Schistosoma is a genus of parasitic DIGENETIC TREMATODES

REVIEWS
THE IMMUNOBIOLOGY OF
SCHISTOSOMIASIS
Edward J. Pearce and Andrew S. MacDonald
Schistosomes are parasitic worms that are a prime example of a complex multicellular
pathogen that flourishes in the human host despite the development of a pronounced immune
response. Understanding how the immune system deals with such pathogens is a daunting
challenge. The past decade has seen the use of a wide range of new approaches to determine
the nature and function of the immune response to schistosomes. Here, we attempt to
summarize advances in our understanding of the immunology of schistosomiasis, with the bulk
of the review reflecting the experimental focus on Schistosoma mansoni infection in mice.
DIGENETIC TREMATODE
Digenetic trematodes, or flukes,
are extremely successful
parasitic worms, the life cycle of
which requires development in
at least two hosts. Importantly,
they can parasitize all classes of
vertebrate, causing widespread
medical and economic
problems.
T HELPER 1/T HELPER 2
(TH1/TH2). Subsets of CD4+
T cells that are characterized by
their cytokine-production
profiles. TH1 cells primarily
produce IFN-γ, and generally
provide protection against
intracellular pathogens, whereas
TH2 cells mainly produce IL-4,
IL-5 and IL-13, and are
important for immunity to
helminth parasites.
Schistosoma is a genus of parasitic DIGENETIC TREMATODES
that chronically infects more than 200 million people in
developing countries (BOX 1). The estimated mortality
owing to Schistosoma mansoni and Schistosoma haematobium in sub-Saharan Africa is 280,000 per year1.
Three early findings piqued the interest of immunologists in schistosomiasis: the immune response is intimately involved in the development of many of the
pathological changes that accompany infection;
infected individuals can have resistance to superinfection; and schistosomes survive for years in the host
despite a strong immune response. More recently, interest in these parasites has increased owing to demonstrations that schistosome maturation and fecundity are, in
some way, dependent on the host immune response.
Schistosomes, like other parasitic helminths, induce
marked T HELPER 2 (TH2) responses, providing a model
system for studying the development and function of
this type of immune response.
Immune-related pathologies during infection
Department of Pathobiology,
University of Pennsylvania,
Philadelphia, Philadelphia
19104-6008, USA.
Correspondence to E.J.P.
e-mail: [email protected].
upenn.edu
doi:10.1038/nri843
Schistosomiasis causes a range of morbidities, the
development of which seems to be influenced to a large
extent by the nature of the induced immune response
and its effects on granuloma formation and associated
pathologies in target organs2,3 (FIG. 1; BOX 2). Field studies in endemic areas, combined with animal experiments, have led to the view that host genetics, infection
intensity, in utero sensitization to schistosome antigen
NATURE REVIEWS | IMMUNOLOGY
and co-infection status all influence the development of
the immune response and, so, disease severity.
Two main clinical conditions are recognized in
S. mansoni-infected individuals — acute schistosomiasis
and chronic schistosomiasis.
Acute schistosomiasis: a TH1 disease? Acute schistosomiasis in humans is a debilitating febrile illness (Katayama
fever) that can occur before the appearance of eggs in
the stool and which is thought generally to peak
between 6 and 8 weeks after infection4. During acute illness, which is less well studied than chronic disease (see
below), there is a measurable level of tumour-necrosis
factor (TNF) in the plasma, and peripheral-blood
mononuclear cells (PBMCs) produce large quantities of
TNF, interleukin-1 (IL-1) and IL-6 (REF. 5). Notably,
cytokine production by PBMCs after stimulation with
parasite antigen reflects a dominant T HELPER 1 (TH1),
rather than TH2, response5. Presumably, in the natural
progression of the disease, the developing egg-antigeninduced TH2 response downregulates the production
and effector functions of these pro-inflammatory mediators (FIG. 1); the production of IL-10 during this period
might have a crucial role in this process6.
Anomalously, the febrile illness that is associated
with the initial stages of schistosome infection seems to
be uncommon in individuals who live in areas that are
endemic for schistosomiasis. It occurs, instead, in individuals who have no previous history of exposure who
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Box 1 | The biology of schistosomes
Of the ~2700 genera of Digenian parasites, the 13 that comprise the Schistosomatidae are unusual in four ways: they
have two rather than three hosts; they are dioecious (having male and female reproductive organs in separate
individuals), rather than hermaphrodite or asexual; they infect their hosts by directly penetrating the body surface,
rather than as a result of being eaten; and they parasitize the intravascular niche138. As for all sexual Digeneans, there is
an alternation of generations, such that asexual reproduction occurs in the intermediate (snail) host and sexual
reproduction occurs in the definitive (mammalian) host. The life cycle of Schistosoma mansoni is shown in the figure.
S. mansoni lives for long periods, with no evidence of immune-mediated clearance of adult worms139, and it has
evolved to use host factors for developmental signalling. By contrast, there is evidence for the immune-mediated
killing of adult Schistosoma haematobium parasites over time139. Infection is initiated by cercariae, which burrow into
the skin, transform into schistosomula, and then enter the vasculature and migrate to the portal system, where they
mature into adult worms. Eggs, which have tough shells, are released by female parasites within the vasculature; they
cross the endothelium and basement membrane of the vein, and traverse the intervening tissue, basement membrane
and epithelium of the intestine (S. mansoni and Schistosoma japonicum) or bladder (S. haematobium) en route to the
exterior. It is not clear yet how this process occurs, although there seems to be an immunological component, because
egg excretion is minimal in immunocompromised mice, but can be increased by the transfer of sera or lymphocytes
from infected animals140. Moreover, in a comparison of S. mansoni-infected HIV+ and HIV− patients, a correlation
between diminished egg excretion and decreased CD4+ T-cell counts was apparent141. It is unclear how eggs initially
attach to the endothelium and initiate penetration during extravasation, although factors that are released from
platelets in response to the eggs seem to be involved140,142.
So far, it has proved to be impossible to culture schistosomes through their complete life cycle in vitro, and there are no
published reports of techniques for routinely expressing transgenes in schistosomes or for targeted gene silencing. Also,
there are no schistosome cell lines. So, analyses of schistosome–host interactions rely on host-focused interventions and
traditional parasitological techniques.
Host-derived mediators
(TGF-β, IL-7, TNF ?)
CD4+
T cells
?
Receptors for hostderived mediators
Liver
Adult female
Adult male
Portal vein
Intestine
Fresh water
Eggs
(~140 µm)
Cercariae
(~800 µm)
Snail
Intermediate host
Miracidia
(~180 µm)
IL-7, interleukin-7; TGF-β, transforming growth factor-β; TNF, tumour-necrosis factor.
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Intensity of immune response
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TH1
Weeks after
infection
TH 2
3
6
Acute
12
Chronic
Eggs
Schistosomula
Cercariae
8
Adult
worms
Figure 1 | Development of the immune response in infection. In the course of an infection, the immune response
progresses through at least three phases. In the first 3–5 weeks, during which the host is exposed to migrating immature
parasites, the dominant response is T helper 1 (TH1)-like. As the parasites mature, mate and begin to produce eggs at weeks
5–6, the response alters markedly; the TH1 component decreases and this is associated with the emergence of a strong TH2
response. This response is induced primarily by egg antigens. During the chronic phase of infection (infections are long lived
and worms continue to produce eggs — ~300 per day in the case of each Schistosoma mansoni female), the TH2 response is
modulated and granulomas that form around newly deposited eggs are smaller than at earlier times during infection. From
work in the mouse, there now seems to be a correlation between the inability to form granulomas, or the development and
persistence of a highly pro-inflammatory TH1-like response beyond the acute phase, and the development of hepatotoxic liver
disease150. By contrast, TH2-cell-mediated granulomas seem to protect hepatocytes, but allow the development of fibrosis3,150.
Although it is clear that severe fibrosis occurs in human schistosomiasis, there is debate over the existence of the hepatotoxic
form of disease3,150. TH2 responses are also strongly implicated in naturally acquired resistance to reinfection with
schistosomes.
become infected after travelling into an endemic area.
One explanation for this difference is that individuals
can become sensitized to schistosomes in utero as a
result of maternal infection, which subsequently allows
them to respond differently from ‘naive’ individuals
when they themselves become infected. Data from
analyses of cord-blood lymphocytes taken from the
babies of infected and uninfected mothers support the
view that in utero sensitization does occur and, moreover, indicate that the fetal response is phenotypically
similar to the response of the mother7,8. The pre-existing
TH2 response in such children might make them less
likely to develop a pro-inflammatory response on first
infection with schistosomes.
An examination of disease in mice has shown that an
inability to develop a TH2 response to regulate the initial
pro-inflammatory response that is associated with acute
schistosomiasis is lethal. This first became apparent
when C57BL/6 Il4 −/− mice were infected with S. mansoni.
Coincident with the onset of parasite egg production in
these animals, a condition that was similar to severe acute
schistosomiasis in humans developed, which was characterized by cachexia and significant mortality9,10. These
mice developed relatively normal hepatic granulomas
(although they lacked an eosinophil component; BOX 2),
NATURE REVIEWS | IMMUNOLOGY
but pathological changes in the intestine were more evident in the absence of IL-4 — non-haemorrhagic lesions
on the mucosal surface9 were associated with the inefficient passage of eggs into the lumen10. This process was
accompanied by detectable levels of lipopolysaccharide
in the plasma, perhaps owing to the translocation of
intestinal bacteria10. Analyses of the immune responses
of infected Il4 –/– mice showed that there was a correlation between elevated levels of nitric oxide (NO) and
disease severity9. Treatment with uric acid, which is a
peroxyradical scavenger, had marked ameliorative
effects11, which indicates that a combination of reactive
oxygen and nitrogen intermediates might have a role in
acute disease.
Chronic schistosomiasis: a TH2 disease? Chronic disease is
graded according to severity. The most serious form is a
life-threatening hepatosplenic disease, which is usually
accompanied by severe hepatic and periportal fibrosis,
portal hypertension and portosystemic shunting of
venous blood2 (BOX 2). Fibrosis itself is ranked on the basis
of ultrasound patterns that provide a quantitative tool for
assessing the severity of disease12.
Although TH2 responses seem to have a crucial role in
modulating potentially life-threatening disease during
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Box 2 | The granuloma
In infection with any schistosome species, chronic disease is the result of the ongoing host response to accumulating
tissue-trapped eggs. In Schistosoma mansoni and Schistosoma japonicum infections, the liver is the principal site that is
affected, because many of the eggs are carried by the blood flow into this organ, the sinusoids of which are too small for
the eggs to traverse. This is a dead-end for the eggs, which eventually die within the tissue. Intestinal damage by
traversing eggs can also be problematic. During Schistosoma haematobium infection, the passage of eggs across the
bladder wall causes damage to this organ. The CD4+ T-cell response that is induced by egg antigens orchestrates the
development of granulomatous lesions — which are composed of collagen fibres and cells, including macrophages,
eosinophils and CD4+ T cells — around the individual eggs2,48 (see figure). As the eggs die, the granulomas resolve,
leaving fibrotic plaques. Severe consequences of infection with S. mansoni and S. japonicum are the result of an increase
in portal blood pressure as the liver becomes fibrotic, congested and harder to perfuse. Under these conditions, the
diameter of the portal vein increases and the wall of the portal vein becomes fibrotic. Associated with these changes is
the development of ascites (the accumulation of serous
Hepatocytes
fluid in the peritoneal cavity) and portal–systemic
venous shunts (new blood vessels that bypass the liver),
which can rupture, leading to life-threatening bleeding.
The most serious effects of infection with
S. haematobium are bladder cancer143 and genital
schistosomiasis, a condition in which eggs pass through
the cervix in women or into the testes in men144,145.
Paradoxically, granulomas might have an essential
host-protective role. In mice that were tolerized against
S. mansoni egg antigen, granuloma development did not
Schistosome
occur during infection and the animals had severe
egg
hepatotoxic liver damage, which was evident as
microvesicular lipid accumulations (or steatoses)
within hepatocytes146. This is thought to be mediated
by hepatotoxins that are secreted from eggs, and the
granuloma, together with egg-antigen-specific
antibodies (which might act in a neutralizing capacity),
is envisaged as sequestering these toxins away from
hepatocytes147. A central role for tumour-necrosis factor
(TNF) in the development of the granuloma has been
Collagen
CD4+ T cell
proposed on the basis of one finding that the injection
Eosinophil
of TNF into infected severe combined immunodeficient
Other cell
(SCID) mice is sufficient to allow the development of a
Macrophage
focal lesion around parasite eggs43 (but, see REF. 47).
SEGREGATION ANALYSIS
This technique is used to predict
the probability that certain
individuals will be of a certain
genotype given information
about the genotypes of ancestors
and assumptions about the
mode of inheritance. It can be
used to distinguish between
different models of inheritance
(for example, major gene versus
multifactorial).
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the initial stages of schistosomiasis, prolonged TH2
responses contribute to the development of hepatic
fibrosis and chronic morbidity3. The main TH2 cytokine
that is responsible for fibrosis is IL-13. So, schistosomeinfected mice in which IL-13 is either absent (Il13 −/−)10,
ineffective (IL-4 receptor α-chain-knockouts; Il4rα −/−)13
or neutralized by treatment with soluble IL-13Rα2–Fc14
fail to develop the severe hepatic fibrosis that normally
occurs during infection, which leads to prolonged survival of these mice10. The mechanism by which IL-13 is
able to promote fibrogenesis has been elucidated in a
series of recent studies15–18 (FIG. 2). These findings might
have implications beyond schistosomiasis for the possible use of IL-13-blocking therapies in other fibrotic diseases. Mediators that are associated with TH1 responses,
such as interferon-γ (IFN-γ), IL-12, TNF and NO can
prevent IL-13-mediated fibrosis18 (FIG. 2).
Infection intensity is one factor that can affect the
severity of chronic schistosomatic disease, perhaps particularly in children (see below)19. However, it seems to
be more important whether an infected individual is
genetically predisposed to disease19,20. In an analysis of
pedigrees in Sudan, in an area where S. mansoni is
endemic, Dessein and colleagues found that severe
hepatic fibrosis (as identified by ultrasound) was more
likely to occur in certain families20. A SEGREGATION ANALYSIS
showed that a codominant major gene, known as SM2,
is responsible for the observed familial distribution of
hepatic fibrosis and portal hypertension.‘Informative’
families, which had multiple cases of severe fibrosis,
were used to map SM2 to 6q22–q23 — a region that
contains the gene that encodes IFN-γ receptor 1 (IFNγR1)20. One interpretation of these data is that mutations in IFN-γR1 that lead to loss of function of the
receptor are associated with a lack of effectiveness of
IFN-γ in suppressing fibrogenesis.
It is not clear yet whether IL-13 is important for
hepatic fibrosis in human schistosomiasis. Most humans
who are infected with schistosomes develop TH2
responses21,22, but, as expected in an outbred population,
the intensity of the response differs between individuals.
On the basis of the amount of IFN-γ or IL-5 (or other
TH2 cytokines) that is produced by PBMCs in response
to antigen, some individuals do seem to have a more
TH1-like response. In one of the few studies that have
attempted systematically to correlate the immune
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IL-12
IFN-γ
TNF
Macrophage
Nitric oxide
+
Citrulline
L- hydroxyarginine
Inducible
nitric oxide
synthase
L-arginine
Arginase
L-ornithine
Proline
Ornithine–
aminotransferase
+
Collagen
synthesis
and fibrosis
IL-4
IL-13
Figure 2 | IL-13 and IFN-γ/IL-12 counter-regulate macrophage-activation status and
control fibrosis. The fibrogenic role of interleukin-13 (IL-13) seems to stem from its ability,
together with IL-4, to induce the expression of arginase in macrophages18. Arginase uses
L-arginine as a substrate to make L-ornithine, which is converted to proline by ornithineaminotransferase. Proline is an essential amino acid that is involved in collagen production and,
therefore, in the development of fibrosis. Fibrosis is inhibited in mice that are immunized with egg
antigens plus IL-12; cytokines that are produced as components of the induced TH1 response
(such as IFN-γ and TNF) prevent TH2-response development (and, so, IL-13 production) and also
activate macrophages to express inducible nitric oxide synthase (iNOS), rather than arginase.
This immunization protocol is ineffective in iNOS-knockout mice, despite the induction of excellent
TH1 responses in these animals. This seems to be due to the fact that iNOS uses arginine to
make nitric oxide (NO) and citrulline — an intermediate in this pathway is L-hydroxyarginine, which
inhibits arginase, effectively reducing the amount of proline that is available for collagen synthesis.
These findings fit nicely with early work in this area, which showed that IFN-γ could have an antifibrogenic role in the schistosome granuloma, as well as in other conditions. Adapted from REF. 18.
IFN-γ, interferon-γ; TNF, tumour-necrosis factor.
IDIOTYPIC REGULATION
The antigen-binding site of an
antibody is an idiotype. As an
immune response develops and
clonal B-cell expansion occurs,
the prevalence of this previously
rare idiotype increases and can
lead to the development of an
anti-idiotypic T- and B-cell
response. Focus on this once
popular area of immunology is
now minimal.
response with disease severity, patients with hepatosplenomegaly owing to S. mansoni infection were found
to have a TH1-like response and high plasma levels of
TNF receptor I (TNFRI) and TNFRII, whereas individuals who had less severe disease but similarly intense
infections (as assessed by counting the number of eggs
in faecal samples) had TH2 responses and low plasma
levels of soluble TNFR23. The finding that severe chronic
disease is associated with TH1, rather than TH2, responses
contrasts with data from the mouse model. However,
hepatosplenic fibrosis in the patients that were used in
this study was not assessed by ultrasound, and it is now
clear that hepatosplenomegaly is not always accompanied by severe fibrosis24. So, clarification of the role of
TH1 responses in severe chronic human schistosomiasis
will require detailed analyses of immune responses in
patients who have been carefully assessed by ultrasound.
Taking into account this caveat, genetic and immunological studies in mice and humans do indicate that IFN-γ is
important for fibrosis during schistosomiasis.
NATURE REVIEWS | IMMUNOLOGY
Although it is thought generally that, during schistosomiasis, immunopathology and immunoregulation
are under the control of egg-antigen-specific TH cells,
there is a large body of data that indicates the importance of IDIOTYPIC REGULATION in these processes (this
complex area is reviewed succinctly in a recent paper by
the only group that continues to work in this area25)
(BOX 3). So, egg-specific antibodies (idiotypes) that are
purified from the sera of patients with less severe
chronic disease are able to stimulate T cells from the
same patients to proliferate. Rabbit antisera that are
raised against these idiotypes bind well to idiotypes
from chronically infected mice and, in so doing, define
crossreactive idotypes (CRIs) that cannot be detected in
the sera of patients with hepatosplenomegaly or in an
unusual subset of infected male CBA/J mice that (for
reasons that are not clear) develop a condition that is
analogous to hepatosplenic disease26. Moreover, the
early appearance of CRIs in infected male CBA/J mice is
a robust predictor that the animals will not develop
severe disease, whereas infected male CBA/J mice that
fail to develop CRIs invariably die early after the onset of
egg production or develop severe chronic disease. In
addition, neonatal mice that are injected with CRIs
develop a regulatory anti-idiotypic T-cell response that,
in later life, has a role in preventing the development of
severe morbidity during chronic infection27. In keeping
with the data that are outlined above — which indicate
that IFN-γ might have a host-protective role in the mitigation of severe chronic disease — the neonatal mice
that were injected with CRIs developed a population of
T cells that were able to produce IFN-γ in response to
schistosome egg antigen. Findings from these studies of
idiotypic regulatory pathways are remarkably consistent
between human and mouse schistosomiasis25.
The importance of a balanced TH response. Interestingly,
the severe disease that is observed in infected Il4 −/− mice
(see above) is not related to increased parasite burden,
but, rather, seems to be linked to the immunological
consequences of the absence of TH2 cytokines. So, an
important function of the TH2 response during infection is to produce cytokines that can prevent or dampen
the production or effector functions of potentially dangerous inflammatory mediators. A more comprehensive view of this issue has emerged recently from a
detailed investigation of the outcome of infection in
IL-4 and IL-10, IL-12 and IL-10, and IFN-γ and IL-10
double-deficient mice 28,29. IL-10 has been considered
primarily to be a regulator of pro-inflammatory
responses, and on the basis of the findings in the Il4 −/−
mice, it was thought that its absence would result in
increased disease severity during schistosomiasis.
Consistent with this, during infection, the Il4 −/−Il10 −/−
animals developed highly polarized TH1 responses and
a lethal acute wasting condition that seemed to be an
exaggerated form of the disease that is observed in
infected Il4 −/− animals (see above), with evidence of
increased hepatoxicity28. Perhaps surprisingly, IL-12
and IL-10, and IFN-γ and IL-10 double-deficient mice,
in contrast to Il12 −/− or Ifnγ −/− mice, also developed
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Box 3 | Some important understudied and/or unresolved areas
• The mechanism that underlies idiotypic regulation in schistosomiasis.
• The role of regulatory T cells148 during schistosomiasis. The magnitude of T-cell
proliferative responses has been linked to disease severity in infected individuals,
which raises the possibility of a role for regulatory T cells in disease modulation.
The importance of interleukin-10 in immune-response regulation during
schistosomiasis
is consistent with a role for these cells.
• The mechanism that is responsible for naturally acquired immunity. Antibodydependent cellular cytotoxicity (ADCC) that is mediated by immunoglobulin E and
eosinophils is implicated in this process, but definitive proof is lacking. This is a
difficult area, because, for reasons that are outlined in the text, the mouse has been
largely discounted as a model for studying naturally acquired immunity.
• Vaccination. Although some vaccines are in human trials, none promises high levels of
efficacy. The need exists for the indentification of an effective antigen and/or delivery
system for vaccination against schistosomiasis.
• The identification of antigens that are involved in the immunopathological response.
• Development of T-cell-receptor transgenic mice that are specific for important
schistosome antigens.
• How schistosomes evade the immune response. This important area of research is in
decline. One of few relevant recent additions to the literature reports that larval
schistosome-derived prostaglandin D2 inhibits the migration of epidermal antigenpresenting Langerhans cells from the site of infection149, which indicates a way in
which the infection might delay the onset of the immune response. However, the
molecular basis for the prolonged survival of adult schistosomes remains unknown.
• Completion of the schistosome genome sequence and life-cycle transcript profiles.
• The development of tools for transgenesis in schistosomes.
• Schistosome biology as it more broadly relates to the interaction with the host.
Important issues include understanding the molecular basis of how schistosomes
interact with immune-system components. Advances in this area will, in part, rely
on progress in the preceding two points.
SEVERE COMBINED
IMMUNODEFICIENCY
(SCID). A condition in which
T-cell responses and antibody
production are virtually nonexistent, which can be caused by
several immunological defects.
In mice, this condition is caused
by the scid mutation.
NUDE
A mutation in mice that causes
both hairlessness and defective
formation of the thymus, which
results in a lack of mature T cells.
RAG
Recombinase activating genes
(Rag1 and Rag2) are expressed
in developing lymphocytes. Mice
that are deficient for either of
these genes fail to produce B or
T cells owing to a developmental
block in the gene rearrangement
that is necessary for receptor
expression.
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severe disease, with excessive TH2 responses, and marked
mortality during the chronic stages of infection that was
associated with increased granuloma size and fibrosis. So,
IL-10 might have an important regulatory role in schistosomiasis, preventing the development of excessive
TH1- and TH2-mediated pathologies.
Evidence from studies of S. haematobium-infected
humans also indicates the importance of IL-10 in regulating morbidity 6,30. The regulation of egg-antigeninduced T-cell proliferation in these individuals — for
whom T-cell proliferation is positively correlated with
disease severity31 — seems to be under the control of
IL-10 (REF. 32).
Given the observed severity of disease that is associated with the excessive development of a TH1 response
in Il4−/−Il10 −/− mice, it is notable that mice that were
deliberately immunized with schistosome eggs plus
IL-12 — to provoke the development of a strong eggantigen-specific TH1 response during subsequent
infection — developed less-severe disease than nonimmunized infected mice33, which was characterized by
reduced granuloma size and fibrosis. Why do these animals not suffer the same fate as infected Il4 −/−Il10 −/−
mice? This issue is particularly interesting in view of the
recent report that mice that were immunized with egg
antigen in complete Freund’s adjuvant (CFA) developed
a strong TH1 response and were sensitized to develop a
lethal acute disease with severe hepatotoxicity on subsequent infection34. One possible explanation is that IL-12,
but not CFA, promotes the production of high levels of
IL-10 (REFS 35,36), which, in turn, are important for protection against potentially lethal pro-inflammatory
mechanisms.
What about B cells? The role of B cells in the regulation
of disease is unclear at present (BOX 3). In one report
(using JH mice), B cells were shown to be essential for
the induction of a TH2 response during infection37.
However, in a contrasting study, TH2 responses were
shown to be intact in the absence of B cells (in µMT
mice), but chronic morbidity was markedly enhanced
with grossly enlarged granulomas38; this process was
Fc-receptor-dependent. Animals in which B-cell–T-cell
interactions are compromised by the targeted deletion
of CD80 and CD86 (REF. 39), or CD154 (CD40L)40 also
fail to develop TH2 responses after infection, although it
is unclear whether B cells are responsible for this effect.
Developmental cues for schistosomes. Given that they
are parasites, it seems logical that schistosomes should
be able to use host-derived signals as cues to guide their
own development and behaviour41 (BOX 1). Indeed, the
simple observation that, so far, it is impossible to satisfactorily grow schistosomes in tissue culture is evidence
that these parasites do require very specific signals from
their hosts42. Attempts to infect mice that have induced
immune-system defects have shown that parasite
fecundity is markedly reduced in mice with SEVERE
COMBINED IMMUNODEFICIENCY (SCID), NUDE mice and T-celldepleted mice43,44. These studies indicate that T cells
might be a source of one such host signal. From recent
studies by Davies and colleagues that examined parasite
development in RAG −/− mice (which lack both T and
B cells), the reduced parasite fecundity seems to be the
result of a delay in the maturation of parasites in the
absence of T cells45. Detailed analyses have shown that a
previously unrecognized subset of CD4+ T cells —
which is present in mice that lack both MHC class I
and II molecules and is localized primarily within the
liver — is likely to have an important role in promoting schistosome maturation. The exact immunological
function of this class of T cells and the mediators that
they produce that affect parasite development remain
to be determined. It is possible that the hepatic T cells
produce, or are dependent on, IL-7, because the phenotype that is described for schistosomes in Rag−/− mice is
similar to that described for parasites that grow in Il7 −/−
mice46. There is ongoing debate about a role for TNF as
a host factor that can stimulate female schistosomes to
produce eggs43,47,48 and, in general, there has been a lack
of success in defining at a molecular level the interface
between schistosomes and their host (BOX 3). However,
schistosomes have been found to express a receptor,
SmRK1, on their surface that can bind the cytokine
transforming growth factor-β (TGF-β), which indicates that host cytokines can have effects on these
parasites49.
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Schistosomiasis: effects on concurrent disease
Most people who live in areas that are endemic for
schistosomiasis are also exposed to many other infectious diseases. Given the counter-regulatory effects that
are exerted by TH1 and TH2 cells on each other’s development, there is growing interest in whether existing
infection with schistosomes (or any other chronic infection that is associated with a strongly polarized TH
response) influences an individual’s immune response
against, and therefore their susceptibility to, disparate
pathogens. In addition, the realization that morbidity
during schistosomiasis is dependent on the TH2–TH1
balance of the immune response raises interesting questions about the potential for co-infection to affect the
outcome of pathological changes that are associated
with schistosome infection.
IL-4, which is one of the main products of TH2 cells,
is important in polarizing TH2 responses50–52. So, in the
environment that is created by chronic schistosome
infection, elevated levels of IL-4 might be expected to
influence the outcome of immune responses to other
antigens. Findings that are consistent with this view
have come from the analysis of the outcome of vaccination in schistosome-infected adults and the babies of
infected mothers, for which responses to vaccines that
normally induce TH1 responses (tetanus toxoid and
Mycobacterium bovis bacillus Calmette–Guerin, respectively) were found to be significantly impaired53,54.
Similar results have been gained from experimental systems using schistosome-infected mice55 and in individuals with other helminth infections56. An important
area of research will be to ascertain whether these types
of effect have any impact on individuals that live in
schistosome-endemic areas, in terms of vaccine efficacy
or susceptibility to infections that are usually controlled by TH1 responses. In experimental settings,
mice that have schistosomiasis are less able to mount
specific anti-viral CD8+ and TH1 immune responses
(and, consequently, are less able to clear virus)57, have
greater susceptibility to malaria58 and are extremely
susceptible to infection with Toxoplasma gondii59, a
parasite that induces marked TH1 responses and that is
lethal in mice that have defects in IFN-γ production.
In clinical settings, co-infection of hepatitis B or C
virus (HBV or HCV) with schistosomes is common
and has been the focus of much attention in the past.
The confluence of these viral and helminth infections
in the liver, together with the opposite requirements for
TH1-like anti-viral immunity and the observed dominant TH2 response during schistosomiasis, offers a possible explanation for the increased occurrence of
chronic hepatitis-virus infection in schistosomiasis
patients. Indeed, there is evidence that schistosomiasis
prevents the development of TH1 responses to HCV60,61,
and some evidence that HBV and HCV infections are a
factor in the development of hepatosplenic schistosomiasis2. However, schistosome infection of HBVtransgenic mice actually suppressed viral replication in
an IFN-γ-dependent manner soon after the onset of
egg production62 — when IFN-γ and inducible nitric
oxide synthase (iNOS) are being expressed63 (FIG. 1).
NATURE REVIEWS | IMMUNOLOGY
Surprisingly, this suppression was found to continue as
the TH2 response developed and became dominant.
Overall then, it is difficult to draw clear conclusions
about alterations in immune responses and associated
changes in disease development in individuals who are
infected with HBV or HCV and schistosomiasis.
Moreover, it now seems clear that in Egypt at least, where
HCV and schistosomiasis are two of the most important
public-health problems and have geographically overlapping distributions, the coincidence of infection is a
result of the unfortunate initial widespread transmission
of HCV by mass parenteral antischistosomal therapy,
which continued into the 1980s64.
Whether schistosomiasis affects susceptibility to
HIV-1 or whether these infections interact in any way is
an area of much interest at present. In vitro, TH2 cells
have, in some cases, been found to support HIV replication more strongly than TH1 cells65, which led to the
hypothesis that helminth infections contribute to the
high prevalence of AIDS and HIV infection in
Africa66,67. Consistent with the in vitro findings, recent
studies have shown that, compared with T cells in the
peripheral blood of S. mansoni-infected individuals,
those in schistosome and HIV co-infected individuals
responded to egg antigen by making less IL-4 and IL-10,
but similar (low) amounts of IFN-γ, which indicates
that there is a swing in the overall balance of the
response from TH2 to TH1 (REF. 68). On the basis of the
various roles that have been established for CD4+ T cells
during schistosomiasis in the mouse model, it would be
anticipated that individuals with AIDS would have
altered patterns of hepatic fibrosis and, perhaps, an
increased risk of liver damage owing to the insufficient
sequestration of egg hepatotoxins and/or the relatively
increased production of pro-inflammatory cytokines.
In direct contrast to the situations that are discussed
above, ongoing TH2 responses in chronic schistosomiasis
might be beneficial during co-infection with other
pathogens (for example, the intestinal nematode
Trichuris muris 69) against which TH2 responses are hostprotective, and in preventing the onset of TH1-mediated
autoimmunity (for example, diabetes mellitus in genetically predisposed non-obese diabetic mice70) and mitigating against allergy. The parallels that exist between the
immunology of allergy and of helminth infections are
obvious, in that both are associated with TH2-dominated
immune responses. Paradoxically, allergic disease seems
to be less frequent in developing countries that still have
widespread helminth infection71, and evidence is accumulating that helminth infection might be inversely
related to the prevalence of allergy (the ‘hygiene hypothesis’)72,73. Several recent studies in human populations
that are infected with S. mansoni 74 and S. haematobium75 have shown a clear inverse relationship between
allergen responsiveness and schistosome infection. It
has been proposed that the regulatory mechanisms that
are induced as a component of the immune response to
chronic helminth infection, such as the production of
IL-10 and, possibly, TGF-β, constitute a pathway by
which inflammatory sequelae during allergic responses
might be non-specifically prevented72. Elucidating the
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cellular basis of this type of regulatory response will be
of considerable interest (BOX 3).
Susceptibility factors for infection
In areas where schistosomiasis is endemic, there is an
obvious pattern of age-dependent intensity of infection; individuals who are below the age of puberty
carry the most parasites, and those in older age brackets are generally less heavily infected76. Drug treatment
of affected populations followed by careful assessment
of reinfection status has shown that children usually
become heavily reinfected, whereas older individuals
might become reinfected, but remain less heavily
infected than they were before treatment. So, in
endemic areas, older individuals are resistant to reinfection. A comparison of immune responses
between those individuals who are susceptible and
those who are resistant to reinfection has shown that
there is a correlation between immunoglobulin-E
responses to worm (not egg) antigens and immunity,
which implicates IgE in the protective effector mechanism77–80. The slow development of appropriate
immune responses to worm antigens might be linked
to the fact that schistosomes are very long-lived parasites and the host becomes exposed to these antigens
only after parasites die81, either as a result of ageing or
drug intervention. Consistent with the immunoepidemiological data, results from studies in Brazil
have shown that the intensity of infection is influenced
by a major gene (SM1) that maps to a region of chromosome 5 (5q31–q33) that encodes the TH2
cytokines82. How IgE functions in a protective capacity
in people is unclear, but interaction with eosinophils in
an antibody-dependent cellular cytotoxicity (ADCC)
reaction that is targeted at schistosomula is a favoured
model83,84 (BOX 3).
Mice that are infected with S. mansoni are unable
to clear the primary infection, but nevertheless are
partially resistant to superinfection. However, the use
of mice for studies of resistance to reinfection has
been questioned on two points. First, resistance in
mice might, in large part, be due to the development
of portosystemic vascular shunts85 (BOX 2). In these
animals, immature parasites of a secondary infection
might find it difficult to localize to the portal vasculature and, instead, will be carried by the blood flow,
through varices, to non-permissive areas of the vasculature. This resistance is, therefore, more anatomical
than immunological, and it is related to pathological
changes that are more prevalent in infected mice than
in infected humans2. Second, the cellular distribution
of the high-affinity receptor for IgE (FcεR1) on mouse
cells differs from that on human cells 84. As IgEdependent eosinophil-mediated ADCC is a possible
effector mechanism of protective immunity in
humans, the lack of FcεR1 on mouse eosinophils is of
particular concern when attempting to model human
immunity using the mouse 84. One consequence of
this is the current lack of definitive data to indicate an
in vivo role for eosinophils in any immunological
process during schistosomiasis (BOX 3).
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How do schistosomes induce TH2 responses?
An inability to make TH2 responses renders mice acutely
sensitive to infection with schistosomes (above) and
highly susceptible to intestinal helminth infections86.
The evolutionary pressure on the immune system to
recognize helminths as pathogens against which TH2
responses should be made is, therefore, apparent.
However, the mechanisms by which the immune system
accomplishes this are unclear, and they are a subject of
intense interest (FIG. 3).
It has been recognized for some time that it is the egg
stage of the schistosome that is responsible for inducing
the TH2 response during infection87,88. By contrast, the
worms themselves seem to be poor inducers of a TH2
response. As for certain other helminth products89, schistosome eggs or soluble antigens that are derived from the
eggs induce an intense TH2 response without the need
for additional adjuvant87,90. Recent work has shown that
carbohydrates on egg antigens are integral to this
process91,92 and, specifically, that a polylactosamine sugar
(lacto-N-fucopentaose III) acts as a TH2 adjuvant93. The
emerging role of carbohydrates as factors that are important for the induction of the immune response during
schistosomiasis opens up the possibility that innate
pattern-recognition receptors that identify carbohydrates might have a crucial role in the induction of a
TH2 response. The recent identification of a wide range
of C-type lectin receptors that are expressed on the surface of dendritic cells (DCs)94 indicates various candidates that could be involved in the innate recognition of
antigens from pathogens that initiate a TH2 response.
It remains to be seen whether Toll-like receptors
(TLRs) — which have crucial roles in the recognition of
viral, bacterial, fungal and protozoal organisms, and in
the development of TH1 immune responses95 — exist
for the recognition of helminth antigens and/or have
any role in the induction of TH2 responses. This would
provide an attractive innate mechanism to allow appropriate immune-response development to the wide
diversity of helminth parasites. However, no specific
pattern-recognition receptors have been identified for
this role so far. Indeed, current data indicate that signalling through MYD88, which is the main adaptor
protein for the known TLRs, is not necessary for the
development of TH2 responses96.
Directly related to these areas, recent data indicate
that schistosomes and other helminths might affect
TH2-response development by influencing the way in
which DCs become activated97–99. Helminth antigens, in
contrast to most microbial pathogens, seem not to ‘classically’ activate DCs; in particular, they fail to induce the
production of IL-12 by DCs. Furthermore, mouse DCs
that are exposed to schistosome egg antigens also fail to
upregulate their expression of surface markers that are
normally associated with the activation or maturation
of DCs98. However, DCs that are exposed to egg antigens are strong inducers of TH2 cells both in vitro and
in vivo98. The mechanism by which DCs induce TH2
responses has been a somewhat neglected area of study,
and, so far, it remains poorly defined100. An attractive
possibility, for which some supporting data exist101, is
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Periphery
Lymphoid
tissue
Glycoproteins
?
IL-12
Immature
dendritic cell
Eggs
Secreted
antigens
No
No n-clas
IL-1 sica
2 p l ac
rod tiva
uct tion
ion
Lectin ?
Mig
TLR ?
rati
on
IL-10
TH 1
Additonal
signals ?
Dendritic
cell
T cell
IL-4
OX40L
?
TH 2
TH 2
MHC
class II
IFN-γ
?
CD40
TH 2
IL-4
IL-5
IL-13
TCR
OX40
CD154
Figure 3 | TH2-response induction by schistosome egg antigens. Immature dendritic cells (DCs) can acquire schistosome egg
antigens and induce T helper 2 (TH2) responses, but the process by which this occurs is unclear. This figure shows one possible
model. Many egg proteins are glycosylated, and carbohydrates are implicated in the induction of TH2 responses by these antigens;
possibly, DCs acquire egg antigens through lectin-like receptors. The exposure of DCs to egg antigens does not result in the
classical activation changes that are described for DCs that are exposed to lipopolysaccharide or Gram-positive bacteria; they do
not make interleukin-12 (IL-12), and they do not upregulate their expression of the co-stimulatory molecules CD40, CD80 or CD86.
Nevertheless, such DCs are able to initiate immune responses, presumably by migrating to lymphoid organs, where they encounter
and activate naive CD4+ T cells. Development of the TH2 response is dependent on IL-4 from a source other than the DC that is
inducing the response. It is possible that IL-10 that is produced by the DC has a role in suppressing IL-12 production and minimizing
the progression of the TH1 response. IL-4 would also be expected to limit TH1-response development and to act as a growth factor
to expand the TH2 response. There is a clear role for CD40–CD154 interactions in TH2-response development during
schistosomiasis; CD80 and CD86 also seem to be important (not shown) and OX40L–OX40 interactions have been implicated in
the development of TH2 responses to schistosome antigens99. IFN-γ, interferon-γ; TCR, T-cell receptor; TLR, Toll-like receptor.
that TH2-response-inducing pathogens stimulate DCs
to produce IL-4, which then promotes TH2-response
development (FIG. 3). However, it is now clear that DCs
do not need to produce IL-4 to direct TH2 development102, because egg-antigen-pulsed Il4 −/− DCs induce
excellent TH2 responses when injected into naive mice,
so long as the recipient animal is able to make IL-4.
Although IL-4 has an important role in this model of
egg-antigen-induced TH2 responses, and is important
for the normal development of TH2 responses during
schistosomiasis (see above), recent evidence indicates
that neither IL-4R nor the downstream signal transducer and activator of transcription 6 (STAT6) are
absolutely required103, because infection of mice that
are deficient in these molecules results in small, but
measurable, TH2 responses.
NATURE REVIEWS | IMMUNOLOGY
Several cytokines other than IL-4 have been implicated in TH2 development, but, on closer examination,
have been found to be of minimal importance for the
expression of this type of immune response during
schistosomiasis. IL-13, which is closely related to IL-4,
seems to be crucial for granuloma formation and fibrosis (see above), but not to be necessary for TH2 development per se 10,14. IL-6 can direct the development of
IL-4-producing T cells104. However, IL-6 does not have a
main role during the development of TH2 responses to
schistosome eggs in vivo105, although it might be
involved at some level in the regulation of IFN-γ and
IL-12 production106. The role of IL-10 in TH2-response
consolidation has been discussed extensively above.
The recent description of effector B cells that can
induce TH2 responses through the production of
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polarizing cytokines107 raises the possibility, supported by
one study37, that B cells might have a role in the establishment or maintenance of TH2 responses in schistosomeinfected mice. The finding that CD40–CD154 interactions are important for TH2-response development
during schistosomiasis40,108 implicates B cells in this
process, because B-cell responses are markedly impaired
in the absence of CD40 signalling109. In addition, it has
become apparent recently that CD40 −/− DCs are incapable of inducing egg-antigen-specific TH2 responses110.
Together, these data indicate that the CD40–CD154
interaction is required for egg-antigen-induced TH2
responses, but they leave open the question of the role of
B cells in this process.
In addition to CD40–CD154, several members of the
B7 superfamily111 have been investigated in terms of
their influence on TH2-response induction by schistosomes. Mice that are doubly deficient for both CD80
and CD86 fail to mount a TH2 response to schistosome
infection and have an impaired ability to form granulomas39. CD86 is probably more important than CD80 in
this regard, because the infection of mice that are singly
deficient for CD86, but not for CD80, results in reduced
egg-antigen-specific proliferation and TH2 cytokine production by cultured T cells from infected mice39.
Furthermore, although anti-CD80 antibodies have no
effect on transcript levels for IL-4 or IL-5 in a pulmonary
model of schistosome egg-induced granuloma formation, treatment with anti-CD86 antibody inhibits the
expression of IL-4, IL-5 and IL-13 (REF. 112). Two other
molecules that have been implicated recently in the
induction of a TH2 response are inducible co-stimulator
(ICOS)113 and the IL-1R-related molecule T1/ST2
(REF. 114). However, blockade of the interaction of ICOS
with its ligand, B7-related protein 1 (B7RP1), using a
soluble ICOS fusion protein, did not affect TH2-cell differentiation in a model of allergic airway inflammation
that used S. mansoni eggs as the antigenic stimulus115.
The expression of T1/ST2 seems to be enhanced on
CD4+ T cells that are isolated from schistosome egginduced lung granulomas or from the livers of infected
mice116. Furthermore, the expression of T1/ST2 has been
implicated in TH2 cytokine production ex vivo after the
intravenous injection of S. mansoni eggs117. It remains to
be determined how important either T1/ST2 or ICOS
might be for TH2-response development during actual
schistosome infection.
So, a wide range of both parasite- and host-derived
candidates have been assessed for their role in the induction of a TH2 response by schistosomes. Determining
exactly how these many components might fit together
is now crucial. A pressing issue is whether TH2-response
development occurs simply as a default pathway when
IL-12 and related mediators are not induced.
Vaccine-induced immunity
Several detailed reviews of the primary candidate vaccines
for schistosomiasis have been published recently118–120.
Consequently, in this review, we focus on the immunological mechanisms that underlie vaccine-induced
immunity. The basis for many of the developments in
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protective immunity to schistosomes is the radiationattenuated cercarial vaccine, which is able to induce
consistently high, although not sterilizing, immunity
against challenge infection in mice121,122. A single exposure to irradiated cercariae induces a TH1 response,
whereas additional boosting leads to a mixed TH1/TH2
response123. In mice that are immunized a single time,
the protective effector mechanism seems to be
cell mediated, and IFN-γ- and/or TNF-activated
macrophages and NO are implicated124–127; consistent
with this, IL-12 and bacterial CpG motifs (which
induce the production of IL-12 by DCs and
macrophages that express the appropriate TLR95) can
be used as adjuvants to boost immunity128,129. However,
an underlying protective B-cell antibody-dependent
mechanism also exists in animals that are vaccinated in
this way127,130. In mice that have been vaccinated many
times, antibodies begin to have a more important protective role131. Optimal protection in all cases is probably linked to the induction of cell-mediated and
humoral responses122,127. Consistent with the development of exaggerated TH1 and TH2 responses in infected
Il10 −/− mice, vaccinated Il10 −/− mice also develop
enhanced immune responses with integral TH1 and TH2
components, and are almost entirely resistant to infection132, which indicates that a high-magnitude multifaceted immune response might be the best option for
induced resistance to schistosome infection. However,
the fact remains that after many years of trying, a rationally designed effective anti-schistosome subunit vaccine has yet to be developed. To obtain an effective
vaccine against such a complex and highly successful
metazoan pathogen is a daunting challenge.
Nevertheless, the dangers that are presented by the possible emergence of drug-resistant schistosomes133, coupled with the fact that the prevalence of schistosomiasis
has remained the same since effective orally administered chemotherapy became widely available, demand
continued and active research in this area (BOX 3).
An alternative approach to vaccination, as discussed
above, is to induce a TH1-like immune response that
can prevent the normal TH1 to TH2 transition that
occurs in infected hosts after the onset of egg production by the parasites, with the aim of preventing
the development of severe chronic morbidity134.
Experimentally, this approach has been promising.
However, there are legitimate concerns about the
potential for exaggerated early-onset liver disease that
is associated with this type of induced immune deviation34,135. Moreover, it is not clear what effect predisposing individuals to make TH1 responses would have on
their ability to subsequently develop resistance to infection, given that the latter seems to be TH2-responsemediated in the endemic setting. Nevertheless, the
philosophy of vaccinating to prevent disease, rather
than infection, remains enticing, and the approach
becomes more plausible as its immunological basis is
increasingly well understood16. It remains to be seen
whether this type of vaccination can be reproduced
using defined antigens that are amenable to large-scale
manufacture.
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REVIEWS
Conclusions and future directions
Schistosomes are remarkable metazoan parasites that
have co-evolved in concert with their mammalian
hosts such that they are dependent on certain immunesystem components for their own biology. The
immune system is largely incapable of resisting primary
infection, and resistance to superinfection takes years to
develop. So, the survival of the host seems to depend on
the ability to make an appropriately balanced TH
response that is able to orchestrate granuloma development, prevent debilitating acute disease, and minimize
fibrosis and severe morbidity during chronic infection.
Amazingly, most (>90%) infected individuals in
endemic areas seem to successfully accomplish this.
Future work using DNA microarray analyses and
refined genetics promises to reveal much about how
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Acknowledgements
E.J.P. is a Burroughs Wellcome Fund Scholar in Molecular
Parasitology, and is supported by grants from the National Institutes
of Health. A.S.M. is a recipient of a Wellcome Trust Prize Travelling
Fellowship. We apologize to those authors whose work we were
unable to cite owing to space limitations.
Online links
DATABASES
The following terms in this article are linked online to:
Entrez: http://www.ncbi.nlm.nih.gov/Entrez/
HBV | HCV | HIV-1 | Mycobacterium bovis | Schistosoma
japonicum | Schistosoma mansoni | Toxoplasma gondii | Trichuris
muris |
LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/
B7RP1 | CD40 | CD80 | CD86 | CD154 | FcεR1 | ICOS | IFN-γ |
Ifnγ | IFN-γR1 | IL-1 | Il4 | Il4rα | IL-5 | IL-6 | IL-7 | Il7 | IL-10 | Il10 |
IL-12 | Il12 | IL-13 | Il13 | IL-13Rα2 | iNOS | MYD88 | OX40 |
OX40L | Rag | SM1 | SM2 | STAT6 | T1/ST2 | TGF-β | TLRs | TNF |
TNFRI | TNFRII
FURTHER INFORMATION
The WHO — Schistosomiasis (Bilharzia):
http://www.who.int/health-topics/schisto.htm
The WHO/UNDP/World Bank Schistosoma Genome
Network: http://www.nhm.ac.uk/hosted_sites/schisto/
University of Cambridge Schistosomiasis Research Group:
http://www.path.cam.ac.uk/~schisto/
Access to this interactive links box is free online.
VOLUME 2 | JULY 2002 | 5 1 1