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Keywords:

  • chemokine;
  • cytokine;
  • fibrosis;
  • immunopathogenesis;
  • immunopathology

SUMMARY

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS
  5. IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS
  6. A MOLECULAR PROFILE OF SCHISTOSOMIASIS
  7. IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS
  8. GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS
  9. CONCLUDING COMMENTS
  10. ACKNOWLEDGEMENTS
  11. REFERENCES

Schistosomiasis continues to be a significant cause of parasitic morbidity and mortality worldwide. This review considers the basic features of the pathology and clinical outcomes of hepatointestinal and genitourinary schistosomiasis, presents an overview of the numerous studies on animal models that have clarified many of the immunopathological features, and provides insight into our current understanding of the immunopathogenesis and genetic control of human schistosomiasis. In murine schistosomiasis, pathology is induced by a CD4+ Th2 driven granulomatous response directed against schistosome eggs lodged in the host liver. The Th2 cytokines IL-4 and IL-13 drive this response, whereas IL-10, IL13Rα2, IFN-γ and a subset of regulatory T-cells act to limit schistosome induced pathology. A variety of cell types including hepatic stellate cells, alternatively activated macrophages and regulatory T-cells have also been implicated in the pathogenesis of schistosomiasis. Current knowledge suggests the immunopathogenic mechanisms underlying human schistosomiasis are likely to be similar. The review also considers the future development of anti-pathology schistosome vaccines. As fibrosis is an important feature of many other diseases such as Crohn's disease and sarcoidosis, a comprehensive understanding of the cellular and molecular mechanisms involved in schistosomiasis may also ultimately contribute to the development an effective disease intervention strategy for other granulofibrotic diseases.


INTRODUCTION

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS
  5. IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS
  6. A MOLECULAR PROFILE OF SCHISTOSOMIASIS
  7. IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS
  8. GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS
  9. CONCLUDING COMMENTS
  10. ACKNOWLEDGEMENTS
  11. REFERENCES

Schistosomiasis is a disease caused predominantly by the host's immune response to schistosome eggs (ova) and the granulomatous reaction they evoke (1–5). The granulomas destroy the eggs and sequester or neutralize otherwise pathogenic egg antigens but also leads to fibrogenesis in host tissues (4). The intensity and duration of infection, in turn, may determine the amount of antigen released from the eggs and the severity of chronic fibro-obstructive disease. The majority of pathology develops at the sites of maximal accumulation of eggs: the intestine and the liver (in the case of Schistosoma mansoni and S. japonicum) and the genitourinary tract (in the case of S. haematobium) (1,3). However, granulomas have been found in many different tissues, including the skin, lung, brain, adrenal glands and skeletal muscle (3). Extensive studies of experimental schistosomiasis, mostly on murine S. mansoni, have revealed that granuloma formation is attributable to a vigorous CD4+ Th2 driven response, akin to a form of delayed-type hypersensitivity, that is tightly regulated by various cell populations, cytokines and chemokines (2,4,5).

This review firstly considers the basic features of the pathology and clinical outcomes of hepatointestinal and genitourinary schistosomiasis, and secondly provides an overview of the extensive studies on animal models of schistosomiasis that have clarified many of the features governing the progression of the granulomatous reaction in schistosome-egg induced hepatic disease. A discussion of the current understanding of the immune-mediated pathology in human schistosomiasis then follows. Immunopathogenic mechanisms elucidated in mice are not easily investigated comparatively in humans, so that knowledge of human responses to schistosomes is far from complete. As schistosome infection in mice differs in many respects from that in humans, caution is required in extrapolating and interpreting results from murine experiments (4–6). Nevertheless, the basic underlying immunopathogenic mechanisms in the two species are likely similar.

CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS
  5. IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS
  6. A MOLECULAR PROFILE OF SCHISTOSOMIASIS
  7. IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS
  8. GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS
  9. CONCLUDING COMMENTS
  10. ACKNOWLEDGEMENTS
  11. REFERENCES

Acute schistosomiasis

Acute schistosomiasis, when it occurs, is similar during infection with the three major schistosome species and is characterized by cercarial dermatitis (CD) and Katayama syndrome (KS) (3,7,8). CD is an IgE-mediated hypersensitivity response directed against penetrating cercariae (1,3,7,8), occurs infrequently among endemic populations but is common among visitors and migrants and after primary infections (1,8–10). CD is characterized by a maculopapular, pruritic rash that manifests within several hours of exposure to contaminated water and may persist for several days (1,3).

KS is an immune-complex mediated hypersensitivity reaction against migrating schistosomula and early egg deposition (1,3,8). The symptoms of KS manifest 14–84 days after individuals are first exposed to schistosome infection or following heavy reinfection and are characterized by rapid onset fever, fatigue, myalgia, malaise, headache, nonproductive cough, and eosinophilia with patchy infiltrates visible on pulmonary radiography (1,3,8). Abdominal symptoms may also occur and correspond with the migration of juvenile worms (1,3,9). Acute schistosomiasis due to S. mansoni or S. haematobium infection is common among individuals exposed for the first time such as travellers or migrants but is rare among endemic populations (1,3,9). In contrast, acute disease due to S. japonicum is common in endemic communities and is associated with severe and persistent manifestations that may rapidly progress to hepatosplenomegaly and portal hypertension (1,3,11).

Chronic schistosomiasis

Chronic disease in schistosomiasis is variable and is dependent on the anatomical location of adult schistosome within the vasculature of the mammalian host. Schistosoma japonicum and S. mansoni infection cause hepatointestinal and hepatosplenic disease, whereas chronic infection with S. haematobium causes genitourinary schistosomiasis (1,3,7,8). The outcome of chronic schistosomiasis may be further complicated by co-infections. For example, co-infection with S. mansoni and Hepatitis C Virus (HCV) or Hepatitis B Virus (HBV) is associated with accelerated progression and increased severity of chronic liver fibrosis (3,12). Additionally, the development of ectopic lesions leading to neuro-, cerebral or pulmonary schistosomiasis may occur but is rare (3,13,14).

Gastrointestinal and liver disease

Gastrointestinal schistosomiasis is characterized by chronic or intermittent abdominal pain and discomfort, loss of appetite and diarrhoea that commonly contains occult blood. These symptoms are caused by a granulomatous response to schistosome eggs in the intestinal mucosa leading to pseudopolyposis, microulceration and superficial bleeding (3,9,10). Hepatosplenic schistosomiasis begins with the deposition of schistosome eggs in the hepatic sinusoids leading to the development of granulomas and hepatomegaly. Chronic infection and granulomatous inflammation leads to the excess deposition of collagen and other extracellular matrix (ECM) components in the liver causing periportal fibrosis and progressive occlusion of the portal veins. In turn, occlusion of the portal veins leads to the development of portal hypertension, splenomegaly, portacaval shunting, ascites, gastrointestinal varices and gastrointestinal bleeding that may eventually be fatal (1,3,13,14). Blood loss through haematuria (S. haematobium), intestinal and variceal bleeding, malnutrition and the production of haemolytic factors by schistosomes can lead to anaemia in schistosomiasis (15). Anaemia, in turn has been associated with wasting in adults and growth retardation and cognitive impairment in children (1,3). In S. mansoni infection progression to chronic hepatosplenic schistosomiasis takes 5–15 years while for schistosomiasis japonica progression to chronic disease is more rapid and severe with little or no interval between acute and chronic disease (1).

Genitourinary disease

Genitourinary tract disease is a specific trait of S. haematobium infection (1,3,16). Adult S. haematobium worms inhabit the vasculature surrounding the genitourinary tract leading to the deposition of schistosome eggs in the wall of the bladder and the ureters. Chronic infection induces fibrosis and calcification of the bladder and ureters and is often complicated by secondary bacterial super-infections. Chronic disease typically manifests as renal colic, hydroureter and hydronephrosis that in severe cases, may culminate in renal failure (1,3,17).

One-third of women infected with S. haematobium will also develop genital schistosomiasis (17). Granulomas around eggs lodged in the vulva, vagina or cervix produce ulcerative lesions that are an increased risk factor for the transmission of sexually transmitted infections such as HIV (1,17). Involvement of the uterus, fallopian tubes and ovaries is less common but fibrotic scarring induced by the granulomatous response may lead to infertility. Genital schistosomiasis is less frequent in males and is characterized by haematospermia and may affect the epididymis, testicles and the spermatic chord (1,17). Genitourinary schistosomiasis has also been epidemiologically linked to carcinoma of the bladder in Egypt and other African foci (1,3,17).

Diagnosis and treatment of schistosomiasis

Diagnosis of both acute and chronic schistosomiasis is currently dependent on the detection of antibodies against parasite antigens or schistosome eggs in the faeces or urine (3,8). Acute schistosomiasis is further characterized by the presence of diffuse pulmonary infiltrates on chest X-ray and almost all cases present with eosinophilia and a history of water contact (1,3,8). These patients respond well to treatment with praziquantel (PZQ) with and without steroids (3). Artemether (ART) treatment given early after exposure may decrease the risk of KS (3,8). Combination therapy with PZQ and ART has been shown safe but is no more effective than PZQ alone against acute schistosomiasis japonica (18).

Ultrasonography provides a safe, rapid, and noninvasive method for the assessment of pathology associated with chronic hepatosplenic disease (19–22). Based on WHO guidelines, the image pattern of liver texture and objective measurements of wall thickness of a peripheral segmental portal vein and main portal vein diameter are used to grade the degree of hepatic fibrosis (23). The grade of fibrosis is in turn used as a predictive factor for the development of portal hypertension and gastrointestinal bleeding (20–22). Ultrasonography may also be used to assess the effectiveness of anti-schistosomal therapy in advanced disease (24). Magnetic resonance imaging (MRI) has shown high sensitivity and specificity for differentiating between cirrhosis and chronic hepatosplenic schistosomiasis (25). Biochemical markers of liver fibrosis (pro-collagen peptides type III and IV, the P1 fragment of laminin, hyaluronic acid, fibrosin, TNF-αR-II and sICAM-1) have the potential to provide a highly sensitive and cost effective method for the assessment of schistosome induced fibrosis but are still under investigation (1,24,26). IL-13 production by PBMC's may be a useful indicator of the persistence of fibrosis following treatment (27).

IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS
  5. IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS
  6. A MOLECULAR PROFILE OF SCHISTOSOMIASIS
  7. IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS
  8. GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS
  9. CONCLUDING COMMENTS
  10. ACKNOWLEDGEMENTS
  11. REFERENCES

Cellular kinetics of the granuloma

Early studies in mice, rhesus monkeys (28) and, later, in pigs (29–31) demonstrated that the granulomatous response around schistosome eggs develops through five pathological stages: the weakly reactive, exudative, exudative-productive, productive and involutional stages (28,30).

The weakly reactive stage is characterized by a gradual accumulation of mononuclear cells, neutrophils and eosinophils around the freshly deposited egg that leads to the formation of a neutrophilic microabscess characteristic of the exudative stage. As the granuloma matures into the exudative-productive stage, histiocytes and epitheloid cells begin to appear at the periphery and gradually replace the leukocytic zone. Fibrocytes also appear at the periphery of the lesion and form an outer zone around the histiocytes and epitheloid cells.

During the productive stage, the schistosome egg becomes degenerated and disintegrated, fibrocytes and collagen fibres become more prominent and lymphocytes, histiocytes, plasma cells and some eosinophils form an additional zone at the periphery of the lesion. Fibrocytes and collagen fibres eventually become the predominant feature of the granuloma whereas other cell types diminish in number (28,30). Granulomas of the involutional stage are greatly reduced in size and may exhibit hyalization of collagen fibres, whereas the egg is typically disintegrated and may become calcified (28,30).

An effective T-cell response is known to be critical for the development of the granulomatous response and host survival. Nude mice infected with a Chinese strain of S. japonicum supported normal parasite survival and fecundity, although transitory growth retardation occurred during the early stage of infection (32). Also, these T-cell deprived mice develop severe necrosis around the eggs in the liver, a situation akin to T-cell-deprived mice infected with S. mansoni but not to that observed in nude mice infected with Philippine S. japonicum (33). These discrepant pathological events in the nude mouse may represent an example of the recognized differences in biological characteristics between S. japonicum strains (32).

B-cell function is required for S. japonicum egg-induced granuloma pathology in early infection (34). OBF-1 knockout mice and µMT mice, both with impaired B-cell development, developed significantly smaller hepatic granulomas at 5 weeks post-infection compared to their wild-type counterparts. In contrast, they displayed no significant difference in granuloma pathology at eight weeks post-infection. This is in concordance with some studies on S. mansoni, also using B-cell-deficient mouse models, which have suggested that B-cells are required for Th2 T-cell responses but not for granuloma formation late in infection (34,35).

Cellular kinetics of hepatic fibrosis

Bartley et al. (36) demonstrated that, in the liver of mice infected with Philippine S. japonicum, activated hepatic stellate cells (HSCs; αSMA+, GFAP+, Desmin+) localize to the periphery of hepatic granulomas, adjacent to fibrotic areas. Similarly, Chang et al. (37) observed a predominance of αSMA+, GFAP+ activated HSCs in the liver during human schistosomiasis mansoni. Together these findings led to the hypothesis that HSCs are the main ECM producing cells in schistosome-induced hepatic fibrosis. In response to tissue damage, these cells undergo transdifferentiation into activated myofibroblast-like cells that produce ECM components, as well as fibrogenic cytokines, Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinases (TIMPs) that contribute to the remodelling of fibrotic tissue in murine and human schistosomiasis (36,38). Related studies have shown that cumulative fibrosis of the liver (39) and colon (40) of mice infected with S. mansoni is associated with an imbalance in MMP:TIMP expression and elevated levels of fibrogenic cytokines. Control of HSC activation and activity may therefore prove important in regulating pathology because of schistosomiasis. Prostaglandin E1 (PGE1) effectively protects rabbit liver from fibrosis, at least in part by inhibiting the activation of HSCs, raising the possibility of combining praziquantel and PGE1 treatment to reverse hepatic fibrosis caused by schistosomiasis (38). There is evidence, however, that non-HSC derived liver myofibroblasts may also be involved in this complex process (41,42).

Alternatively activated macrophages (aaMϕ) are hypothesized to contribute to schistosome induced fibrosis (4,5,43,44). Alternative activation of macrophages is induced by Th2 responses and promotes collagen synthesis and fibrogenesis via the metabolism of l-arginine to proline and polyamine by Arginase-1 (Arg-1 4,43,45,46). Cationic amino acid transporter-2 (CAT-2) may be an important regulator of this process by modulating the activity of Arg-1 (47). Furthermore, Fizz-1 (Found in inflammatory zone-1/RELMα), a surface molecule of aaMϕ, may induce activation of fibroblasts (4,48).

Despite the similarities in S. mansoni and S. japonicum granuloma formation demonstrated by different animal models, some important differences exist between granulomas elicited by these parasites. Schistosoma japonicum eggs tend to be laid in clusters favouring the development of large lesions that are more neutrophilic (28,49). As well, the much higher egg production by S. japonicum (10 times that of S. mansoni) results in increased pathology (3). The smaller size of S. japonicum eggs allows them to be swept to the small portal veins and causing fibrosis in both the peripheral and central areas of the liver (50,51), whereas S. mansoni eggs remain in the large portal veins and cause fibrosis in the central part of the organ (50,51). Calcification of S. japonicum eggs is common but occurs rarely for S. mansoni eggs (28,52). Nevertheless, extensive studies by Cheever et al. (e.g. Ref (33)) suggest the immunopathogenic mechanisms associated with these two forms of schistosomiasis are likely to be similar.

Kinetics of the Th1/Th2 response to schistosome infection

The major components of the schistosome induced granulomas and the cytokines and chemokines that drive this response are illustrated in Figure 1. During the first 4–6 weeks of infection in the mouse, a moderate T-helper type 1 (Th1) response is generated against migrating schistosomula and immature adult worms. This response is characterized by increased levels of circulating pro-inflammatory cytokines including TNF-α, IL-1, IL-6 and IFN-γ (2,4,5,36,53). Elevated levels of these cytokines have also been associated with the development of KS in humans (16). The immune response then switches to a T-helper type 2 (Th2) dominant response with the onset of egg-laying, characterized by increased expression of IL-4, IL-5, IL-10 and IL-13 (2,36,53,54). The Th2 response reaches a peak at approximately 8 weeks post-infection and is then down-modulated with progression to chronic infection (2,4,5,54).

image

Figure 1. Major components of the granulomatous response to schistosome eggs in the host liver and the main cytokines and chemokines that regulate this response. Legend: Egg, Neutrophil, Eosinophil, Macrophage, Hepatic Stellate CellFibroblast, Collagen Fibres, CD4+ T-cell/B-cells, Hepatocytes.

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Cytokine regulation of the granulomas and fibrosis

Pivotal studies with IL-13 and IL-4 deficient and IL-13/IL-4 doubly deficient mice demonstrated that IL-4 drives the development of the granulomatous response whereas IL-13 is the key profibrotic cytokine in the development of schistosome induced hepatic fibrosis (55). IL-4 is responsible for determining granuloma size, inducing the proliferation of Th2 cytokine-producing lymphocytes and is important for the production of IL-5 and IL-13 by granuloma associated cells (56–60). Furthermore, IL-4 is not required for the development of fibrosis but enhances the effects of IL-13 on fibrogenesis (55). As well as promoting fibrosis, IL-13 is known to have an additive effect with IL-4 in the establishment of the Th2 dominant, eosinophil-rich, granulomatous reaction (55). Kaviratne et al. (61), by using mice deficient for TGF-β, demonstrated that IL-13 acts directly on target cells to activate fibrogenic pathways in a TGF-β independent fashion.

Furthermore, the key role of IL-13 and IL-4 in fibrogenesis is evidenced by their effects on the proliferation of and production of collagen by LI90 cells, a human HSC line (62). LI90 cells express the type-II IL-4 receptor complex (IL-4Rα/IL-13Rα1) for IL-4 and IL-13 and up-regulate collagen production in response to treatment with recombinant IL-4 or IL-13. The type-II IL-4 receptor signalling is important in the development of fibrosis, chronic morbidity and mortality not only in schistosomiasis, but also in allergic asthma (63). Additionally, IL4-Rα expression on nonbone marrow derived cells is required for granuloma formation and fibrosis during S. mansoni infection (64). IL-4 and IL-13 may also contribute to the development of fibrosis by inducing the alternative activation of macrophages (4,43,45,46).

IL-5 is required for the recruitment of eosinophils to the granulomatous response as granulomas in mice deficient in IL-5 are virtually devoid of these cells (65). Eosinophils are an important source of Th2 cytokines such as IL-13 (59) and, therefore, IL-5 indirectly contributes to the polarization of the immune response through the recruitment of these cells (59,66). It has been proposed that IL-2 regulates the expression of IL-5 as production of IL-5 is significantly reduced in schistosome infected mice with treated with an anti-IL-2 mAb (67,68). The recruitment of the large numbers of eosinophils to granulomas in both humans and mice suggest these cells contribute to the disease process although their precise role remains undetermined (69,70).

IL-10 plays a key regulatory role in facilitating the shift from a Th1 to Th2 response and preventing the development of severe pathology due to excessive Th1 and/or Th2 responses (4). In the early stages of the granulomatous response, IL-10 acts to suppress the production of Th1 cytokines such as IFN-γ (71,72), possibly by regulating IL-12/IL-12R expression which, in turn, modulates IFN-γ expression (73). Hoffmann et al. (74) have also demonstrated that IL-10 is essential to prevent excessive Th2 responses in IL-10 knockout mice.

The role of Th1 cytokines in schistosome induced granulomas and fibrosis are not as well defined. Experiments with IFN-γ knockout mice (58) and anti-IFN-γ mAb (65) treated mice have shown that in schistosomiasis japonicum, IFN-γ is critical in the development of granulomas and contributes to the recruitment of neutrophils to the granulomatous response. Results with IFN-γ deficient mice infected with S. mansoni have been conflicting with reports of reduced, increased or no change in granuloma sizes compared with wild-type controls (57,58).

The recent description of a third T-helper-cell subset (Th17) and its involvement in a variety of other chronic inflammatory diseases has prompted investigations of its role in schistosomiasis (75). The Th17 subset does not appear to be involved in the pathogenesis of schistosomiasis in mice with moderate pathology but has been associated with the development of severe pathology in Th1 polarized mice and CBA mice that develop a strong inflammatory response characterized by high levels of IFN-γ (4,76–78). The induction of severe pathology and expression of IL-17 in Th1 polarized mice has subsequently been shown to be dependent on the presence of IL-23, another Th17 cytokine (76,77).

Although the immunopathology of S. mansoni and S. japonicum infections appears to be similar, there are indications that S. mansoni and S. japonicum-induced pathology responds differently to cytokine regulation, at least in the mouse, and these differences in cytokine response might provide important clues regarding the progression to chronic disease (58). A comparison of the pathology and cytokine responses in schistosomiasis mansoni and schistosomiasis japonica is shown in Table 1.

Table 1.  Comparison of the pathology and cytokine responses in schistosomiasis mansoni and schistosomiasis japonica
Schistosomiasis mansoniSchistosomiasis japonica
Egg laying commences 6 weeks post infectionEgg laying commences 3–4 weeks post infection
Eggs are laid singly (28)Eggs are laid in clusters leading to the formation of larger granulomas (28)
Granulomas are composed predominately of eosinophils (28)Granulomas are composed predominantly of neutrophils (28)
Calcification of eggs within granulomas is infrequent (28)Calcification of eggs within granulomas is common (28)
The response of infected mice to purified SEA is of a delayed-type-hypersensitivity reaction (79)The response of infected mice to purified SEA is of an immediate-type-hypersensitivity reaction (79)
Katayama Syndrome occurs mainly in previously unexposed individuals and is uncommon in endemic regions (1)Katayama Syndrome is common in endemic regions and its symptoms are more severe (1)
Fibrosis occurs in the central region of the liver (50,51)Fibrosis occurs in the centre and the periphery of the liver (50,51)
IL4−/– knockout mice have granulomas of a similar size to wild-type mice (55)IL-4−/– knockout mice have an impaired granulomatous response (58)
Anti-IL-5 antibody treatment does not affect the size of granulomas (80)Anti-IL-5 antibody treatment decreases granuloma volume (65)
Anti-IFN-γ antibody treatment increases granuloma size (57) while IFN-γ deficiency has no effect (81)Anti-IFN-γ antibody treatment and IFN-γ deficiency decreases granuloma size (58,65)

Regulation of the granulofibrotic response

Tight regulation of the Th1, Th2 and possibly Th17 cytokine responses generated during schistosome infection is essential to prevent excessive pathology. As discussed above IL-10 plays key roles in facilitating the switch from a Th1 to a Th2 dominant response with the onset of egg laying and in preventing the development of an excessive Th2 response which would be detrimental to host survival.

Binding of parasite antigens by pattern recognition receptors on dendritic cells (DCs), macrophages and other immune cells may play a role in the polarization of the immune response against schistosome eggs. For example Galectin-3, a cell surface molecule that binds glycoconjugates, is important in host defence against other pathogens but reports of its role in the development of Th2 responses and overall egg granuloma formation are contradictory (82–84), so its relevance in murine schistosomiasis remains elusive.

Regulatory T-cells (Tregs) also help regulate the granulofibrotic response. These cells are classified as a CD4+CD25+ subset of T-cells that may be divided into naturally occurring Tregs (naTregs) or inducible Tregs (iTregs). Naturally occurring Tregs are characterized by the expression of forkhead/winged helix transcription factor 3 (FoxP3) and are recruited to the site of inflammation after undergoing selection in the thymus. Inducible Tregs are FoxP3 and develop in the periphery from activated effector cells (4,85). Studies using an adoptive transfer model in IL-10/Recombination activating gene-2(RAG-2)-deficient mice have demonstrated that iTregs are an important source of IL-10 that regulates Th1/Th2 balance during schistosome-induced pathology (71). In a follow up study naTregs were shown to be capable of suppressing the expression of both Th1 and Th2 cytokines (86). T-regulatory cells therefore contribute to the regulation of schistosome-induced pathology by both suppressing the Th1 response and preventing the development of an excessive Th2 response during the development of granulomatous inflammation (4,71,85,86). The regulation of T-cells and Th2 response in schistosome infection is however complex (87) and the precise contribution of CD4+CD25+ T-cells to the overall regulatory process of granuloma formation is uncertain. Most work on CD4+CD25+ cells has been undertaken on S. mansoni infection but there is evidence they are also activated by S. japonicum eggs (88) and may play a role in protection in against murine models of ulcerative colitis (89) and asthma (88).

Down Modulation of the Th2 driven granulomatous response

Down-modulation of the granulomatous response is essential to prevent excessive chronic morbidity and to promote host survival (90), and is characterized by a decreased cellular inflammatory response to newly deposited eggs and the simultaneous down regulation of the Th2 cytokine responses (2,44). Multiple mechanisms are thought to be involved in this down modulation. Elegant studies in murine schistosomiasis have revealed that IL-13Rα2 is essential for the down-regulation of the granulomatous response and is pivotal in the control of IL-13-mediated fibrosis (4,90–92). IL-13Rα2 acts as a potent decoy receptor, competing with IL-13Rα1 for binding of IL-13 and preventing signalling through the IL-4/IL-13Rα1 receptor complex (4,90–92). The dynamics of IL-13Rα1 and IL-13Rα2 expression may therefore influence the outcome of schistosomiasis and defining how their expression it regulated is an important area for future investigation, not only for understanding granuloma modulation in schistosomiasis but also for other Th2-associated diseases (4). A role for apoptosis, particularly apoptosis by neglect of CD4+ T-cells, has been hypothesized to contribute to the down-modulation of the granulomatous response (93). Apoptosis of CD4+ T-cells has been shown to occur at a higher rate in low pathology C57BL/6 mice which develop smaller granulomas compared with high pathology CBA mice (93). B-cell mediated FcR dependent signalling has also been implicated in the down-modulation of the Th2 response as mice deficient in B-lymphocytes or the Fc-receptor exhibited marked exacerbation of granulomatous inflammation (35).

Chemokines in hepatic schistosomiasis

The activities chemokines in schistosome-induced hepatic fibrosis are poorly understood, but one likely role lies in cellular recruitment of cells to the granuloma (44,94). CCL3 (Macrophage Inflammatory Protein-1α; MIP-1α), CCL17 (Thymus and Activation Regulated Chemokine; TARC) and CCL22 (Macrophage Derived Chemokine; MDC) are thought to promote the granulofibrotic response as mice deficient in these chemokines develop smaller granulomas and less fibrosis (94–96). Furthermore, human studies report an association between elevated plasma CCL3 and an increased risk of developing severe hepatic disease, suggesting that CCL3 may be a determining factor in the development of severe schistosomiasis (94,97). In contrast, CCL5 (Regulated on Activation Normal T-cell Expressed and Secreted; RANTES) is thought to negatively regulate granuloma development as mice deficient in this chemokine show significant augmentation of the granulomatous response (98). Expression of genes encoding other chemokines and chemokine receptors such as CCL2 (Monocyte Chemoattractant Protein-1; MCP-1), CCL4 (MIP-1β), CCL7 (MCP-3), CCL11 (Eotaxin-1), CCL12 (MCP-5), CCR1, CCR2, CCR3 and CCR4 have been shown to be induced in pulmonary models of schistosome induced granuloma formation (99–102) but the effect of these chemokines on granuloma formation and fibrosis is unknown. Together these findings suggest the balance of chemokine production and chemokine receptor activation is likely important in determining the fate of schistosome infection in animals and humans (103).

A MOLECULAR PROFILE OF SCHISTOSOMIASIS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS
  5. IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS
  6. A MOLECULAR PROFILE OF SCHISTOSOMIASIS
  7. IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS
  8. GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS
  9. CONCLUDING COMMENTS
  10. ACKNOWLEDGEMENTS
  11. REFERENCES

Despite the numerous studies in mice documenting the effects of immune polarization or specific cytokines on schistosome induced granuloma formation and fibrosis, little is known of the global molecular mechanisms involved or the gene signalling pathways involved in granuloma formation and ECM remodelling (5). Results from a series of tissue microarray studies of murine schistosomiasis (104,105) have, however, shed some light on the molecular and biochemical mechanisms regulating S. mansoni-induced pathology and have confirmed the important role of Th2 cytokines in granuloma formation and fibrogenesis. The studies used microarray analysis of mRNA extracted from granulomatous tissues from type-1 (Th1) polarized (IL-10/IL-4 knockout mice; limited granulomatous pathology), type-2 (Th2) polarized (IL-10/IL-12 knockout mice; pronounced granulomatous pathology) and wild-type mice, either infected with S. mansoni or sensitized intraperitoneally and challenged intravenously with S. mansoni eggs, to define the global gene expression profiles that characterize the distinct pathological and immunological mechanisms affecting the outcome of infection.

Type-1 polarization leads to the development of smaller nonfibrotic granulomas but is associated with increased tissue damage because of the development of a strong pro-inflammatory response (74). Accordingly, genes up-regulated in these mice were associated with IFN-γ activation including chemokines and chemokine receptors associated with a type-1 response such as CCL5 (RANTES) and CXCL10 (IFN-γ-inducible protein-10; IP-10) (105). Increased tissue damage observed in these mice was reflected in the identification of two additional major groups of genes associated with the immune response in type-1-polarized mice: those involved in the acute-phase reaction and those in apoptosis (104). The up-regulation of macrophage C-type lectin and the absence of arginase expression suggest the predominance of classically activated macrophages, presumably contributing to the pro-inflammatory response via the production inducible nitric oxide (NO) (105).

Type-2 polarization induces the development of large, eosinophil rich granulomas and excessive fibrosis (74). The gene expression profile of these mice was associated with wound healing and fibrogenesis and was characterized by the massive up regulation of procollagens, enzymes involved in collagen synthesis and tissue repair and enhanced expression of IL-13 (104,105). A number of genes, including those coding for small proline-rich proteins (SPRRs) (105), associated with wound healing were increased (akin to the response that is critical for rapid cure in murine cutaneous leishmaniasis (106)); and there was high expression of Arg-1, Ym1, and FIZZ-1 (105) most likely reflecting the continuing presence and activity of a large population of aaMφ in granulomatous tissues, consistent with the proposed role of these cells in schistosome induced fibrosis. A variety of chemokines including CCL8 (MCP-2), CCL7 (MCP-3), and CCL12 (MCP-5), as well as CCL17 (TARC), CCL6 (C10), CCL11 (Eotaxin), and CCL24 (Eotaxin-2) were preferentially expressed in the type-2 mice (105), likely recruiting activated Th2 cells, eosinophils, and monocytes; several markers of eosinophil activation such as eosinophil-associated ribonucleases were also up-regulated. Overall, these results clearly illustrated that the different pathological outcomes of Type-1 and type-2 polarization in the murine model of schistosomiasis are associated with distinct gene expression profiles. Type-1 responses promote a more pro-inflammatory outcome leading to increased apoptosis, whereas type-2 responses promote gene transcription pathways associated with granuloma formation, collagen synthesis and matrix remodelling.

Gene expression profiling of splenic CD4+ T-cells confirmed that progression of S. japonicum infection is associated with a switch from a Th1 to Th2 dominant response that involves the up-regulation of a variety of immune regulators, including many cytokine and chemokine genes, immunoglobulin-related genes, and genes related to apoptosis and the stress response (107,108). The onset of egg laying was associated with an increase in the ratio of IL4+CD4+ T-cells: IFN-γ+CD4+ T-cells and was reflected by increased expression of the Th2 cytokines IL4 and IL-10 (107,108). Conversely, a significant portion of the genes that were down-regulated encoded IFN-γ-inducible molecules suggesting that, although IFN-γ expression was up-regulated, IFN signalling and the Th1 response may be impaired during S. japonicum infection (108). The observed switch to a Th2 dominant response was associated with increased apoptosis of CD4+ T-cells and an increase in the number CD4+CD25+ regulatory T-cells, consistent with the proposed roles of apoptosis and regulatory T-cells in regulating the immunopathogenesis of schistosomiasis (71,86,93,107).

IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS
  5. IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS
  6. A MOLECULAR PROFILE OF SCHISTOSOMIASIS
  7. IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS
  8. GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS
  9. CONCLUDING COMMENTS
  10. ACKNOWLEDGEMENTS
  11. REFERENCES

It remains to be determined to what extent the pathological pathways established for the murine model of schistosomiasis can be directly extrapolated to humans particularly in light of the important differences existing between schistosome-induced disease in the two hosts (Table 2) (6,109). For example, some features of chronic human schistosomiasis such as a low and sustained intensity of infection and the pattern of Symmer's pipestem fibrosis are difficult to replicate in mice (6). Indeed, in humans, the regulation of liver fibrosis during schistosomiasis may be even more complex with multiple mediators, including re-infection, co-infections, environmental factors and the age, gender and genetic background of the host, influencing the outcome of infection (6,110).

Table 2.  Differences between the murine model of schistosomiasis and human disease (After Abath et al. (6))
Murine modelHuman disease
Experimental infections involve a single exposureMost infections are acquired gradually and involve continued re-exposure
Intensity of infection is generally highInfection intensity varies but is generally low
Animals are infected with defined schistosome isolatesInfection occurs with various isolates of the parasite
Duration of infection and parasite burden are definedIt is difficult to define how long individuals have been infected and the parasite burden
Studies are conducted in animals with similar parasite burdenStudies with similar parasite burden are difficult to control and re-infection is a complicating factor
Some pathological features of chronic infection are difficult to reproduce in mice, e.g. experimental infections exhibit perioval fibrosisChronic liver disease is characterized by Symmers’ pipe stem (periportal) fibrosis
Genetic background of the host can be homogeneousGenetic background of the host is heterogeneous
Experimental design defines the length of investigationLong-term investigation of patients with active disease is ethically precluded
Co-infection with other parasites can be avoidedCo-infection with other parasites is common and may influence the outcome of infection

Studies in human patients of the association between disease severity and the production of cytokines and/or chemokines in vitro have shown that different clinical forms of schistosomiasis are associated with distinct immunological profiles (111,112). Patients with intestinal schistosomiasis (INT) typically display a mixed Th1/Th2 response with higher levels of IL-4 production in comparison to acute schistosomiasis (111). INT patients also have an increased frequency of IL-10+ T-cells as well as CD4+CD25High+ T-cells in the peripheral blood (112). Following in vitro antigen stimulation, PBMCs from patients with INT showed higher expression of CXCR4+, and low expression of CXCR3+ where CXCR4 expression was closely associated with IL-10 expression (112). Patients with hepatic fibrosis (HF) exhibit an increased number of IL4+ and IL5+ T-cell subsets compared with patients with hepatosplenic disease, but fewer IL10+ T-cells in comparison to patients with intestinal disease (112). Furthermore, low levels of IFN-γ production against soluble egg antigen (SEA) (113–115), elevated levels of TNF-α against SEA (113), high levels of IL-4 against soluble worm antigen preparation (SWAP) and elevated levels of IL-10 against both SWAP and SEA (114) have been associated with an increased risk of developing severe HF. Additionally, high levels of the Th2 cytokines IL-4 against SWAP and IL-13 and IL-5 against SWAP and SEA correlate with the persistence of fibrosis following treatment with praziquantel (114). Up-regulation of activation-related surface markers on eosinophils from chronic S. mansoni-infected patients as well as increased levels of eosinophils derived cytokines, including TNF-α, IL-4 and IL-5, in the blood have been shown to be a hallmark of periportal fibrosis (116). In addition, a lack of association between cytokine production, activation marker expression, and the number of IL-10 positive lymphocytes in the fibrotic group suggest that impaired IL-10-driven immunoregulatory function may play an important role in the establishment of pathology in patients with periportal fibrosis (116). In contrast, patients with hepatosplenic disease (HS) have an impaired Type-2-immune response associated with increased production of IFN-γ following stimulation with SEA or SWAP (111) and decreased expression of IL-10 by T-cells (112) that leads to the development of a predominant pro-inflammatory immune response. Taken together the results of these studies suggest that the outcome of human schistosomiasis is influenced by the nature of the Th1/Th2 immune response against schistosome antigens and is regulated by IL-10 and a putative population of CD4+CD25High+ regulatory T-cells.

Overall, the results of these studies tend to corroborate those in mice suggesting that Th2 cytokines, including IL-4 and IL-13, promote immunopathology while IFN-γ protects against the development of severe fibrosis (4). The situation may be more complex in schistosomiasis japonica where IFN-γ is associated with protection against peripheral portal fibrosis, but IL-10 is associated with protection against central portal fibrosis, because of its anti-inflammatory and anti-fibrotic effects (117). The pro-inflammatory cytokines IL-1 and IL-6 are elevated in sera of S. japonicum-infected individuals with severe hepatic fibrosis (118).

GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS
  5. IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS
  6. A MOLECULAR PROFILE OF SCHISTOSOMIASIS
  7. IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS
  8. GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS
  9. CONCLUDING COMMENTS
  10. ACKNOWLEDGEMENTS
  11. REFERENCES

Genetic background plays a pivotal role in determining the susceptibility to and outcome of schistosome infections (119–124). Segregation analysis of a Brazilian population has revealed that susceptibility to infection is controlled by the ‘SM1’ (‘S. mansoni 1’) gene locus that has been linked to the 5q31–q33 chromosome region comprising the genes IL4, IL5 and IL13 (125,126), although other polymorphisms in genes of the type-2 cytokine pathway may also be important (127). Further, two single nucleotide polymorphisms within IL-5 have been associated with the development of symptomatic infection with S. japonicum in a Chinese population (124). Another study involving a Sudanese population indicated that the segregation of a co-dominant gene (SM2) could account for the familial distribution of severe schistosomiasis mansoni in this population. Linkage analysis indicated that this gene occurred within the 6q22–q23 region with polymorphisms close to and in the IFN-γ receptor 1 gene (IFNGR1)(122). A later study of an Egyptian population confirmed linkage of severe schistosomiasis with the IFNGR1 locus and also suggested a possible association with the IL-13/IL-4 region and the TGF-β1 gene (119). Further, IFN-γ production by egg-antigen stimulated PBMCs correlates with protection against severe schistosomiasis mansoni (115) and two polymorphisms in IFN-γ have been found to be associated with advanced hepatic disease (121) consistent with the anti-fibrogenic role of IFN-γ and the low IFN-γ production by subjects with severe disease (121,128). As indicated previously, IFN-γ is also associated with protection against peripheral fibrosis in humans infected with S. japonicum whereas IL-10 protects against severe hepatic central fibrosis and it is likely the two fibrotic outcomes are under different genetic control (117).

Associations have also been reported between the clinical manifestations of chronic schistosomiasis mansoni and japonica and gene alleles within the major histocompatibility complex (120,129–134) although no consistent picture has emerged from these studies.

CONCLUDING COMMENTS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS
  5. IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS
  6. A MOLECULAR PROFILE OF SCHISTOSOMIASIS
  7. IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS
  8. GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS
  9. CONCLUDING COMMENTS
  10. ACKNOWLEDGEMENTS
  11. REFERENCES

Despite extensive studies, there is still much that remains unknown about the immunopathology of schistosomiasis not only that caused by S. mansoni but also by S. japonicum and, especially, S. haematobium. As well, further work is required to gain a better understanding of immune processes regulating development of pathology in the human liver and to confirm assumed similarities to murine models of the disease. A more comprehensive understanding the immunopathological mechanisms and gene-expression pathways that underlie the development of chronic schistosomiasis will be essential if new therapeutic strategies such as pathology/morbidity limiting anti-schistosome vaccines are to be developed.

Schistosomiasis continues to be an important cause of parasitic morbidity and mortality globally and recent systematic reviews (135–138) indicate that the geographical extent and burden of the disease exceed official estimates. Collectively, close to 800 million individuals are at risk of schistosomiasis, and over 200 million people are infected in many parts of South America, the Middle East, and Southeast Asia, but being particularly pronounced in sub-Saharan Africa (136). The continued spread of the disease and reports of praziquantel treatment failures have highlighted the need for the development of drug alternatives and new control strategies against schistosomiasis including the use of vaccines (139,140).

Protection against schistosomiasis should not only reduce infection and protect from re-infection, but also enhance immune responses in infected humans that offer protection against granuloma-related pathology and/or worm fecundity (140), which is a characteristic of one anti-schistosome vaccine candidate, Sh28GST, that has progressed the furthest toward clinical development (at the Phase II Clinical Trial) (141). Anti-pathology schistosome vaccines could be designed to prevent the development of fibrosis and chronic morbidity by skewing the immune response (142–144). This could be achieved by priming the immune system towards a Th1 phenotype by immunization with SEA, principal egg components recently identified by proteomic analysis (145,146), or with appropriate recombinant antigens or DNA plasmids (140), suitably adjuvanted with, for example, IL-12. Care will need to be taken with this approach since murine studies have shown that immune responses skewed in the Th1 direction may also lead to exacerbated pathology and premature death (74,147).

Finally, fibrosis is important to many other diseases such as Crohn's disease and sarcoidosis, and is also a major complication in asthma, chronic graft rejection, and several autoimmune diseases (148,149). The understanding of the cellular and molecular mechanisms involved in fibrogenesis and the immunopathogenesis caused by schistosomes may have broad implications for human health, ultimately translating into an effective disease intervention strategy not only for schistosomiasis but also for other granulofibrotic diseases.

ACKNOWLEDGEMENTS

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS
  5. IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS
  6. A MOLECULAR PROFILE OF SCHISTOSOMIASIS
  7. IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS
  8. GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS
  9. CONCLUDING COMMENTS
  10. ACKNOWLEDGEMENTS
  11. REFERENCES

The authors’ research on schistosomiasis is supported by the National Health and Medical Research Council of Australia, The Wellcome Trust (UK) and the Dana Foundation (USA). The first author is a recipient of a University of Queensland Joint Research Scholarship.

REFERENCES

  1. Top of page
  2. SUMMARY
  3. INTRODUCTION
  4. CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS
  5. IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS
  6. A MOLECULAR PROFILE OF SCHISTOSOMIASIS
  7. IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS
  8. GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS
  9. CONCLUDING COMMENTS
  10. ACKNOWLEDGEMENTS
  11. REFERENCES
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