to bystander pathogens or antigens. Proteins in the ESPs can also be taken up by different immune cells and affect macrophages or dendritic cells to modulate antigen processing and presentation (29–33). These ESPs can prime macrophages or dendritic cells for Th subset polarization and also directly interact with T cells and regulate T cell function (29–31, 34). Therefore, these schistosome-derived products are involved in all phases of the immune response.

MODULATION OF THE INNATE IMMUNE SYSTEM

Macrophages.

Macrophages are important components of the innate immune system. These cells act as cellular mediators in host antiparasitic immunity as well as schistosome immune escape. Macrophages are diverse and are phenotypically and functionally dynamic in response to environmental stimuli. Based on in vitro studies, macrophages have been classified as M1, a type which develops when cells are stimulated with gamma interferon (IFN-γ) and lipopolysaccharide (LPS), and as M2, which develops when cells are stimulated with interleukin 4 (IL-4)/IL-13 (35).

These in vitro studies have shown that macrophage M2 polarization was enhanced by infection with S. japonicum, while LPS-stimulated differentiation to M1 macrophages was inhibited (36). Soluble schistosome egg antigen (SEA) also stimulated M2 macrophage polarization, and treatment with SEA in vitro induced increased expression of CD163, IL-10, and transforming growth factor β1 (TGF-β1) (36). However, SEA did not suppress the activation of M1 macrophages (36). The effect of SEA on the activation of M2 macrophages has been shown to depend on STAT6 and phosphatidylinositol 3-kinase (PI3K) pathways, as macrophages stimulated by SEA showed increased phosphorylated STAT6 and PI3K, and this effect was inhibited by selective inhibitors of PI3K (36). Recent studies have also shown that ESP antigens derived from S. japonicum eggs promoted M2 polarization through a variety of mechanisms (37–42).

As a key component of SEA, S. japonicum CP1412 (referred to here as Sj-CP1412), which belongs to the RNase T2 family, can induce M2 macrophage polarization (38). Macrophages showed increased expression of the typical M2 macrophage markers CD206, arginase 1, and IL-10 when stimulated with recombinant Sj-CP1412 (rSj-CP1412), which was dependent on its RNase activity (38). Without Sj-CP1412, SEA failed to induce M2 macrophage polarization (38). Therefore, these in vitro studies support the idea that Sj-CP1412 may have a key role in SEA-mediated M2 macrophage differentiation.

The bioactive proinflammatory lipid lysophosphatidylcholine (LPC) derived from S. mansoni promoted M2 macrophage differentiation and the LPC-triggered M2 macrophage profile, as shown by the upregulation of arginase 1, Chi3l3, and TGF-β (43). Enhanced M2 polarization induced by LPC is mediated by peroxisome proliferator-activated receptor gamma (PPARγ) signaling, as LPC-treated M2 macrophages showed increased expression of PPARγ, while treatment with a PPARγ antagonist reduced the expression of arginase 1 in LPC-treated macrophages in vitro (43).

Sm16 is an anti-inflammatory and immunomodulatory protein secreted by S. mansoni (44). Sm16, acting as a TGF-β1 receptor inhibitor, inhibits the generation of M1 macrophages induced by LPS or IFN-γ (45). Sm16 stimulation has been shown to delay antigen processing by macrophages (45). Similar to Sm16, the S. japonicum-derived protein Sj16 was reported to contribute to activation of M2 in S. japonicum infection to assist immune evasion. Pretreatment with recombinant Sj16 impaired LPS-induced activation of macrophages and inhibited proliferation, phagocytosis, and cell migration in vitro (41). Furthermore, Sj16 treatment reduced LPS-induced production of proinflammatory cytokines, including IL-1β, tumor necrosis factor alpha (TNF-α), IL-6, and IL-12, but increased the level of IL-10, an immunosuppressive cytokine (41). Although the mechanism remains unclear, Sj16 shows significant ability to shape M2 polarization.

In contrast to promoting M2 macrophage differentiation, some components showed potential for inducing an M1-like phenotype. Omega-1 is a glycoprotein secreted from S. mansoni and also belongs to the T2 RNases (46). However, omega-1 is capable of modulating inflammasome activity in macrophages and enhancing Toll-like receptor 2 (TLR2)-mediated secretion of IL-1β (39). In addition, omega-1 seems to be one of the major components in SEA capable of regulating IL-1β. This effect depends on Dectin-1, as IL-1β induced by omega-1 was decreased when Dectin-1 was blocked. Also, omega-1-induced secretion of IL-1β requires caspase-8 and the inflammasome adaptor protein ASC, indicated by abrogated IL-1β secretion when this pathway was ablated (39). Besides, omega-1 seems to bind to actin and induce cytoskeletal changes in macrophages to alter their phagocytosis and antigen presentation (31, 39). However, further research is warranted to confirm these functions and the underlying mechanisms.

In addition to schistosome ESP mediators, exosomes and extracellular vesicles are also important immune mediators. Exosomes and extracellular vesicles contain lipids and proteins as well as RNA species and exhibit a significant impact in cellular communication. Exosomes and extracellular vesicles participate in parasite-mediated pathology and also regulate the host immune system to facilitate the survival of schistosomes. Both exosomes and extracellular vesicles released by S. japonicum have been reported to be capable of modifying immune responses (23, 27). In contrast to typical M2 macrophages in mice infected with S. japonicum, either exosomes or extracellular vesicle components stimulated M1 macrophage polarization, characterized by increased expression of inducible nitric oxide synthase (iNOS), TNF-α, and CD16/32 (26–28). Studies have shown that S. japonicum extracellular vesicle miR-125b and bantam miRNAs can be taken up by macrophages, resulting in increased expression of TNF-α by regulating transcription of Pros1, Fam212b, and Clmp in the RAW264.7 monocyte/macrophage cell line (27). Treatment of S. japonicum extracellular vesicles resulted in a mixture of M1 and M2 macrophages (27). However, the relative contribution of each macrophage subset to the pathogenesis of schistosomiasis and the modulation of the immune system remains unclear. Additionally, other active agents that modulate cytokine production and the phenotype of macrophages remain to be investigated.

Dendritic cells.

Dendritic cells are primary antigen-presenting cells in the immune response. Also, dendritic cells use several costimulatory molecules to modulate Th cell differentiation. Exposure to the cercariae of S. mansoni led to upregulation of PD-L1, PD-L2, and IL-10 in dermal dendritic cells (47). Also, cercaria-primed dermal dendritic cells are capable of impairing Th1 responses and enhancing IL-10 production in T cells (47). Therefore, the interaction with cercariae and dermal dendritic cells may be associated with local immune suppression. Schistosome ESPs from the skin can stimulate the maturation of dendritic cells and allow dendritic cells to promote Th2 polarization by upregulating the expression of CD40 (48).

During chronic infection, schistosome ESPs also showed effects on dendritic cells. Lacto-N-fucopentaose III (LNFPIII) is a bioactive molecule released by S. mansoni (34). In an in vitro model, LNFPIII treatment impaired the migration of dendritic cells across cerebral endothelium (34). LNFPIII has also been reported to drive dendritic cell maturation with a Th2-promoting phenotype via the CD14/TLR4–mitogen-activated protein kinase (MAPK) (ERK) signaling pathway (49, 50).

As a major released protein, Sj16 is an immune modulation molecule that inhibits LPS-mediated dendritic cell maturation via an IL-10-dependent mechanism (32, 33, 51). Sj16 translocates to the nuclei of dendritic cells with the help of a functional N-terminal nuclear translocation signal and leads to increased expression of IL-10 and impaired LPS-induced maturation of dendritic cells (32, 33, 51). Also, treating bone marrow-derived dendritic cells with recombinant Sj16 prevented cell maturation, which contributed to the induction of CD4⁺ CD25⁺ Tregs from CD4⁺ CD25⁻ T cells (34).

The Sm29 antigen of S. mansoni is also capable of inducing maturation and activation of dendritic cells, as stimulating dendritic cells with a recombinant Sm29 increased the expression of the cell maturation-associated molecule CD83 and the costimulatory molecules CD80 and CD86 (52). Also, schistosomal lysophosphatidylserine can activate TLR2 and prime dendritic cells to stimulate the generation of IL-10-producing Tregs (53).

Cysteine protease inhibitors from some helminths have been shown to have immunosuppressive effects on their host. Sj-C, a novel cysteine protease inhibitor derived from S. japonicum, showed the ability to suppress murine dendritic cells (54). Following incubation of dendritic cells with recombinant Sj-C and a soluble form of adult worm antigen (AWA) of S. japonicum, the expression of major histocompatibility complex II (MHC-II) on the surfaces of dendritic cells decreased (54). Compared with controls, expression levels of the T cell cytokines IL-4 and TGF-β were significantly increased (54). Sj-C can be considered a new schistosome-associated immunosuppressive factor.

Emerging studies have also demonstrated the roles of SEA in regulating dendritic cells. SEA is a mixture of antigens that are capable of conditioning dendritic cells to prime Th2 immune responses. As a key component of SEA, omega-1 is capable of conditioning dendritic cells for Th2 polarization by blocking protein synthesis (29, 30). Besides, omega-1 can modulate the signaling from pattern recognition receptors (PRRs) of the innate immune system and pathways stimulated by Toll-like receptor (TLR) signals in dendritic cells. Omega-1 is able to suppress LPS-induced IL-12p40 production and promote TGF-β secretion in bone marrow-derived dendritic cells but unable to enhance IL-1β secretion in dendritic cells when stimulated by TLR2 signaling (55). Thus, omega-1 stimulation seems to stimulate an anti-inflammatory response in dendritic cells. Also, SEA can induce dendritic cells to generate Th2 responses in an omega-1-independent mechanism. It was reported that SEA triggered the expression of the inflammatory mediator prostaglandin E2 (PGE2) and subsequently induced the expression of OX40L, enabling dendritic cells to promote Th2 immune responses (56). However, as a component of SEA, Sj-CP1412 is a negative regulator of dendritic cell maturation, as it has been shown to suppress LPS-induced dendritic cell maturation (38).

Other innate cells.

In addition to macrophages and dendritic cells, schistosome infection or schistosome-derived products also influence other innate immune cells, including neutrophils, eosinophils, basophils, and mast cells. SmKI-1, a protease inhibitor belonging to ESPs of S. mansoni, impaired neutrophil migration and function by inhibiting trypsin and neutrophil elastase (57). In addition, in models of inflammatory disease, evidence showed that treatment with SmKI-1 led to reduced neutrophil recruitment and accumulation, decreased IL-1β secretion, and lower overall pathological scores of inflammation (57). Eosinophilia is a characteristic of chronic helminth infection, particularly following infection with S. mansoni. Eosinophils are a major source of Th2 cytokines, particularly IL-4 (58). In a clinical study of group 2 innate lymphoid cells (ILC2), S. haematobium infection led to reduced ILC2 in young children, while helminth elimination restored the levels of ILC2 (59). Although further studies are needed to detect the mechanism, this study indicated a role of ILC2 in immune responses to S. haematobium infection before the development of acquired protective immunity (59). However, S. mansoni SEA and S. mansoni egg-derived omega-1 induced increased ILC-2 and Th2 cytokines, depending on the increased expression of IL-33 following administration of S. mansoni egg-derived omega-1 (60).

Studies also demonstrated that basophils and mast cells are regulated by schistosome-derived products. As one of the most abundant egg-secreted proteins, IPSE (immune-polarizing side effects) activated IgE-bearing basophils and mast cells and triggered these cells to release IL-4/IL-13 (61–64). IPSE is also capable of sequestering chemokines and has the potential to orchestrate anti-inflammatory responses via a possible mechanism of translocating into host cell nuclei and altering transcription (65–67). These effects of IPSE on innate cells were also reflected by their protective role in hemorrhagic cystitis (63, 68).

REGULATION OF THE ADAPTIVE IMMUNE SYSTEM

T cells.

The immunological profile varies in different stages of schistosome infection. Both Th1 and Th2 immune responses are involved in immune responses to helminths (69). The early stages of schistosomiasis are characterized by Th1 immune responses, while Th2 responses follow the deposition of eggs (69). However, in chronic infection, Tregs are expanded and contribute to immune suppression (69). Although schistosomiasis can activate many innate cells to drive Th2 responses, schistosome ESP mediators can also interact with adaptive immune cells.

During the invasion of the skin, schistosome ESP mediators can stimulate Th2 responses (48). However, this effect relies on dendritic cells and the increased expression of CD40 on these cells (48). The omega-1 molecule of S. mansoni eggs is recognized to be the major Th2-polarizing component of S. mansoni SEA, and its Th2-inducing activity relies upon its RNase activity as well as glycosylation (29, 30, 70). However, the biological activity of omega-1 requires mannose receptor-mediated internalization, as mannose receptor deficiency failed to prime a Th2 polarized response (29). Consistently, knockout of omega-1 impaired the capacity of SEA to induce Th2 cytokine expression (IL-4 and IL-5) in macrophage and T cell cocultures (70). S. mansoni egg-derived omega-1 regulated the pattern recognition receptor (PRR) signaling pathways in dendritic cells, which subsequently drove the development of Th2 immune responses (39). However, depletion of omega-1 in S. mansoni SEA did not impair the capacity to induce Th2 responses in vivo (30). Thus, omega-1 is the main Th2-inducing stimulator in S. mansoni SEA, but other components can compensate for the Th2 induction of this antigen. Similar to omega-1, Sj-CP1412 primed Th2 polarization from CD4⁺ T cells in the host through its RNase activity (38). In addition, recombinant Sj-C induced an enhanced Th2 response in schistosome-infected mice, as indicated by increased expression of IL-4 by T cells (54). However, this effect was not observed in normal mice, indicating that this function requires certain costimulatory signals. Nonetheless, these costimulatory factors remain poorly defined. Last, LNFPIII was able to induce a strong Th2 immune response in vivo by favoring the maturation of Th2-promoting dendritic cells (42).

Tregs have a critical role in maintaining immune homeostasis and tolerance. Recent studies have shown that schistosome-derived products exerted a significant impact on the development and function of Tregs. Administration with recombinant Sj-CP1412 resulted in increased CD4⁺ CD25⁺ Foxp3⁺ T cells in mouse spleens (38). Consistent with in vivo studies, stimulation with Sj-CP1412 significantly promoted the differentiation of CD4⁺ CD25⁺ Foxp3⁺ T cells in vitro (38). Also, rSj16 showed the ability to promote CD4⁺ CD25⁺ Tregs, as higher levels of CD4⁺ CD25⁺ Tregs were detected in mice that received rSj16 injections, and this effect was also observed in an in vitro study (34). These CD4⁺ CD25⁺ Tregs were functional and mediated reduced proliferation of CD4⁺ CD25⁻ T cells (34). Omega-1 is recognized to be an important factor that induces Tregs, as it is capable of inducing the generation of Foxp3⁺ Treg cells in mice relying on TGF-β and retinoic acid (39, 55). Furthermore, immunizing mice with rSj-C resulted in an increased number of CD4⁺ CD25⁺ Foxp3⁺ T cells in mice with schistosome infection but not in normal mice, constant with the findings in Th2 cells (54). Although rSj-C contributes to enhanced generation of Tregs, the mechanisms remain unknown. Thus, various schistosome-derived products contribute to induction of Tregs, but further study is needed to investigate the mechanism and to validate their roles in humans.

B cells.

Bregs are regulatory immune cells that suppress proinflammatory immune responses. Several mechanisms are involved in Breg-mediated immunoregulation. However, the expression of the immunosuppressive cytokine IL-10 and the ability to drive Treg induction are the main mechanisms involved in immunoregulation (71). The expansion of the Breg cell population is a key feature of chronic schistosomiasis, resulting in the suppression of immune responses and reduced immunopathology (69). As components of regulatory cell networks, Bregs contribute to protect chronically infected patients from developing disease that is associated with increased mortality.

Studies have shown that schistosomes are capable of inducing Bregs in both humans and mice (72). In preclinical studies, S. mansoni SEA enhanced the development of B cells capable of producing IL-10 and driving the development of Tregs (72–75). S. mansoni SEA directly binds and interacts with B cells, and subsequent internalization of S. mansoni SEA results in the secretion of IL-10 to support the generation of Tregs (72–75). However, the mechanism of internalization of S. mansoni SEA and the downstream signaling remains unknown.

The glycoprotein IPSE/α-1 is derived from S. mansoni eggs and has the capacity to induce Bregs (72). However, S. mansoni SEA can also promote Breg induction without IPSE/α-1, indicating that there are other Breg-inducing molecules in S. mansoni SEA (72). Increased Bregs have also been observed in human schistosome infection (76, 77). Children with S. haematobium infection had higher levels of IL-10-producing CD1dhi Bregs in the peripheral blood (76, 77). Although recent studies have shown that schistosome-associated products were able to enhance Breg induction, the underlying mechanisms are unclear, and other Breg-stimulatory molecules remain to be identified.

THERAPEUTIC POTENTIALS OF SCHISTOSOME AND EGG ESPs

Allergic disorders.

Recent clinical studies have shown a negative association between parasite infection and allergic diseases (17, 78). Patients with helminth infection have a lower rate of developing allergic diseases, but anthelmintic treatment resulted in increased allergic reactions (17, 78). Studies have shown that schistosome infection can also provide protection against allergic disorders (17, 78). A study in an area where schistosomiasis is endemic showed that compared with noninfected individuals, children with S. haematobium were less likely to have atopic skin reactions (78). Also, a cross-sectional study reported that patients infected with S. mansoni had reduced episodes of type I hypersensitivity or allergic responses (17). Increased levels of the anti-inflammatory cytokine IL-10 were observed in children with schistosomiasis, which was associated with a decreased prevalence of atopy. Reduced allergic reactivity in individuals infected with S. mansoni was associated with parasite burden as well as reduced serum concentrations of inflammatory cytokines (17). The modulatory effects of S. mansoni infection on allergic response suggested helminth-derived products as a new therapeutic strategy for the treatment of allergic diseases. However, the causal relationship remains unclear, and further clinical studies are needed.

The effects of schistosome infection on allergic disorders have been extensively reported in animal studies (18, 22, 76, 79, 80). In a mouse model of airway allergic inflammation, schistosome infection reduced allergic inflammation by driving the generation of Breg cells, which are capable of producing IL-10 and promoting Tregs (76). S. japonicum SEA also had a protective effect on the development of asthma, as treatment with the antigens increased the number and activity of CD4⁺ CD25⁺ Tregs in a murine model of asthma (80). Mice that received SEA showed reduced airway inflammation and lower expression of IL-4 and IL-5 induced by ovalbumin (80). Reduced inflammatory cells in the lung and lower levels of Th2 cytokines were found in mice infected with S. mansoni or treated with eggs, indicating the beneficial effects of S. mansoni infection or egg treatment in preventing ovalbumin-induced airway allergic inflammation (81). However, modulation of experimental asthma was dependent on increased CD4⁺ CD25⁺ Tregs independent of IL-10, and emerging studies have shown that components of S. mansoni SEA have beneficial effects on allergic diseases (82–84). However, further clinical studies are required to investigate the mechanisms of immunomodulation by schistosomes in allergic responses.

Autoimmune disease.

Autoimmune diseases in patients with schistosomiasis show reduced disease severity, possibly due to the effects of schistosome-derived products. Rheumatoid arthritis is an autoimmune disease that is mediated by Th1 cells and exacerbated by Th17 responses, resulting in synovial inflammation (85–87). Recent studies indicated that schistosomes or schistosome-derived mediators are protective in rheumatoid arthritis (19, 51, 88–93). Schistosome infection dramatically attenuated the severity and reduced the incidence of collagen-induced arthritis (CIA), a mouse model of human rheumatoid arthritis. The anti-arthritic effects were associated with augmentation of Th2 cytokines, downregulation of the pro-arthritic cytokines IL-17A and TNF-α, and increased production of IL-10 during the development of arthritis (19, 91, 93, 94). STAT6 and IL-10 were required for the reduction of the effects of arthritis, as reduced levels of mouse CIA were found in STAT6 knockout mice with schistosome infection, and no beneficial effects were detected in schistosome-infected IL-10 knockout mice (94). However, weakened autoreactive responses are associated with the acute stage of schistosome infection (92). Therefore, it is necessary to identify individual molecules with therapeutic potential for the treatment of rheumatoid arthritis and avoid the deleterious effects of schistosome infection. Animal studies showed that administration of schistosome-derived products, including autoclaved S. japonicum HSP60-derived SJMHE1 peptide as well as Sj16, reduced the symptoms of adjuvant-induced arthritis (AA) or CIA, characterized by reduced polyarthritis, improved gait, and reduced paw swelling in an animal model (19, 51, 88, 89). The anti-arthritic activity can be attributed to increased Tregs and higher levels of IL-10. Adoptive transfer of Tregs is able to suppress osteoclastogenesis and CIA; in addition, enhanced Treg polarization is capable of not only downregulating the incidence and severity of CIA but also inhibiting the autoimmune response to restore immune homeostasis (88, 95, 96). Furthermore, the inhibition of maturation and function of dendritic cells by schistosome-derived immunomodulators also contributed to suppressing arthritis in animal models (51).

The S. mansoni SmKI-1 serine protease inhibitor is capable of regulating inflammatory diseases by blocking of neutrophil recruitment as well as elastase activity (57). SmKI-1 has been reported to reduce acetaminophen-mediated liver damage but also to reduce nociceptor sensitization (hyponociception) and the degree of inflammation seen histologically (57). Also, schistosome-derived products showed potential in the treatment of multiple sclerosis (42). Treatment with the pentasaccharide lacto-N-fucopentaose III (LNFPIII) significantly reduced the symptoms of experimental autoimmune encephalomyelitis (42). Histology showed reduced central nervous system inflammation, and cytokine analysis showed enhanced Th2 immune responses and reduced Th1/Th17 profiles (42).

Transplant immunopathology.

Recent studies suggest a role for schistosome in transplant immunopathology. Evidence indicated that there is a possibility of using organ donation from patients with schistosomiasis (16, 97–102). In some cases, liver transplantation from donors with schistosomiasis has been successfully performed without obvious adverse effects; also, infected-kidney transplants showed no critical side effects due to schistosome infection (103). Although donation from schistosome-infected patients is not included in clinical recommendations for transplant donor acquisition, these preliminary findings highlight a new approach to expand donor pools and deserve further studies in the clinical setting.

Although schistosomes or schistosome ESP mediators are capable of modulating immune responses, their potential in prolonging graft survival or even inducing transplant tolerance remains unclear. Studies on full-thickness skin grafts have shown that the graft survival in schistosome-infected patients was much longer than that in healthy volunteers at 60 days after skin grafting (104). Because HLA matching was not performed, the role of schistosomiasis in this small clinical study remained unclear (104). However, animal studies have shown that skin grafts in mice infected with S. mansoni survived for 50% longer than noninfected recipient mice (105). Moreover, a positive correlation was observed between graft survival and the number of live parasites in recipients in this study (105). Collectively, these studies demonstrated a protective role for schistosomes in suppressing transplant immunopathology and promoting graft survival. Thus, treatment based on schistosome-derived products has the potential to help reduce the use of immunosuppressants and even to induce transplant tolerance. However, the exact mechanism for this response remains to be elucidated, and further studies are required to validate the impact of such treatments on patients.

PERSPECTIVE AND CONCLUSIONS

This review provides an update on the potential role of schistosome-associated factors as therapeutic modulators of the immune system, supported by recent literature. Schistosome-associated ESPs, including schistosome egg-derived products, are factors that modulate cells of the innate and adaptive immune systems. Schistosome-associated factors have potential therapeutic roles in allergic and autoimmune diseases and transplant immunopathology. Schistosome-associated factors induce enhanced Th2, Treg, and Breg responses, with impaired Th1/Th17 differentiation. Although animal models support roles for schistosome-associated factors in allergic disorders, autoimmune disease, and transplant immunopathology, future clinical studies are required to address the many remaining questions regarding the identification of the key molecules and the underlying mechanisms. The possibility of using recombinant proteins to develop a therapeutic schistosome-associated ESP proteome may be important in the development of novel therapeutic strategies that may be studied in vitro, followed by pharmacokinetic and in vivo studies.