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Parasite Immunology, 2009, 31, 163–176

DOI: 10.1111/j.1365-3024.2009.01098.x

Review Article
Immunopathogenesis
REVIEW
ARTICLEof
human schistosomiasis
Blackwell Publishing
Ltd

Immunopathogenesis of human schistosomiasis
M. L. BURKE,1,2 M. K. JONES,1,3 G. N. GOBERT,1 Y. S. LI,1 M. K. ELLIS1 & D. P. McMANUS1
1

Molecular Parasitology Laboratory, Division of Infectious Diseases and Immunology, The Queensland Institute of Medical Research,
Herston, Queensland, Australia; 2The School of Population Health, The University of Queensland, Herston, Queensland, Australia;
3
The School of Veterinary Science, The University of Queensland, St Lucia, Queensland, Australia

SUMMARY

INTRODUCTION

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.

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

Keywords chemokine, cytokine, fibrosis, immunopathogenesis,
immunopathology
Correspondence: Donald McManus, Molecular Parasitology
Laboratory, Division of Infectious Diseases and Immunology,
Queensland Institute of Medical Research, PO Royal Brisbane
Hospital, Herston, QLD 4029, Australia
(e-mail: donald.mcmanus@qimr.edu.au).
Received: 27 November 2008
Accepted for publication: 9 January 2009
Disclosures: M. L. Burke, M. K. Jones, G. N. Gobert, Y.S. Li, M. K. Ellis, D P. McManus – None

© 2009 Blackwell Publishing Ltd

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Anaemia.17).10). Genitourinary schistosomiasis has also been epidemiologically linked to carcinoma of the bladder in Egypt and other African foci (1. Burke et al. microulceration and superficial bleeding (3.17). fatigue.M. intestinal and variceal bleeding. mansoni infection cause hepatointestinal and hepatosplenic disease. Granulomas around eggs lodged in the vulva. Involvement of the uterus.16). malaise.3. occlusion of the portal veins leads to the development of portal hypertension. haematobium). pruritic rash that manifests within several hours of exposure to contaminated water and may persist for several days (1. CD is an IgE-mediated hypersensitivity response directed against penetrating cercariae (1.12). 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. 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. malnutrition and the production of haemolytic factors by schistosomes can lead to anaemia in schistosomiasis (15). splenomegaly. Parasite Immunology. In turn. fallopian tubes and ovaries is less common but fibrotic scarring induced by the granulomatous response may lead to infertility. portacaval shunting. Hepatosplenic schistosomiasis begins with the deposition of schistosome eggs in the hepatic sinusoids leading to the development of granulomas and hepatomegaly. and eosinophilia with patchy infiltrates visible on pulmonary radiography (1. haematobium infection is common among individuals exposed for the first time such as travellers or migrants but is rare among endemic populations (1.3.3.11).8). © 2009 Blackwell Publishing Ltd. japonicum is common in endemic communities and is associated with severe and persistent manifestations that may rapidly progress to hepatosplenomegaly and portal hypertension (1. 164 Parasite Immunology Gastrointestinal and liver disease Gastrointestinal schistosomiasis is characterized by chronic or intermittent abdominal pain and discomfort. Schistosoma japonicum and S.3.3.7.3.8).9). Genitourinary disease Genitourinary tract disease is a specific trait of S.3). Additionally. headache. Chronic infection induces fibrosis and calcification of the bladder and ureters and is often complicated by secondary bacterial super-infections.8).17). 31.3. These symptoms are caused by a granulomatous response to schistosome eggs in the intestinal mucosa leading to pseudopolyposis. co-infection with S.13. Blood loss through haematuria (S. acute disease due to S. mansoni or S.17).3.7.9. the development of ectopic lesions leading to neuro-. gastrointestinal varices and gastrointestinal bleeding that may eventually be fatal (1. occurs infrequently among endemic populations but is common among visitors and migrants and after primary infections (1.14).13. 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). haematobium causes genitourinary schistosomiasis (1. CLINICAL MANIFESTIONS OF SCHISTOSOMIASIS Acute schistosomiasis Acute schistosomiasis. when it occurs. KS is an immune-complex mediated hypersensitivity reaction against migrating schistosomula and early egg deposition (1. hydroureter and hydronephrosis that in severe cases.7. Genital schistosomiasis is less frequent in males and is characterized by haematospermia and may affect the epididymis. 163–176 . Acute schistosomiasis due to S. Abdominal symptoms may also occur and correspond with the migration of juvenile worms (1.8). For example. ascites. Adult S. In contrast. nonproductive cough.9). One-third of women infected with S. Chronic disease typically manifests as renal colic. in turn has been associated with wasting in adults and growth retardation and cognitive impairment in children (1. is similar during infection with the three major schistosome species and is characterized by cercarial dermatitis (CD) and Katayama syndrome (KS) (3. vagina or cervix produce ulcerative lesions that are an increased risk factor for the transmission of sexually transmitted infections such as HIV (1.3. myalgia. basic underlying immunopathogenic mechanisms in the two species are likely similar. may culminate in renal failure (1. The outcome of chronic schistosomiasis may be further complicated by co-infections. testicles and the spermatic chord (1.14). 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.8–10). mansoni and Hepatitis C Virus (HCV) or Hepatitis B Virus (HBV) is associated with accelerated progression and increased severity of chronic liver fibrosis (3. loss of appetite and diarrhoea that commonly contains occult blood. In S. haematobium infection (1.3. L.8). haematobium will also develop genital schistosomiasis (17). CD is characterized by a maculopapular. whereas chronic infection with 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.3). cerebral or pulmonary schistosomiasis may occur but is rare (3.3.

the P1 fragment of laminin. In contrast. productive and involutional stages (28. japonicum. Desmin+) localize to the periphery of hepatic granulomas. in pigs (29–31) demonstrated that the granulomatous response around schistosome eggs develops through five pathological stages: the weakly reactive. During the productive stage. Artemether (ART) treatment given early after exposure may decrease the risk of KS (3. histiocytes and epitheloid cells begin to appear at the periphery and gradually replace the leukocytic zone. hyaluronic acid. (37) observed a predominance of αSMA+. OBF-1 knockout mice and μMT mice. April 2009 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. IMMUNOPATHOLOGY OF HEPATIC SCHISTOSOMIASIS Immunopathogenesis of human schistosomiasis of the exudative stage. These discrepant pathological events in the nude mouse may represent an example of the recognized differences in biological characteristics between S. histiocytes. 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. both with impaired B-cell development. whereas the egg is typically disintegrated and may become calcified (28. 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 (1.8). although transitory growth retardation occurred during the early stage of infection (32). in the liver of mice infected with Philippine S. exudative.30). The grade of fibrosis is in turn used as a predictive factor for the development of portal hypertension and gastrointestinal bleeding (20–22). Ultrasonography provides a safe. adjacent to fibrotic areas. and noninvasive method for the assessment of pathology associated with chronic hepatosplenic disease (19–22). αSMA+. fibrocytes and collagen fibres become more prominent and lymphocytes. japonicum strains (32). later.8). Fibrocytes also appear at the periphery of the lesion and form an outer zone around the histiocytes and epitheloid cells. The weakly reactive stage is characterized by a gradual accumulation of mononuclear cells. also using B-cell-deficient mouse models. These patients respond well to treatment with praziquantel (PZQ) with and without steroids (3). japonicum (33). mansoni but not to that observed in nude mice infected with Philippine S. As the granuloma matures into the exudative-productive stage. GFAP+.3. Nude mice infected with a Chinese strain of S.30). Combination therapy with PZQ and ART has been shown safe but is no more effective than PZQ alone against acute schistosomiasis japonica (18). Chang et al.8). Ultrasonography may also be used to assess the effectiveness of anti-schistosomal therapy in advanced disease (24).26). Together these findings led to the hypothesis that HSCs are the main ECM producing 165 .35). activated hepatic stellate cells (HSCs. Parasite Immunology. fibrosin. rhesus monkeys (28) and.24. neutrophils and eosinophils around the freshly deposited egg that leads to the formation of a neutrophilic microabscess characteristic © 2009 Blackwell Publishing Ltd. developed significantly smaller hepatic granulomas at 5 weeks post-infection compared to their wild-type counterparts. This is in concordance with some studies on S. plasma cells and some eosinophils form an additional zone at the periphery of the lesion. GFAP+ activated HSCs in the liver during human schistosomiasis mansoni.30). Biochemical markers of liver fibrosis (pro-collagen peptides type III and IV. (36) demonstrated that. 163–176 Cellular kinetics of hepatic fibrosis Bartley et al. Number 4. B-cell function is required for S.Volume 31. exudative-productive. Based on WHO guidelines. they displayed no significant difference in granuloma pathology at eight weeks post-infection. An effective T-cell response is known to be critical for the development of the granulomatous response and host survival. japonicum egg-induced granuloma pathology in early infection (34). 31. Also. Cellular kinetics of the granuloma Early studies in mice. the schistosome egg becomes degenerated and disintegrated. IL-13 production by PBMC’s may be a useful indicator of the persistence of fibrosis following treatment (27). Similarly. 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. 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). rapid. japonicum supported normal parasite survival and fecundity. mansoni. Fibrocytes and collagen fibres eventually become the predominant feature of the granuloma whereas other cell types diminish in number (28. Granulomas of the involutional stage are greatly reduced in size and may exhibit hyalization of collagen fibres. Magnetic resonance imaging (MRI) has shown high sensitivity and specificity for differentiating between cirrhosis and chronic hepatosplenic schistosomiasis (25). which have suggested that B-cells are required for Th2 T-cell responses but not for granuloma formation late in infection (34.

japonicum granuloma formation demonstrated by different animal models. mansoni is associated with an imbalance in MMP:TIMP expression and elevated levels of fibrogenic cytokines.43. 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 166 Parasite Immunology are illustrated in Figure 1.51). Calcification of S. mansoni) results in increased pathology (3). demonstrated that IL-13 acts directly on target cells to activate fibrogenic pathways in a TGF-β independent fashion. This response is characterized by increased levels of circulating pro-inflammatory cytokines including TNF-α. Fizz-1 (Found in inflammatory zone-1/RELM α ). IL-1. Parasite Immunology. mansoni and S.g. characterized by increased expression of IL-4. Cationic amino acid transporter-2 (CAT-2) may be an important regulator of this process by modulating the activity of Arg-1 (47). Prostaglandin E1 (PGE1) effectively protects rabbit liver from fibrosis. Burke et al. but also in allergic asthma (63).38).46). that non-HSC derived liver myofibroblasts may also be involved in this complex process (41. IL-5. 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). 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. 31. japonicum eggs is common but occurs rarely for S. L. a surface molecule of aaM ϕ. IL-13 is known to have an additive effect with IL-4 in the establishment of the Th2 dominant. some important differences exist between granulomas elicited by these parasites. Furthermore.4. chronic morbidity and mortality not only in schistosomiasis.45.43.M. The type-II IL-4 receptor signalling is important in the development of fibrosis. During the first 4–6 weeks of infection in the mouse. Related studies have shown that cumulative fibrosis of the liver (39) and colon (40) of mice infected with S. Kaviratne et al. Additionally.5. IL-4 is responsible for determining granuloma size.46).4.36.5.43. Furthermore. whereas S. at least in part by inhibiting the activation of HSCs. Control of HSC activation and activity may therefore prove important in regulating pathology because of schistosomiasis.53. eosinophil-rich. The Th2 response reaches a peak at approximately 8 weeks post-infection and is then down-modulated with progression to chronic infection (2. the much higher egg production by S. Schistosoma japonicum eggs tend to be laid in clusters favouring the development of large lesions that are more neutrophilic (28. raising the possibility of combining praziquantel and PGE1 treatment to reverse hepatic fibrosis caused by schistosomiasis (38). IL4-Rα expression on nonbone marrow derived cells is required for granuloma formation and fibrosis during S. therefore. Eosinophils are an important source of Th2 cytokines such as IL-13 (59) and. Alternatively activated macrophages (aaMϕ) are hypothesized to contribute to schistosome induced fibrosis (4. As well. As well as promoting fibrosis. by using mice deficient for TGF-β.49). 163–176 . 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. Matrix Metalloproteinases (MMPs) and Tissue Inhibitors of Metalloproteinases (TIMPs) that contribute to the remodelling of fibrotic tissue in murine and human schistosomiasis (36.52). extensive studies by Cheever et al. mansoni eggs remain in the large portal veins and cause fibrosis in the central part of the organ (50. (61).5. IL-5 indirectly contributes to the polarization © 2009 Blackwell Publishing Ltd. (e. as well as fibrogenic cytokines. IL-4 is not required for the development of fibrosis but enhances the effects of IL-13 on fibrogenesis (55).51). Elevated levels of these cytokines have also been associated with the development of KS in humans (16). however. 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).44). granulomatous reaction (55). There is evidence. Ref (33)) suggest the immunopathogenic mechanisms associated with these two forms of schistosomiasis are likely to be similar.48). 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). may induce activation of fibroblasts (4. In response to tissue damage. Furthermore. cells in schistosome-induced hepatic fibrosis. Despite the similarities in S.54).36. a human HSC line (62). mansoni eggs (28. 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 4.45. a moderate T-helper type 1 (Th1) response is generated against migrating schistosomula and immature adult worms. japonicum (10 times that of S. IL-6 and IFN-γ (2. IL-10 and IL-13 (2.53). Nevertheless. The immune response then switches to a T-helper type 2 (Th2) dominant response with the onset of egg-laying. IL-4 and IL-13 may also contribute to the development of fibrosis by inducing the alternative activation of macrophages (4. 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. The smaller size of S. mansoni infection (64).54). these cells undergo transdifferentiation into activated myofibroblast-like cells that produce ECM components.42).

68). Number 4. modulates IFN-γ expression (73). Results with IFN-γ deficient mice infected with S. of the immune response through the recruitment of these cells (59.72). Hepatocytes. Collagen Fibres. © 2009 Blackwell Publishing Ltd. Eosinophil. Macrophage. 163–176 The role of Th1 cytokines in schistosome induced granulomas and fibrosis are not as well defined. 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. 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). CD4 + T-cell/B-cells. In the early stages of the granulomatous response. Parasite Immunology. mansoni have been conflicting with reports of reduced. increased or no change in granuloma sizes compared with wild-type controls (57. 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 167 . 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 (67.58). Experiments with IFN-γ knockout mice (58) and anti-IFN-γ mAb (65) treated mice have shown that in schistosomiasis japonicum.66). IL-10 acts to suppress the production of Th1 cytokines such as IFN-γ (71. Hepatic Stellate CellFibroblast. April 2009 Immunopathogenesis of human schistosomiasis 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. in turn.70).Volume 31. Neutrophil. 31. IFN-γ is critical in the development of granulomas and contributes to the recruitment of neutrophils to the granulomatous response. Legend: Egg. Hoffmann et al. (74) have also demonstrated that IL-10 is essential to prevent excessive Th2 responses in IL-10 knockout mice. possibly by regulating IL-12/IL-12R expression which. 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).

mansoni infection but there is evidence they are also activated by S.86). 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). and these differences in cytokine response might provide important clues regarding the progression to chronic disease (58). Parasite Immunology.51) IL-4–/– knockout mice have an impaired granulomatous response (58) Granulomas are composed predominately of eosinophils (28) Calcification of eggs within granulomas is infrequent (28) The response of infected mice to purified SEA is of a delayed-type-hypersensitivity reaction (79) Katayama Syndrome occurs mainly in previously unexposed individuals and is uncommon in endemic regions (1) Fibrosis occurs in the central region of the liver (50. 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. japonicum infections appears to be similar.85). there are indications that S. A comparison of the pathology and cytokine responses in schistosomiasis mansoni and schistosomiasis japonica is shown in Table 1. For example Galectin-3. 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. Parasite Immunology Table 1 Comparison of the pathology and cytokine responses in schistosomiasis mansoni and schistosomiasis japonica Schistosomiasis mansoni Schistosomiasis japonica Egg laying commences 6 weeks post infection Eggs are laid singly (28) Egg laying commences 3 – 4 weeks post infection Eggs are laid in clusters leading to the formation of larger granulomas (28) Granulomas are composed predominantly of neutrophils (28) Calcification of eggs within granulomas is common (28) The response of infected mice to purified SEA is of an immediate-type-hypersensitivity reaction (79) Katayama Syndrome is common in endemic regions and its symptoms are more severe (1) Fibrosis occurs in the centre and the periphery of the liver (50.85. L. Studies using an adoptive transfer model in IL10/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 schistosomeinduced pathology (71). 163–176 . at least in the mouse. 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. Although the immunopathology of S.M.71. Regulation of the granulofibrotic response Tight regulation of the Th1. a cell surface molecule that binds glycoconjugates. Binding of parasite antigens by pattern recognition receptors on dendritic cells (DCs).51) IL4–/– knockout mice have granulomas of a similar size to wild-type mice (55) Anti-IL-5 antibody treatment does not affect the size of granulomas (80) Anti-IFN-γ antibody treatment increases granuloma size (57) while IFN-γ deficiency has no effect (81) response characterized by high levels of IFN-γ (4.77). macrophages and other immune cells may play a role in the polarization of the immune response against schistosome eggs. 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 © 2009 Blackwell Publishing Ltd. japonicum eggs (88) and may play a role in protection in against murine models of ulcerative colitis (89) and asthma (88). japonicum-induced pathology responds differently to cytokine regulation. 31.65) Regulatory T-cells (Tregs) also help regulate the granulofibrotic response. mansoni and S. Inducible Tregs are FoxP3− and develop in the periphery from activated effector cells (4. Burke et al. Th2 and possibly Th17 cytokine responses generated during schistosome infection is essential to prevent excessive pathology. another Th17 cytokine (76.76–78). Most work on CD4+CD25+ cells has been undertaken on S. 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. mansoni and S. 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). 168 Anti-IL-5 antibody treatment decreases granuloma volume (65) Anti-IFN-γ antibody treatment and IFN-γ deficiency decreases granuloma size (58. In a follow up study naTregs were shown to be capable of suppressing the expression of both Th1 and Th2 cytokines (86). 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. so its relevance in murine schistosomiasis remains elusive.

Results from a series of tissue microarray studies of murine schistosomiasis (104. CCR2. TARC) and CCL22 (Macrophage Derived Chemokine. however. CCL5 (Regulated on Activation Normal T-cell Expressed and Secreted. 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). MIP-1α). genes upregulated 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. 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 Fcreceptor exhibited marked exacerbation of granulomatous inflammation (35). Expression of genes encoding other chemokines and chemokine receptors such as CCL2 (Monocyte Chemoattractant Protein-1.Volume 31. Parasite Immunology. CCL17 (Thymus and Activation Regulated Chemokine. CCL12 (MCP-5). mansoni or sensitized intraperitoneally and challenged intravenously with S. MDC) are thought to promote the granulofibrotic response as mice deficient in these chemokines develop smaller granulomas and less fibrosis (94–96). IL-13Rα2 acts as a potent decoy receptor. eosinophil rich granulomas and excessive fibrosis (74). Chemokines in hepatic schistosomiasis The activities chemokines in schistosome-induced hepatic fibrosis are poorly understood.44). mansoni-induced pathology and have confirmed the important role of Th2 cytokines in granuloma formation and fibrogenesis. The gene expression profile of these mice was associated with 169 . suggesting that CCL3 may be a determining factor in the development of severe schistosomiasis (94. little is known of the global molecular mechanisms involved or the gene signalling pathways involved in granuloma formation and ECM remodelling (5). A role for apoptosis. and is characterized by a decreased cellular inflammatory response to newly deposited eggs and the simultaneous down regulation of the Th2 cytokine responses (2. In contrast. April 2009 survival (90). has been hypothesized to contribute to the down-modulation of the granulomatous response (93). mansoni eggs. 163–176 Immunopathogenesis of human schistosomiasis induced in pulmonary models of schistosome induced granuloma formation (99–102) but the effect of these chemokines on granuloma formation and fibrosis is unknown. RANTES) is thought to negatively regulate granuloma development as mice deficient in this chemokine show significant augmentation of the granulomatous response (98). presumably contributing to the pro-inflammatory response via the production inducible nitric oxide (NO) (105). 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. Furthermore. not only for understanding granuloma modulation in schistosomiasis but also for other Th2-associated diseases (4). to define the global gene expression profiles that characterize the distinct pathological and immunological mechanisms affecting the outcome of infection. MCP-1).90–92). human studies report an association between elevated plasma CCL3 and an increased risk of developing severe hepatic disease. A MOLECULAR PROFILE OF SCHISTOSOMIASIS Despite the numerous studies in mice documenting the effects of immune polarization or specific cytokines on schistosome induced granuloma formation and fibrosis. type-2 (Th2) polarized (IL-10/IL-12 knockout mice. CCR3 and CCR4 have been shown to be © 2009 Blackwell Publishing Ltd. CCL11 (Eotaxin-1). CCL3 (Macrophage Inflammatory Protein-1α. 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). Number 4.97). CCR1.105) have. but one likely role lies in cellular recruitment of cells to the granuloma (44. limited granulomatous pathology). shed some light on the molecular and biochemical mechanisms regulating S. The up-regulation of macrophage C-type lectin and the absence of arginase expression suggest the predominance of classically activated macrophages. IP-10) (105). 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. 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). Type-2 polarization induces the development of large. CCL4 (MIP-1β). 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 studies used microarray analysis of mRNA extracted from granulomatous tissues from type-1 (Th1) polarized (IL-10/ IL-4 knockout mice. either infected with S. 31.94). particularly apoptosis by neglect of CD4+ T-cells. Accordingly.90–92). Multiple mechanisms are thought to be involved in this down modulation. competing with IL-13Rα1 for binding of IL-13 and preventing signalling through the IL-4/IL-13Rα1 receptor complex (4. pronounced granulomatous pathology) and wild-type mice. CCL7 (MCP-3).

Patients with intestinal schistosomiasis © 2009 Blackwell Publishing Ltd. L. 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. co-infections. as well as CCL17 (TARC). the regulation of liver fibrosis during schistosomiasis may be even more complex with multiple mediators. including those coding for small proline-rich proteins (SPRRs) (105).M. Parasite Immunology. Parasite Immunology Table 2 Differences between the murine model of schistosomiasis and human disease (After Abath et al. Type-1 responses promote a more pro-inflammatory outcome leading to increased apoptosis. For example. whereas type-2 responses promote gene transcription pathways associated with granuloma formation. and there was high expression of Arg-1. and genes related to apoptosis and the stress response (107.93.107). in humans. 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. e. IFN signalling and the Th1 response may be impaired during S. environmental factors and the age. and monocytes. 31. consistent with the proposed role of these cells in schistosome induced fibrosis.105). Ym1. influencing the outcome of infection (6. and CCL24 (Eotaxin-2) were preferentially expressed in the type-2 mice (105).86. enzymes involved in collagen synthesis and tissue repair and enhanced expression of IL-13 (104. Indeed. Overall. Gene expression profiling of splenic CD4+ T-cells confirmed that progression of S. experimental infections exhibit perioval fibrosis Genetic background of the host can be homogeneous Experimental design defines the length of investigation Co-infection with other parasites can be avoided Genetic background of the host is heterogeneous Long-term investigation of patients with active disease is ethically precluded Co-infection with other parasites is common and may influence the outcome of infection wound healing and fibrogenesis and was characterized by the massive up regulation of procollagens. gender and genetic background of the host.108).112). a significant portion of the genes that were down-regulated encoded IFN-γ-inducible molecules suggesting that. CCL11 (Eotaxin).110). Burke et al. including re-infection. eosinophils. Conversely. 163–176 . A number of genes. likely recruiting activated Th2 cells. consistent with the proposed roles of apoptosis and regulatory T-cells in regulating the immunopathogenesis of schistosomiasis (71. although IFN-γ expression was up-regulated. associated with wound healing were increased (akin to the response that is critical for rapid cure in murine cutaneous leishmaniasis (106)). CCL6 (C10).g.109). immunoglobulinrelated genes. IMMUNOPATHOLOGY IN HUMAN SCHISTOSOMIASIS 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 schistosomeinduced disease in the two hosts (Table 2) (6. (6)) Murine model Human disease Experimental infections involve a single exposure Intensity of infection is generally high Animals are infected with defined schistosome isolates Duration of infection and parasite burden are defined Most infections are acquired gradually and involve continued re-exposure Infection intensity varies but is generally low Infection occurs with various isolates of the parasite It is difficult to define how long individuals have been infected and the parasite burden Studies with similar parasite burden are difficult to control and re-infection is a complicating factor Chronic liver disease is characterized by Symmers’ pipe stem (periportal) fibrosis Studies are conducted in animals with similar parasite burden Some pathological features of chronic infection are difficult to reproduce in mice. 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. including many cytokine and chemokine genes. 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). 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. and CCL12 (MCP-5).108). A variety of chemokines including CCL8 (MCP-2). The onset of egg laying was associated with an increase in the ratio of IL4+CD4+ T-cells: IFN- 170 γ+CD4+ T-cells and was reflected by increased expression of the Th2 cytokines IL4 and IL-10 (107. and FIZZ-1 (105) most likely reflecting the continuing presence and activity of a large population of aaMφ in granulomatous tissues. collagen synthesis and matrix remodelling. several markers of eosinophil activation such as eosinophilassociated ribonucleases were also up-regulated. CCL7 (MCP-3).

Additionally. The situation may be more complex in schistosomiasis japonica where IFN-γ is associated with protection against peripheral portal fibrosis. two single nucleotide polymorphisms within IL-5 have been associated with the development of symptomatic infection with S. 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. japonicum and. In contrast. INT patients also have an increased frequency of IL-10+ T-cells as well as CD4+CD25High+ Tcells in the peripheral blood (112). IL5 and IL13 (125. IFN-γ is also associated with protection against peripheral fibrosis in humans infected with S. but fewer IL10+ T-cells in comparison to patients with intestinal disease (112). low levels of IFN-γ production against soluble egg antigen (SEA) (113–115). haematobium. As well. but IL-10 is associated with protection against central portal fibrosis. japonicum in a Chinese population (124). The pro-inflammatory cytokines © 2009 Blackwell Publishing Ltd. the results of these studies tend to corroborate those in mice suggesting that Th2 cytokines.Volume 31. Following in vitro antigen stimulation.126). there is still much that remains unknown about the immunopathology of schistosomiasis not only that caused by S. CONCLUDING COMMENTS Despite extensive studies. japonicum-infected individuals with severe hepatic fibrosis (118). IL-4 and IL-5.β1 gene (119). As indicated previously. although other polymorphisms in genes of the type-2 cytokine pathway may also be important (127). elevated levels of TNF-α against SEA (113). Number 4. Parasite Immunology. GENETIC CONTROL OF ADVANCED SCHISTOSOMIASIS Genetic background plays a pivotal role in determining the susceptibility to and outcome of schistosome infections (119–124). including IL-4 and IL-13. further work is required to gain a better understanding of immune processes regulating development of pathology in the human liver and 171 . Segregation analysis of a Brazilian population has revealed that susceptibility to infection is controlled by the ‘SM1’ (‘S. Overall. 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. 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). japonicum whereas IL-10 protects against severe hepatic central fibrosis and it is likely the two fibrotic outcomes are under different genetic control (117). 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. in the blood have been shown to be a hallmark of periportal fibrosis (116). Further. S. promote immunopathology while IFN-γ protects against the development of severe fibrosis (4). Up-regulation of activation-related surface markers on eosinophils from chronic S. Associations have also been reported between the clinical manifestations of chronic schistosomiasis mansoni and japonica and gene alleles within the major histocompatibility complex (120. 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. In addition. 163–176 Immunopathogenesis of human schistosomiasis IL-1 and IL-6 are elevated in sera of S. 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.129–134) although no consistent picture has emerged from these studies. mansoni 1’) gene locus that has been linked to the 5q31–q33 chromosome region comprising the genes IL4. 31. and low expression of CXCR3+ where CXCR4 expression was closely associated with IL-10 expression (112). including TNF-α. Patients with hepatic fibrosis (HF) exhibit an increased number of IL4+ and IL5+ T-cell subsets compared with patients with hepatosplenic disease. mansoniinfected patients as well as increased levels of eosinophils derived cytokines. April 2009 (INT) typically display a mixed Th1/Th2 response with higher levels of IL-4 production in comparison to acute schistosomiasis (111). Further. a lack of association between cytokine production. PBMCs from patients with INT showed higher expression of CXCR4+. 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). mansoni but also by S.128). 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). Furthermore. especially. because of its anti-inflammatory and anti-fibrotic effects (117). activation marker expression. 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.

Parasite Immunology. 85: 148 –154. Mentink-Kane MM. London. 31. Wynn TA & Montenegro SM. 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. 15 Friedman JF. Human schistosomiasis. Immunol Rev 2004. In: Mahmoud AA (ed.): Schistosomiasis. Gray DJ. McManus DP. Katayama Syndrome. that has progressed the furthest toward clinical development (at the Phase II Clinical Trial) (141). Clerinx J & Kestens L. Finally. 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. In: Mahmoud AA (ed. 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. J Infect Dis 2002. Sleigh AC. 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. London. 2001: 265 – 295. 2001: 297 – 332. Teles HM.146). 185: 98 –105. and several autoimmune diseases (148. Silveira AM. suitably adjuvanted with. London. 28: 483 – 496. Immunopathogenesis of schistosomiasis. principal egg components recently identified by proteomic analysis (145. Gryschek RC. Thompson R & Wynn TA. This could be achieved by priming the immune system towards a Th1 phenotype by immunization with SEA.147). 17 King CH. 368: 1106 –1118. Oliveira RC & Gazzinelli G. 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