Parasite Immunology, 2014, 36, 428–438 DOI: 10.1111/pim.

12084

Review Article

Immune responses to Schistosoma haematobium infection

J. I. ODEGAARD1 & M. H. HSIEH2

1
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA, 2Department of Urology, Stanford University
School of Medicine, Stanford, CA, USA

SUMMARY tentive funding agencies and the difficulties inherent in

studying fastidious organisms with complicated lifecycles.
Urogenital schistosomiasis is one of the greatest single infec-
Nevertheless, recently refocused philanthropic and govern-
tious sources of human morbidity and mortality known.
mental funding has enabled several critical advancements
Through a complex cycle of infection, migration and even-
in our ability to experimentally manipulate S. haematobi-
tual maturation and mating, S. haematobium (the aetiologi-
um, opening the species-specific biology of this important
cal agent of urogenital schistosomiasis) deposits highly
organism to systematic study for the first time.
immunogenic eggs within the bladder and other pelvic
In this review, we discuss the recent evolution of S. hae-
organs, activating a wide range of immune programs that
matobium-specific reagents and techniques and how these
determine both infection outcome as well as downstream
complement traditional clinical studies to describe the
immunopathology. In this review, we discuss the experimen-
unique pathology of S. haematobium infection. More spe-
tal and observational bases for our current understanding of
cifically, we will focus on the complex immune response to
these immune programs, focusing specifically on how the
urogenital egg deposition and discuss how the parasite-
balance of type 1 and type 2 responses governs subsequent
host interaction evolves to either parasite elimination or
immunopathology and clinical outcome.
progressive clinical disease.
Keywords immune modulation, immunoepidemiology, Schis-
tosoma haematobium, Schistosoma spp, schistosomiasis, SCHISTOSOMA HAEMATOBIUM BIOLOGY
urogenital
Like other schistosomes, S. haematobium occupies a com-
plex and specific biological niche (reviewed in (4)). The
INTRODUCTION lifecycle begins in fresh water aquatic environments, where
eggs hatch into miracidia and infest various species of
With well over one-half billion people affected worldwide,
freshwater snail (Bulinus), which act as the intermediate
schistosomiasis is one of the most wide-reaching clinically
host. Upon maturation, S. haematobium emerges as free-
significant infections on the planet (1,2). Moreover, Schis-
swimming cercariae that traverse the water column until
tosoma haematobium, as the most prevalent member of the
they come into contact with human skin, into which they
genus, is one of the greatest single sources of human
burrow. With access to the dermal vasculature, the cerca-
morbidity and mortality known with an African disease
riae mature to schistosomulae, migrate through the host
burden that equals and may possibly exceed even that of
circulation, mature and eventually lodge in specific venous
malaria (3). Despite such impressive infamy, much of
plexuses within the body as adult worm mating pairs and
S. haematobium’s biology and pathology remains
begin to lay eggs. Importantly, this migration is not at all
surprisingly enigmatic, due in perhaps equal parts to silent
random and instead demonstrates remarkable tissue speci-
infections, a decades-long clinical course, historically inat-
ficity; S. haematobium, for example, migrates to venous
plexuses in the pelvis (primarily those draining the bladder
Correspondence: Michael H. Hsieh, Department of Urology, Stan- and female genital tract), whereas S. mansoni and
ford University School of Medicine, Stanford, CA 94305, USA S. japonicum lodge in the portal circulation. This anatomi-
(e-mail: mhhsieh@stanford.edu).
Disclosures: None.
cal particularity is crucial to understanding the varied clin-
Received: 24 May 2013 ical manifestations associated with schistosome infection
Accepted for publication: 20 October 2013 as it tethers subsequent pathology to specific tissues,

428 © 2013 John Wiley & Sons Ltd

Volume 36, Number 9, September 2014
setting the stage for hepatosplenic (as in S. mansoni and
S. japonicum infection) or urogenital disease (as in S. hae-
matobium infection). Once in place, adult worm pairs may
persist for many fecund years and produce thousands of
eggs. Though many eggs eventually pass into the intestinal
or bladder lumens and are excreted, many become trapped
within the host tissue, evoking a potent immune response
that, over months and years, results in dramatic tissue
remodelling and long-term pathological consequences.
Much of our knowledge of the pathophysiology of
schistosome infections is derived from two basic
approaches: clinical observation and animal models. Clini-
cal observation has formed the basis for urogenital schis-
tosomiasis research since its inception, generally in the
form of serological/urinary analyses (antibody responses
or hematuria, for example), ultrasound examination, or in
monitoring end pathology (such as renal failure or urothe-
lial carcinoma), all of which lend valuable insights into the
natural history of chronic infection including the various
possible immunopathological outcomes. Moreover, studies
involving urine and serum analysis provide a serial view of
infection evolution over time. Neither of these approaches,
however, is able to provide the standardization or experi-
mental manipulability necessary for rigorous definition or
mechanistic investigation. Moreover, the absence of acute
clinical stigmata of infection largely precludes identifica-
tion of recently infected individuals and, thus, study of the
nascent phases of infection including those early determi-
nants of resistance to chronic infection.
Where heterogeneous patient backgrounds and environ-
ments, unknown infection duration and ethical restrictions
on intervention complicate human studies, animal models
are relatively free of these shortcomings as their genetic
backgrounds, environmental exposures and infection tim-
ing may be rigorously controlled and manipulated.
Because of this tractability, animal models are indispens-
able in infectious agent research; however, care must be
taken to ensure faithful recapitulation of human disease.
Importantly, animal model fidelity has proven to be par-
ticularly problematic in the study of urogenital schistoso-
miasis. For most disease research, mice are the favoured
model organism—their genetics are both defined and
manipulable, they breed and subsist successfully in con-
strained lab environments, and a bevy of species-specific
tools and experience is available for them. In an unfortu-
nate contrast to human disease, however, S. haematobium
worm pairs exhibit a tropism for the portal circulation in
the mouse and other commonly employed rodents, elicit-
ing pathology quite distinct from urogenital disease.
Indeed, researchers have had to resort to costly and ethi-
cally fraught primate models to approximate human uro-
genital pathology, none of which have proven tenable for
© 2013 John Wiley & Sons Ltd, Parasite Immunology, 36, 428–438
Immune responses to S. haematobium infection
routine use. Due to this experimental intransigence, much
of schistosome-directed research has focused instead on
rodent models of S. mansoni and, to a lesser extent, S. ja-
ponicum, both of which approximate human hepatosplenic
disease in the mouse. As these models have established
important paradigms that apply to S. haematobium as
well, mounting evidence suggests that species- and tissue-
specific factors make such approaches poor surrogates in
the study of urogenital schistosomiasis. For example, the
effects of egg expulsion are very different in the bacteria-
rich environment of the gut lumen when compared with
the sterile bladder, just as the biochemical functionality of
the liver is affected differently than the biomechanical
function of the bladder. Indeed, even within the same
pathological context of hepatosplenic disease, S. haemato-
bium, S. mansoni and S. japonicum infections all result in
different histological appearances, pathological sequelae
and disease kinetics.
As S. haematobium fails to establish urogenital disease
in all but a small fraction of infected mice (5,6), studies of
mouse hepatic schistosomiasis demonstrate that the basic
host immune response is intact and similar to that of
human hepatosplenic disease, strongly supporting the gen-
eral applicability of this model of infection. To circumvent
S. haematobium’s lack of pelvic organ involvement in the
mouse, our laboratory developed a novel model of urogen-
ital schistosomiasis in which S. haematobium eggs—the
primary determinants of the host immune responses—are
surgically implanted into the mouse bladder lamina pro-
pria (the layer of loose connective tissue between the uro-
thelium and the smooth muscle in which eggs lodge in
human infection), effectively simulating bladder oviposi-
tion in urogenital disease (7). Importantly, this model
faithfully recapitulates the salient architectural, pathologi-
cal and immunological sequelae of human disease, thus
offering the first experimentally tractable model of urogen-
ital schistosomiasis. This model in combination with
recent in vitro technological advances (such as S. haemato-
bium-directed short interfering RNA technology (8)) and
bioinformatic resources (such as the publication of the
S. haematobium genome (9)) has, for the first time, placed
many of the fundamental questions in schistosomal uro-
genital immunity and pathology within reach.
INNATE IMMUNE RESPONSES TO
SCHISTOSOME INFECTION
As discussed above, schistosome infections begin with
cercarial penetration of the skin, migration into the der-
mal vasculature and eventual deposition in a terminal
venous plexus, the location of which determines the specif-
ics of the eventual clinical disease. During this weeks-long
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migration, cercariae mature into adult worms and form (a)

male-female pairs, offering the host immune system a
potentially broad array of antigens. Despite this antigenic
diversity, however, the host immune response to cercarial
and adult worm antigens is, by comparison to later egg-
triggered disease, muted (10–13). Indeed, aside from rare
cases of cercarial dermatitis (swimmer’s itch) and Katay-
ama syndrome (hypersensitivity responses to acute and
mid-stage infection, respectively, both of which are espe-
cially rare in S. haematobium infection relative to other
schistosome species), S. haematobium infection is rarely
clinically apparent until egg deposition occurs (as high-
lighted in (4)). Importantly, the immune response to adult
worms, while less intense than that to tissue-embedded
eggs, is the primary determinant of infection outcome,
with those individuals who mount robust antibody (partic- (b)
ularly IgE) responses to adult worm antigens more likely
to resist reinfection than others with more tepid responses
(14).
In contrast to the relatively ineffectual response to via-
ble cercariae and adult worms, the eggs produced by adult
S. haematobium evoke a robust immune response. Unfor-
tunately, early immune responses to egg deposition are lar-
gely undefined in the human due to our inability to
identify and study newly infected individuals. The advent
of the mouse model of direct oviposition (7), however,
opens this response accessible to study. In this context,
S. haematobium eggs elicit an immediate (within 24 h) and
brisk host response from local and recruited innate
immune cells. Interestingly, the character of the initial Figure 1 Schistosoma haematobium egg granuloma structure.
response is mixed, with induction of inflammatory media- (a) Within 4 days, the immune response to surgically implanted
S. haematobium eggs (arrows) forms a loosely organized mass
tors (such as TNF-a) as well as cytokines associated with
lesion (dashed line) within the bladder lamina propria dominated
type 2 responses (such as CCL11). As with many other by dyshesive macrophages admixed with eosinophils, lymphocytes
infectious stimuli, such immediate responses have two sali- and neutrophils. (b) Over time, this response evolves into a highly
ent effects—additional innate immune cells are recruited organized granuloma (dashed line), which comprises a core of
to maintain and amplify the initial response, whereas the multinucleated syncytial macrophages (giant cells) and tightly
cohesive single macrophages surrounding the now-calcified eggs
adaptive immune system is recruited and activated.
(arrows) with admixed eosinophils and peripheral lymphoid
Innate immune cell recruitment is, of course, a hallmark aggregates (asterisks). These features are histologically identical to
of many immune responses; however, schistosome egg-elic- those observed in human infection.
ited responses are distinguished by their degree and persis-
tence—indeed, the recruitment of innate immune cells to
sites of schistosome egg deposition results in the develop- Characteristically, eggs are engulfed by multinucleated syn-
ment of a highly specialized secondary immune tissue cytial macrophages (giant cells), which are in turn sur-
known as a granuloma (Figure 1), an especially impressive rounded by an organized and cohesive cuff of epithelioid
feat in the bladder given the relative paucity of leucocytes macrophages with admixed eosinophils and, to varying
in uninfected tissue. At time points as early as 4 days after degrees, neutrophils concentrated around the granuloma
oviposition in the mouse model (7), S. haematobium eggs periphery. Within the mouse urogenital model, this archi-
are segregated from surrounding tissue by a dense but tecture persists for more than 100 days after oviposition
loosely cohesive aggregate of newly recruited macrophages with minimal but progressive loss of cellularity similar to
and eosinophils. Over the subsequent 7 days, this highly what is observed in mouse models of hepatosplenic dis-
cellular innate immune admixture organizes into a cohe- ease. Most importantly, this response is histologically iden-
sive granuloma centred on the inciting schistosome egg(s). tical to the egg-centred granulomata observed in human

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Volume 36, Number 9, September 2014
disease (15–19), although the polypoid lesions occasionally
seen in human disease (20) are not apparent.
Macrophages
As the primary structural constituent of the granuloma,
macrophages unsurprisingly play a central role initiating
and guiding the overall innate immune response. In vitro
and in vivo experiments have long ago established the mac-
rophage’s ability to mount robust type 2 responses to
schistosome eggs including expression of high levels of
ARG1, MRC and CHI3L3 (reviewed in (21)). Indeed,
S. mansoni infection of mice deficient in type 2 macro-
phage responses (such as mice lacking IL-4Ra in macro-
phages) results in fatal inflammatory responses due to
their inability to form proper granulomata to segregate
eggs from surrounding tissue (22). Moreover, numerous
observations of hepatic disease models have implicated
type 2 macrophages in the initial fibrotic stabilization of
the granuloma and subsequent associated tissue fibrosis
(23–25). Ex vivo interrogation of granuloma-derived leuco-
cytes in the mouse model of urogenital disease, however,
unexpectedly revealed elevated expression of type 1 macro-
phage activation markers (such as NOS2 and CD40) con-
current with expression of type 2-associated genes (such as
ARG1, MRC and CHI3L3) (26), suggesting that egg
deposition in this context involves either a mixed pheno-
type or a mixed population of type 1 and type 2 macro-
phages. Moreover, expression analyses of developing
granulomata have described extensive expression of both
type 1- and type 2-associated cytokine and chemokine sig-
nalling pathways (26), further suggesting that urogenital
oviposition triggers both macrophage activation programs.
Eosinophils
Eosinophil infiltration and eosinophiluria are cardinal his-
tological and clinical signs of parasitic infection (27,28);
however, much of this cell’s functional significance
remains elusive. In the pre-egg stages of the S. haematobi-
um lifecycle, eosinophils are important effector cells capa-
ble of killing cercariae and adult worms in a
degranulation- and IgE-dependent manner (29). In fact,
the ability of rats to clear schistosome infections without
developing chronic disease may be attributable, in part, to
the ease with which rat eosinophils degranulate in
response to IgE-decorated worms relative to eosinophils
from mice, an animal susceptible to chronic infection (30).
(This particular observation may also be due, in part, to
the absence of high-affinity IgE receptor I—a surface
receptor on human eosinophils involved in IgE-mediated
anti-schistosome activity in vitro (31)—on mouse
© 2013 John Wiley & Sons Ltd, Parasite Immunology, 36, 428–438
Immune responses to S. haematobium infection
eosinophils; however, the overall significance of the rat
infection phenotype is unclear and may, in fact, be an idi-
osyncrasy of the model itself.) Upon urogenital oviposi-
tion, however, eosinophils rapidly migrate to the bladder,
presumably in response to CCL5/RANTES), CCL11/
eotaxin-1 and CCL24/eotaxin-2 (although CCL11 is the
only one of these chemokines known to be highly
expressed in the immediate response), where they accumu-
late as the most numerous cell type within the granuloma
(although due to their larger size, macrophages occupy far
more volume) (7). Indeed, in schistosome-infected humans,
eosinophils are even detectable (albeit at much reduced
numbers) near old, long-calcified egg remnants in long-
standing lesions where much of the granulomatous
response has long since disappeared (18,19) (Odegaard,
unpublished observations). Though their functional contri-
bution in urogenital schistosomiasis has not yet been
described, eosinophils serve as an important source of IL-
4 prior to the emergence of the Th2 response in many
other immunological contexts (such as in adipose tissue
and skeletal muscle) (32,33) and remain one of the pri-
mary sources of IL-13 throughout the evolution of hepatic
granulomatous responses (34). Indeed, eosinophil-derived
IL-13 has been suggested to be an important driver of
fibrosing responses in hepatosplenic schistosomiasis both
directly through activation of hepatic stellate cells and
indirectly through the promotion of type 2 macrophage
activation (34). Congruent with this hypothesis, mice defi-
cient in IL-5 demonstrate smaller S. mansoni granulomata
and significantly reduced liver fibrosis (34). More recently,
however, the role of the eosinophil has been called into
question by the absence of any substantial difference
between wild type and DdblGATA or TgPHIL mice (both
of which entirely lack eosinophils but demonstrate pre-
served IL-5 production) during infection with S. mansoni
(35). Though the absence of a phenotype is striking, these
studies examined hepatic egg-induced pathology only,
which does not exclude a role in the elimination of adult
worms and cercariae.
Dendritic cells
As the principal antigen-presenting cell, dendritic cells
constitute a critical bridge between early innate and later
adaptive immune responses to S. haematobium infection;
however, the specifics of this role have not yet been
described. Indeed, even in well-studied models of S. man-
soni infection, dendritic cell activation remains somewhat
enigmatic. Dendritic cells (broadly—if inaccurately—
defined in many studies by CD11c expression) are
necessary for proper Th2 responses to schistosome egg
deposition (36); however, numerous experiments have
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J. I. Odegaard & M. H. Hsieh
demonstrated that even highly immunoreactive schisto-
some antigen preparations (soluble egg antigen, for exam-
ple) fail to elicit canonical maturation of dendritic cells or
expression of activating cytokines or costimulatory mole-
cules in vitro (37–39). Despite this apparent apathy, how-
ever, these cells demonstrate a surprisingly potent capacity
to induce an activated Th2 phenotype in na€ıve T cells in a
CD40-, OX40L- and NFjB activation-dependent manner
(39–42). These apparently contradictory findings have
generated multiple proposed novel maturation pathways;
however, in general, little evidence exists to support their
in vivo relevance. One such recently proposed mechanism
involves omega-1, a T2 RNase abundant in SEA and
secreted by viable S. mansoni eggs (43). When internalized
by immature dendritic cells, this particular molecule drives
Th2 polarizing capacity through an ill-defined mechanism
involving RNase-dependent nonspecific degradation of
host mRNA and rRNA pools (43). How nonspecific RNA
degradation is linked to T cell stimulation and Th2 polari-
zation capacity is unclear; however, this finding suggests a
novel mechanistic link between the observed in vitro and
in vivo effects of schistosome antigens. Whether such
mechanisms govern dendritic cell participation in urogeni-
tal disease is entirely unclear (43), as initial studies failed
to detect omega-1 in S. haematobium infection (44).
Natural killer cells
As the primary and secondary outcomes of schistosome
infections correlate strongly with the relative balance
between type 1 and type 2 immune responses, there is con-
siderable interest in how these activation programs are ini-
tiated, how their relative contributions are regulated and
in what ways might they be manipulated for therapeutic
effect. As a major source of IFN-c and other type 1-bias-
ing cytokines, natural killer (NK) cells are of natural inter-
est in this context; however, the data supporting their role
in schistosome infection is limited to three direct observa-
tions. First, NK cells are recruited to schistosome egg-
associated hepatic granulomata (45), where their presence
corresponds to locally increased levels of IL-12 (although
they do not appear to contribute significantly to IFN-c
levels within the granuloma or serum) (46). Second, deple-
tion of NK cells results in increased schistosome egg-asso-
ciated granuloma volume and fibrosis, whereas their
activation (along with many that of several other lineages)
by TLR3 ligands has the opposite effect (46–48). Finally,
activated NK cells are capable of killing activated hepatic
stellate cells—a key fibrogenic cell in hepatic fibrosis—in
vitro and in vivo in the context of toxin-induced fibrosis
(49). Though these observations are compelling and sug-
gest a role in limiting the granulomatous response, the
432
Parasite Immunology
true contribution of NK cells even in relatively well-stud-
ied hepatic schistosomiasis is unclear, and their relevance
to urogenital disease is entirely unknown.
Basophils
Despite the past use of basophil degranulation as a diag-
nostic assay for urogenital schistosomiasis (50), the contri-
bution of basophils to human urogenital schistosomiasis is
entirely unknown (as is true in much of basophil biology).
The ability of basophils to produce substantial amounts of
IL-4 in response to S. mansoni infection in mice long sup-
ported the belief that these cells innately produce IL-4 in
response to schistosome exposure and initiate the observed
type 2 bias in the schistosome-associated immune
response. The description of IL-4 inducing principle from
S. mansoni eggs (IPSE)/alpha-1—an aptly-named protein
secreted from viable schistosome eggs that triggers IL-4
release from basophils—seemed to support this hypothesis
(51); however, careful dissection of this putative pathway
in mice using multiple helminth species including S. man-
soni recently debunked this theory through three major
observations. First, basophil deletion yielded no defect in
Th2 responses or any other demonstrable infection-related
phenotype (51). Second, basophils were incapable of IL-4
production in the absence of T cells (52). Lastly, interac-
tions between basophils and T cells were shown to be
kinetically incompatible with antigen presentation and
were demonstrated instead to represent a necessary licens-
ing process only after which basophils were capable of
IL-4 production (52). However, basophils were able to res-
cue the phenotype of mice lacking IL-4 and IL-13 in their
T cells, suggesting that though it is not required in wild-
type mice, basophil-derived IL-4 can functionally replace
IL-4 production by Th2 cells during S. mansoni infection
(52). As such, the basophil lineage remains a potential
contributor to schistosome-associated immune responses
and immunopathology; however, the nonredundant func-
tions of this putative role remain unclear.
Mast cells
Due to the strong correlation between serum IgE levels
and resistance to S. haematobium, investigators have long
proposed mast cells (one of the primary effector cell types
for IgE-dependent parasite killing) as potential mediators
of IgE’s protective effects. Observational studies in indi-
viduals vocationally exposed to S. mansoni, however, dem-
onstrated that circulating mast cell precursor numbers
were, in fact, negatively correlated with resistance (53),
although verification of this effect and mechanistic expla-
nation are absent. Interestingly, mast cell-derived IL-10
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Volume 36, Number 9, September 2014
was recently implicated in chronic bacterial urinary tract
infection (54), suggesting a possible role for this lineage in
the regulation of chronic inflammatory responses in the
genitourinary tract and, perhaps, in the eventual induction
of regulatory T cell responses. Unsurprisingly, however, lit-
tle direct data are available regarding the potential role of
mast cells in urogenital schistosomiasis.
ADAPTIVE IMMUNE RESPONSES TO
SCHISTOSOME INFECTION
T cells
Though macrophages form the structural bulk of the gran-
uloma, multiple lines of evidence suggest that T lympho-
cytes play a critical role in both the local and the systemic
responses to infection. First, T cells rapidly infiltrate egg-
exposed tissues and are already present in large numbers
in the nascent granuloma at day 4 in the mouse model of
bladder oviposition (7). In later time points and in human
samples, these cells are found scattered throughout the
granuloma as well as concentrated in lymphoid follicles in
the granuloma’s periphery. Second, T cell-deficient mouse
models of S. japonicum and S. mansoni hepatic disease
demonstrate egg-centred zones of hepatocyte necrosis
accompanied by an exaggerated neutrophil response
(55,56) suggesting that T cells are required to restrain the
inflammatory response. Similarly, mouse models of
S. mansoni infection require an effective Th2 response to
sequester highly phlogistic eggs from surrounding tissue
and prevent lethal inflammation (22). Third, both T cells
present locally and in the draining lymph node robustly
express Th2-associated cytokines (e.g. IL-4 and IL-13) well
in advance of systemic Th2 responses (7), supporting the
hypothesis that this activation bias is established by early
T cell responses in the granuloma. Lastly, interference with
key Th2-restricted factors (such as IL-4) by either genetic
deletion in mice or polymorphisms in human populations
results in severe restriction of granuloma-forming
responses and exacerbated disease (22,57–59). These data
in aggregate support a model in which the initial innate
immune response generates Th2 cells, which then support
granuloma formation through IL-4 production, recruit
and maintain eosinophils via IL-5, and promote fibrosing
responses via IL-13.
In contrast, Th1 and Th17 inflammatory responses are
largely suppressed after an initial spike in the mouse uro-
genital oviposition model (7). Indeed, S. mansoni infection
in mice deficient in IFN-c, IL-12, or IL-17 is little differ-
ent than in wild-type controls (60–62). Congruently, sys-
temic levels of type 2 cytokines increase markedly by day
7 post-oviposition and remain elevated for at least
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Immune responses to S. haematobium infection
28 days, whereas Th1- and Th17-associated mediators
remain equivalent to controls (7). This pattern further
holds in mouse models of hepatic disease where the Th1
response acts to limit granuloma size and fibrotic stabiliza-
tion through both direct and indirect effects (22). Impor-
tantly, serological studies in humans consistently report
similar elevations in Th2 cytokines with suppression of
their Th1/Th17 counterparts (63). One important distinc-
tion between the human data and the mouse model of ovi-
position, however, resides in the regulatory T cell (Treg)
response. In the mouse model, markers of Treg cells and
responses are suppressed (7), as human reports describe
increased levels of IL-10 and Treg responses, although at
levels much lower than those of Th2 mediators (63). This
discrepancy is likely to be due to idiosyncratic rather than
species-specific effects as mouse models of S. mansoni
infection recapitulate Treg induction, which are required
here for controlling inflammation throughout the process
of egg expulsion into the gut lumen (21). Regardless, there
is ample evidence in both mice and humans that schisto-
some soluble egg antigens induce IL-10, which in turn
suppresses T cell responses (64–69). These immunomodu-
latory pathways may ultimately serve to reduce the host
pathophysiology associated with schistosomiasis.
Congruent with observations from mouse models, the
human data strongly suggest that induction of Th1/Th17
mediators, as it is not uniformly correlated with infection,
is strongly associated with increased urogenital morbidity
and end-stage pathology, whereas Th2 responses are asso-
ciated with decreased disease sequelae (63). Congruently,
polymorphisms that either impair type 2 (e.g. hypomor-
phic variants in IL13 and STAT6) or enhance type 1
responses (e.g. hypomorphic variants in CTLA4) are both
associated with increased S. haematobium infection inten-
sity in endemic populations (70,71). Taken in aggregate,
these data suggest that the balance of type 1 responses rel-
ative to type 2 is an important determinant of the local
control of urogenital disease and contributes to infection
resistance.
Natural killer T cells
Natural killer T (NKT) cells have not been well studied in
the context of schistosome infection; however, studies uti-
lizing CD1d / mice, which lack all NKT cells, suggest
that these cells play a role in type 2/regulatory responses
to S. mansoni infections, although direct measures of
infection (such as worm and egg counts and hepatic
pathology) are unaffected (72). Interestingly, Ja18 / mice,
which specifically lack only type I NKT cells, demonstrate
impaired type 1 responses whereas type 2/regulatory
responses remain intact (72). Moreover, these mice
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demonstrate larger granulomata, enhanced IgE responses
and slightly lower egg counts (72), suggesting that NKT
cell promotion of type 2 responses may be specifically due
to type 2 NKT cells and that type 1 cells may favour type
1 responses. This is in contrast to other immunological
contexts (such as in adipose tissue and liver metabolism)
and other studies of schistosome infection (73) in which
type I NKT cells have been reported to favour type 2/regu-
latory responses. As such, the actual contribution of this
lineage to S. mansoni infection is unclear, whereas
their role in S. haematobium infection remains entirely
undescribed.
B cells
Though T lymphocytes play a critical role in managing
schistosome egg-associated pathology, B lymphocytes are
more directly involved in infection clearance and resistance.
As in T cells, high levels of S. haematobium-specific type 2 B
cell effector molecules (primarily IgE) have been associated
with reduced susceptibility to reinfection (14); however, B
cell-deficient animals are still able to sequester deposited
S. japonicum eggs within granulomata, although with some-
what delayed kinetics (74). In human populations where
S. haematobium is endemic, however, B cell responses are
critical to the development of parasite resistance (14). In
these populations, exposure is nearly universal as defined by
the ubiquity of S. haematobium-specific IgM (75); however,
chronic disease and end-stage pathology is restricted to a
minority of individuals with a substantial subgroup evincing
no demonstrable evidence of disease. This population is dis-
tinguished by several B cell-related criteria including high
titres of S. haematobium-specific IgE, anti-AWA (adult
worm antigen) IgG1 and anti-Sh13 IgG3 as well as high
IgE:IgG4 (63,76–78). Importantly, these resistance-associ-
ated immunoglobulin responses are directed not against im-
munopathogenic egg antigens but against the adult worm.
It is also important to note, however, that these responses
generally tend to increase with age and that these specific
antigens are unlikely to represent the only immunologically
productive targets, as anti-S. haematobium antibody reper-
toire diversity beyond these specific targets remains a pow-
erful predictor of resistance (79). This observation has
important implications for the nascent efforts to develop
effective schistosome-specific vaccines.
IMMUNOPATHOLOGY OF UROGENITAL
SCHISTOSOMIASIS
Schistosoma haematobium infection evokes a complex array
of immune responses targeting either the egg or adult
worm/cercarial stages. As responses to the latter appear to
434
Parasite Immunology
govern resistance to infection, parasite clearance and sus-
ceptibility to re-infection, the proximal determinant of
S. haematobium-related morbidity and mortality is the egg-
directed immune response. In productive (from S. haemato-
bium’s point of view) oviposition, the cascade of immune
responses detailed above facilitate the segregation of immu-
nogenic eggs from the host and shepherd them to the organ
lumen, where they may be expelled from the body and per-
petuate the helminth’s life cycle. For unclear reasons, how-
ever, a subset of eggs fails to be expelled and instead persists
within the tissue, chronically activating the host immune
system. This activation comprises a remarkable diversity of
immune pathways; however, these may be broadly classified
as type 1, type 2, or regulatory responses and are typified by
their associated T lymphocyte phenotypes with Th1, Th2
and Treg activation. Though the human data are far from
clear and are confounded by cohort effects and other biases,
the eventual outcome of S. haematobium infection is
thought to be directly related to the balance between these
various immune programs and the tissue responses they
direct—Th1 responses are associated with tissue damage
and heightened infection intensity in many human studies,
whereas Th2 bias is correlated with decreased egg burden
and infection resistance (56). It should be noted, however,
that these are general trends and studies exist in each cate-
gory suggesting contrasting interpretations. The generalized
consequences of regulatory responses are similarly unclear
(although control of type 1 responses has been proposed).
Moreover, it remains unclear whether these responses direct
the disease course or are merely markers thereof. What is
clear, however, is that as some egg-directed immune
responses are necessary to protect the host from deleterious
inflammation and tissue damage during egg transit and
expulsion, chronic activation can have marked pathological
consequences.
One of the primary sources of morbidity and mortality
in S. haematobium-infected individuals is egg-induced uri-
nary tract fibrosis. Here, chronic activation of egg-directed
immune responses leads to recruitment and activation of
myofibroblast-like cells and the progressive accumulation
of collagen, which culminates in tissue fibrosis (80). Unlike
schistosome-associated hepatic fibrosis, however, where
fibrosis has been linked to the hepatic stellate cell (30,44),
the origin of myofibroblast-like cells in urogenital disease
is unclear. Regardless, the direct biomechanical conse-
quences of fibrosis include stricture, obstruction and gen-
eral urinary dysfunction, which can progress to
obstructive renal pathology, renal failure and death
(81,82). Secondary consequences of chronic infection also
include hematuria, increased propensity to renal and uri-
nary tract coinfections and the progressive accumulation
of urothelial damage/atypia that culminates in squamous
© 2013 John Wiley & Sons Ltd, Parasite Immunology, 36, 428–438
Volume 36, Number 9, September 2014
cell carcinoma, an especially aggressive type of bladder
cancer, as well as urothelial carcinoma (83,84).
In addition to the bladder pathology, 30% to 75%
(depending on the population studied and examination
techniques) of S. haematobium-infected females develop
genital pathology detectable on examination as sandy
patches (physical stigmata of tissue-entrapped eggs) on the
cervical mucosa with the vagina, upper tract and external
genitalia less commonly affected (85–90). Importantly, as
sandy patches of the cervix are pathognomonic for FGS
in women, the early appearance and subsequent evolution
of cervical lesions in girls with FGS remains unknown. In
addition, as the basic pathophysiology here is much the
same as in the bladder, the tissue-specific consequences
include increased susceptibility to sexually transmitted
infections (especially HIV), dyspareunia and infertility
(85–90). Importantly, infection and genital disease is often
established during childhood, long before the onset of sex-
ual maturity, leading to lifelong pathological consequences
(91). Less commonly, S. haematobium can involve the male
genital organs, where it generally manifests as hematosper-
mia and possibly infertility (92).
Though S. haematobium infection physically localizes to
the urogenital tract, its infectious sequelae may systemi-
cally manifest. Indeed, a major source of S. haematobi-
um’s disease burden manifests as developmental delay of
chronically infected children both as a consequence of
nutritional deficiencies (most commonly due to iron defi-
ciency associated with chronic inflammation and hematu-
ria) and repeated urinary tract coinfections (93–98).
Moreover, S. haematobium-infected individuals demon-
strate increased susceptibility to Plasmodium species due,
in large part, to IL-10’s influence on cytokine and anti-
body responses (99,100). These same alterations in
immune timbre, however, provide one of the few poten-
tially positive effects of infection—infected individuals
demonstrate substantially reduced off-target immunoreac-
tivity such as occurs in atopic and autoimmune conditions.
Given the potent type 2 immune deviation associated with
schistosomal infection, it is unsurprising that disease sever-
ity in such type 1-driven immune pathologies as Crohn’s
disease, type 1 diabetes and multiple sclerosis would be
significantly reduced (reviewed in (101)); however, similarly
beneficial effects are observed in type 2-driven pathologies
such as asthma and atopic disease (102,103), suggesting
that disease amelioration might be due to regulatory influ-
ences rather than type 1-type 2 antagonism. Indeed, schis-
tosome-infected individuals demonstrate enhanced basal
and stimulated IL-10 production capable of effectively
inhibiting both autoimmune and atopic pathologies (104).
Congruently, studies of asthma in S. mansoni-endemic
populations demonstrate that infected asthmatics not only
© 2013 John Wiley & Sons Ltd, Parasite Immunology, 36, 428–438
Immune responses to S. haematobium infection
demonstrated lower disease severity than uninfected con-
trols but that this difference vanished on treatment with
the schistosomicide praziquantel (105). Interestingly, func-
tionally significant IL10 promoter polymorphisms corre-
late with atopic disease and total IgE levels but not with
schistosome infection susceptibility or outcome (106), sug-
gesting that IL-10 exercises a more potent influence over
atopic immunopathology than schistosome-associated dis-
ease. The mechanisms underlying this observation are
unclear; however, a leading hypothesis involves schisto-
some-specific IgE out-competing allergen-specific IgE for
mast cell surface receptor occupancy. It is perhaps more
likely, however, that schistosome-elicited IL-10 directly
inhibits the pro-atopic activity of target lineages, as has
been demonstrated in basophils (107). As in other aspects
of human schistosome studies, the significance of these
effects is often unclear as effect magnitude and even direc-
tion varies between reports.
CONCLUSION
Urogenital schistosomiasis comprises a significant and
under-appreciated source of human morbidity and mortal-
ity; however, very little is known of the host or pathogen
determinants of disease. This lack of clarity is, in part, due
to the relatively enigmatic nature of the aetiological agent,
S. haematobium, and the historical lack of experimentally
tractable disease models. With the recent advent of S. hae-
matobium-specific tools and a mouse model of urogenital
infection, however, the field is poised to dissect urogenital
disease away from its better-studied hepatosplenic cousin
and define the unique immunopathology that governs our
interaction with this deadly schistosome. To facilitate the
study of S. haematobium infection, we present below a
summary of areas of particular interest to the field. Glean-
ing insights in these areas will further our understanding
of fibrosing disease (both urogenital and otherwise),
cancer and immunopathology in general and, hopefully,
further arm us to intervene therapeutically therein.
OPPORTUNITIES FOR SCHISTOSOMA
HAEMATOBIUM INFECTION RESEARCH
• Development of animal models of S. haematobium
infection conducive to the study of the role of IgE.
• Identification of major secreted products of S. haemato-
bium eggs and comparisons of their structure and func-
tion to homologs in other schistosome species.
• Determination of how and by what mechanisms S. hae-
matobium adult worms track to the pelvic circulation.
• Elucidation of how inflammatory cervicovaginal lesions
evolve during female genital schistosomiasis.
435
J. I. Odegaard & M. H. Hsieh
REFERENCES
1 World Health Organization, The Control of
Schistosomiasis. Report of a WHO Expert
Committee. Technical Report Series no.
728. Geneva, WHO, 1985.
2 Strickland GT & Ramirez BL. Schistosomi-
asis. In: Strickland GT, (ed): Hunters Tropi-
cal Medicine and Emerging Infectious
Diseases. Philadelphia, W.B. Saunders Com-
pany. 2000: 804–832.
3 King CH. Health metrics for helminthic
infections. Adv Parasitol 2010; 73: 51–69.
4 Gryseels B, Polman K, Clerinx J & Kestens
L. Human schistosomiasis. Lancet 2006;
368: 1106–1118.
5 Loker ES. A comparative study of the life-
histories of mammalian schistosomes. Para-
sitology 1983; 2: 343–369.
6 Rheinberg CE, Mone H, Caffrey CR,
Imbert-Establet D, Jourdane J, Ruppel A.
Schistosoma haematobium, S. intercalatum,
S. japonicum, S. mansoni, and S. rodhaini
in mice: relationship between patterns of
lung migration by schistosomula and perfu-
sion recovery of adult worms. Parasitol Res
1998; 84: 338–342.
7 Fu C-L, Odegaard JI, Herbert DR & Hsieh
MH. A novel mouse model of Schistosoma
haematobium egg-induced immunopathol-
ogy. PLoS Pathog 2012; 8: e1002605.
8 Rinaldi G, Okatcha TI, Popratiloff A, et al.
Genetic manipulation of Schistosoma hae-
matobium, the neglected schistosome. PLoS
Negl Trop Dis 2011; 5: e1348.
9 Young ND, Jex AR, Li B, et al. Whole-
genome sequence of Schistosoma haemato-
bium. Nat Genet 2012; 44: 221–225.
10 Beaver Jung RC & Cupp EWPC. Clinical
Parasitology. Philadelphia, PA, Lea and
Febiger. 1984.
11 El Ridi R, Ismail S, Gaafar T & El Demel-
lawy M. Differential responsiveness of
humans with early-stage schistosomiasis
haematobium to Schistosoma haematobium
soluble adult-worm and egg antigens.
Parasitol Res 1997; 83: 471–477.
12 Gaafar T, Helmy M, Ismail S, Afifi A,
Guirguis N, el Ridi R. Identification of the
Schistosoma haematobium soluble egg anti-
gens inducing antibody production and/or
T cell proliferation in humans. J Egypt Soc
Parasitol 1992; 22: 441–451.
13 Gaafar T, Ismail S, Helmy M, Afifi A,
Guirguis N, el Ridi R. Identification of
Schistosoma haematobium soluble egg
antigens that elicit human granuloma
formation in vitro. Parasitol Res 1993; 79:
103–108.
14 Hagan P, Blumenthal UJ, Dunn D, Simp-
son AJ & Wilkins HA. Human IgE, IgG4
and resistance to reinfection with Schistoso-
ma haematobium. Nature 1991; 349: 243–
245.
15 Cheever AW, Kamel IA, Elwi AM, Mosi-
mann JE & Danner R. Schistosoma man-
soni and S. haematobium infections in
Egypt. II. Quantitative parasitological find-
436
ings at necropsy. Am J Trop Med Hyg
1977; 26: 702–716.
16 Cheever AW, Kamel IA, Elwi AM, Mosi-
mann JE, Danner R, Sippel JE. Schistoso-
ma mansoni and S. haematobium infections
in Egypt. III. Extrahepatic pathology. Am J
Trop Med Hyg 1978; 27: 55–75.
17 Ghoneim I, Rabets J & Mawhorter S. Camp-
bell-Walsh urology/editor-in-chief, Alan J.
Wein; [editors, Louis R. Kavoussi… et al.].
In: Wein AJ, Kavoussi LR & Campbell MF
(eds): Campbell-Walsh Urology. Philadelphia,
PA: Elsevier Saunders. 2011: p. 4 v. (xxxvii,
3753, 95 p.).
18 Sadun EH, Von Lichtenberg F, Cheever
AW, Erickson DG & Hickman RL. Experi-
mental infection with Schistosoma haemato-
bium in chimpanzees. Am J Trop Med Hyg
1970; 19: 427–458.
19 Von Lichtenberg F, Edington GM, Nwabu-
ebo I, Taylor JR & Smith JH. Pathologic
effects of schistomiasis in Ibadan Western
State of Nigeria. II. Pathogenesis of lesions
of the bladder and ureters. Am J Trop Med
Hyg 1971; 20: 244–254.
20 Smith JH, Torky H, Kelada AS & Farid Z.
Schistosomal polyposis of the urinary blad-
der. Am J Trop Med Hyg 1977; 26: 85–88.
21 Wilson MS, Mentink-Kane MM, Pesce JT,
Ramalingam TR, Thompson R, Wynn TA.
Immunopathology of schistosomiasis. Immu-
nol Cell Biol 2007; 85: 148–154.
22 Herbert DR, Holscher C, Mohrs M,
et al. Alternative macrophage activation is
essential for survival during schistosomiasis
and downmodulates T helper 1 responses
and immunopathology. Immunity 2004; 20:
623–635.
23 Chu D, Du M, Hu X, Wu Q & Shen J.
Paeoniflorin attenuates schistosomiasis
japonica-associated liver fibrosis through
inhibiting alternative activation of macro-
phages. Parasitology 2011; 138: 1259–1271.
24 Burke ML, McManus DP, Ramm GA,
et al. Temporal expression of chemokines
dictates the hepatic inflammatory infiltrate
in a murine model of schistosomiasis. PLoS
Negl Trop Dis 2010; 4: e598.
25 Hams E, Aviello G & Fallon PG. The
Schistosoma granuloma: friend or foe? Front
Immunol 2013; 4: 89.
26 Ray D, Nelson TA, Fu C-L, et al. Tran-
scriptional profiling of the bladder in uro-
genital schistosomiasis reveals pathways of
inflammatory fibrosis and urothelial com-
promise. PLoS Negl Trop Dis 2012; 6:
e1912.
27 Eltoum IA, Suliaman SM, Ismail BM, Ismail
AI, Ali MM, Homeida MM. Evaluation of
eosinophiluria in the diagnosis of schistoso-
miasis hematobium: a field-based study. Am
J Trop Med Hyg 1992; 46: 732–736.
28 Reimert CM, Mshinda HM, Hatz CF, et al.
Quantitative assessment of eosinophiluria
in Schistosoma haematobium infections:
a new marker of infection and bladder
© 2013 John Wiley & Sons Ltd, Parasite Immunology, 36, 428–438
Parasite Immunology
morbidity. Am J Trop Med Hyg 2000; 62:
19–28.
29 Verwaerde C, Joseph M, Capron M, et al.
Functional properties of a rat monoclonal
IgE antibody specific for Schistosoma
mansoni. J Immunol 1987; 138: 4441–4446.
30 Rousseaux-Prevost R, Capron M, Bazin H
& Capron A. IgE in experimental schistoso-
miasis. II. Quantitative determination of
specific IgE antibodies against S. mansoni:
a follow-up study of two strains of infected
rats. Correlation with protective immunity.
Immunology 1978; 35: 33–39.
31 Gounni AS, Lamkhioued B, Ochiai K,
et al. High-affinity IgE receptor on eosin-
ophils is involved in defence against para-
sites. Nature 1994; 367: 183–186.
32 Molofsky AB, Nussbaum JC, Liang H-E,
et al. Innate lymphoid type 2 cells sustain
visceral adipose tissue eosinophils and alter-
natively activated macrophages. J Exp Med
2013; 210: 535–549.
33 Heredia JE, Mukundan L, Chen FM, et al.
Type 2 innate signals stimulate fibro/adipo-
genic progenitors to facilitate muscle regen-
eration. Cell 2013; 153: 376–388.
34 Reiman RM, Thompson RW, Feng CG,
et al. Interleukin-5 (IL-5) augments the
progression of liver fibrosis by regulating
IL-13 activity. Infect Immun 2006; 74: 1471–
1479.
35 Swartz JM, Dyer KD, Cheever AW, et al.
Schistosoma mansoni infection in eosinophil
lineage-ablated mice. Blood 2006; 108:
2420–2427.
36 Phythian-Adams AT, Cook PC, Lundie
RJ, et al. CD11c depletion severely
disrupts Th2 induction and develop-
ment in vivo. J Exp Med 2010; 207:
2089–2096.
37 Kane CM, Cervi L, Sun J, et al. Helminth
antigens modulate TLR-initiated dendritic
cell activation. J Immunol 2004; 173: 7454–
7461.
38 Van Liempt E, van Vliet SJ, Engering A,
et al. Schistosoma mansoni soluble egg anti-
gens are internalized by human dendritic
cells through multiple C-type lectins
and suppress TLR-induced dendritic cell
activation. Mol Immunol 2007; 44: 2605–
2615.
39 Perona-Wright G, Jenkins SJ & MacDon-
ald AS. Dendritic cell activation and func-
tion in response to Schistosoma mansoni.
Int J Parasitol 2006; 36: 711–721.
40 MacDonald AS, Straw AD, Dalton NM &
Pearce EJ. Cutting edge: Th2 response
induction by dendritic cells: a role for
CD40. J Immunol 2002; 168: 537–540.
41 Blazquez AB & Berin MC. Gastrointestinal
dendritic cells promote Th2 skewing via
OX40L. J Immunol 2008; 180: 4441–4450.
42 Jenkins SJ & Mountford AP. Dendritic cells
activated with products released by schisto-
some larvae drive Th2-type immune
responses, which can be inhibited by
Volume 36, Number 9, September 2014
manipulation of CD40 costimulation. Infect
Immun 2005; 73: 395–402.
43 Everts B, Hussaarts L, Driessen NN,
et al. Schistosome-derived omega-1 drives
Th2 polarization by suppressing protein
synthesis following internalization by the
mannose receptor. J Exp Med 2012; 209:
1753–1767.
44 Dunne DW, Jones FM & Doenhoff MJ.
The purification, characterization, serologi-
cal activity and hepatotoxic properties of
two cationic glycoproteins (alpha 1 and
omega 1) from Schistosoma mansoni eggs.
Parasitology 1991; 2: 225–236.
45 Remick DG, Chensue SW, Hiserodt JC,
Higashi GI & Kunkel SL. Flow-cytometric
evaluation of lymphocyte subpopulations in
synchronously developing Schistosoma man-
soni egg and Sephadex bead pulmonary
granulomas. Amer J Pathol 1988; 131: 298–
307.
46 Asseman C, Pancre V, Quatennens B &
Auriault C. Schistosoma mansoni-infected
mice show augmented hepatic fibrosis and
selective inhibition of liver cytokine produc-
tion after treatment with anti-NK1.1 anti-
bodies. Immunol Lett 1996; 54: 11–20.
47 Hou X, Yu F, Man S, et al. Negative regula-
tion of Schistosoma japonicum egg-induced
liver fibrosis by natural killer cells. PLoS Negl
Trop Dis 2012; 6: e1456.
48 Hashimoto A, Pincelli C, Fujioka A,
Fukuyama K & Epstein WL. Relationship
between NK cells and granulomatous
inflammation in mice. J Clin Lab Immunol
1990; 33: 41–47.
49 Gao B & Radaeva S. Natural killer and
natural killer T cells in liver fibrosis.
Biochim Biophys Acta 2013; 1832: 1061–
1069.
50 Niel G, Sainte-Laudy J, Carme B, et al. The
comparative value of the human basophil
degranulation test and classical serology
(immunofluorescence, haemagglutination,
electrosyneresis, Vogel and Minnings Test) in
the diagnosis of bilharzioses due to Schisto-
soma mansoni and Schistosoma haematob.
Ann Biol Clin 1982; 40: 573–577.
51 Schramm G, Mohrs K, Wodrich M, et al.
Cutting edge: IPSE/alpha-1, a glycoprotein
from Schistosoma mansoni eggs, induces IgE-
dependent, antigen-independent IL-4 produc-
tion by murine basophils in vivo. J Immunol
2007; 178: 6023–6027.
52 Sullivan BM, Liang H-E, Bando JK, et al.
Genetic analysis of basophil function in
vivo. Nat Immunol 2011; 12: 527–535.
53 Ganley-Leal LM, Mwinzi PNM, Cetre-Sos-
sah CB, et al. Higher percentages of circu-
lating mast cell precursors correlate with
susceptibility to reinfection with Schistoso-
ma mansoni. Am J Trop Med Hyg 2006; 75:
1053–1057.
54 Chan CY, St John AL, Abraham SN & St.
John AL. Mast cell interleukin-10 drives
localized tolerance in chronic bladder infec-
tion. Immunity 2013; 38: 1–11.
55 Cheng Y, Song W, Liu W, et al. The effects
of T cell deficiency on the development of
© 2013 John Wiley & Sons Ltd, Parasite Immunology, 36, 428–438
Immune responses to S. haematobium infection
worms and granuloma formation in mice
infected with Schistosoma japonicum. Paras-
itol Res 2008; 102: 1129–1134.
56 Byram JE & von Lichtenberg F. Altered
schistosome granuloma formation in nude
mice. Am J Trop Med Hyg 1977; 26: 944–
956.
57 Kouriba B, Chevillard C, Bream JH, et al.
Analysis of the 5q31-q33 locus shows an
association between IL13-1055C/T IL-13-
591A/G polymorphisms and Schistosoma
haematobium infections. J Immunol 2005;
174: 6274–6281.
58 Isnard A, Kouriba B, Doumbo O & Chevil-
lard C. Association of rs7719175, located in
the IL13 gene promoter, with Schistosoma
haematobium infection levels and identifica-
tion of a susceptibility haplotype. Genes Im-
mun 2011; 12: 31–39.
59 He H, Isnard A, Kouriba B, et al. A
STAT6 gene polymorphism is associated
with high infection levels in urinary schisto-
somiasis. Genes Immun 2008; 9: 195–206.
60 Yap G, Cheever A, Caspar P, Jankovic D &
Sher A. Unimpaired down-modulation of
the hepatic granulomatous response in CD8
T-cell- and gamma interferon-deficient mice
chronically infected with Schistosoma man-
soni. Infect Immun 1997; 65: 2583–2586.
61 Chensue SW, Warmington K, Ruth JH,
Lukacs N & Kunkel SL. Mycobacterial
and schistosomal antigen-elicited granu-
loma formation in IFN-gamma and IL-4
knockout mice: analysis of local and regio-
nal cytokine and chemokine networks. J
Immunol 1997; 159: 3565–3573.
62 Wynn TA, Morawetz R, Scharton-Kersten
T, et al. Analysis of granuloma formation in
double cytokine-deficient mice reveals a cen-
tral role for IL-10 in polarizing both T
helper cell 1- and T helper cell 2-type cyto-
kine responses in vivo. J Immunol 1997; 159:
5014–5023.
63 Burke ML, Jones MK, Gobert GN, Li YS,
Ellis MK, McManus DP. Immunopathogene-
sis of human schistosomiasis. Parasite Immu-
nol 2009; 31: 163–176.
64 Wahl SM, Frazier-Jessen M, Jin WW, Kopp
JB, Sher A, Cheever AW. Cytokine regula-
tion of schistosome-induced granuloma and
fibrosis. Kidney Int 1997; 51: 1370–1375.
65 Okano M, Satoskar AR, Nishizaki K, Abe
M & Harn DA. Induction of Th2 responses
and IgE is largely due to carbohydrates
functioning as adjuvants on Schistosoma
mansoni egg antigens. J Immunol 1999; 163:
6712–6717.
66 Lundy SK & Boros DL. Fas ligand-express-
ing B-1a lymphocytes mediate CD4(+)-T-cell
apoptosis during schistosomal infection:
induction by interleukin 4 (IL-4) and IL-10.
Infect Immun 2002; 70: 812–819.
67 Reis EAG, Azevedo TM, McBride AJA,
Harn DA & Reis MG. Na€ıve donor
responses to Schistosoma mansoni soluble
egg antigens. Scand J Immunol 2007; 66:
662–670.
68 Teixeira-Carvalho A, Martins-Filho OA,
Peruhype-Magalh~aes V, et al. Cytokines,
chemokine receptors, CD4+CD25HIGH+
T-cells and clinical forms of human schisto-
somiasis. Acta Trop 2008; 108: 139–149.
69 Vella AT & Pearce EJ. CD4 + Th2
response induced by Schistosoma mansoni
eggs develops rapidly, through an early,
transient, Th0-like stage. J Immunol 1992;
148: 2283–2290.
70 Isnard A & Chevillard C. Recent advances
in the characterization of genetic factors
involved in human susceptibility to infec-
tion by schistosomiasis. Curr Genomics
2008; 9: 290–300.
71 Maizels RM. Parasite immunomodulation
and polymorphisms of the immune system.
J Biol 2009; 8: 62.
72 Mallevaey T, Fontaine J, Breuilh L, et al.
Invariant and noninvariant natural killer T
cells exert opposite regulatory functions on
the immune response during murine
schistosomiasis. Infect Immun 2007; 75:
2171–2180.
73 Mallevaey T, Zanetta JP, Faveeuw C, et al.
Activation of invariant NKT cells by the
helminth parasite Schistosoma mansoni. J
Immunol 2006; 176: 2476–2485.
74 Ji F, Liu Z, Cao J, Li N, Liu Z, et al. B cell
response is required for granuloma forma-
tion in the early infection of Schistosoma
japonicum. PLoS ONE 2008; 3: e1724.
75 Nash TE. Antibody response to a polysac-
charide antigen present in the schistosome
gut. I. Sensitivity and specificity. Am J Trop
Med Hyg 1978; 27: 939–943.
76 Grogan JL, Kremsner PG, van Dam GJ, De-
elder AM & Yazdanbakhsh M. Anti-schisto-
some IgG4 and IgE at 2 years after
chemotherapy: infected versus uninfected
individuals. J Infect Dis 1997; 176: 1344–
1350.
77 Iskander R, Das PK & Aalberse RC. IgG4
antibodies in Egyptian patients with schis-
tosomiasis. Int Arch Allergy Immunol 1981;
66: 200–207.
78 Naus CW, van Dam GJ, Kremsner PG,
Krijger FW & Deelder AM. Human IgE,
IgG subclass, and IgM responses to worm
and egg antigens in schistosomiasis haemat-
obium: a 12-month study of reinfection in
Cameroonian children. Clin Infect Dis
1998; 26: 1142–1147.
79 Mutapi F, Burchmore R, Mduluza T, Midzi
N, Turner CMR, Maizels RM. Age-related
and infection intensity-related shifts in anti-
body recognition of defined protein anti-
gens in a schistosome-exposed population.
J Infect Dis 2008; 198: 167–175.
80 Rauterberg J, Voss B, Pott G & Gerlach U.
Connective tissue components of the nor-
mal and fibrotic liver. I. Structure, local dis-
tribution and metabolism of connective
tissue components in the normal liver and
changes in chronic liver diseases. Klinische
Wochenschrift 1981; 59: 767–779.
81 Von Lichtenberg F. Schistosomiasis
as a worldwide problem: pathology. J Toxi-
col Environ Health 1975; 1: 175–184.
82 Abdel-Wahab MF, Ramzy I, Esmat G, El
Kafass H & Strickland GT. Ultrasound for
437
J. I. Odegaard & M. H. Hsieh
detecting Schistosoma haematobium urinary
tract complications: comparison with radio-
graphic procedures. J Urol 1992; 148:
346–350.
83 Gelfand M, Weinberg RW & Castle WM.
Relation between carcinoma of the bladder
and infestation with Schistosoma haemato-
bium. Lancet 1967; 1: 1249–1251.
84 Brand KG. Schistosomiasis--cancer: etiolog-
ical considerations. A review. Acta Trop
1979; 36: 203–214.
85 Kjetland EF, Kurewa EN, Ndhlovu PD,
et al. Female genital schistosomiasis--a dif-
ferential diagnosis to sexually transmitted
disease: genital itch and vaginal discharge as
indicators of genital Schistosoma haematobi-
um morbidity in a cross-sectional study in
endemic rural Zimbabwe. Trop Med Int
Health 2008; 13: 1509–1517.
86 Jourdan PM, Roald B, Poggensee G, Gun-
dersen SG & Kjetland EF. Increased vascu-
larity in cervicovaginal mucosa with
Schistosoma haematobium infection. PLoS
Negl Trop Dis 2011; 5: e1170.
87 Kjetland EF, Mduluza T, Ndhlovu PD,
et al. Genital schistosomiasis in women:
a clinical 12-month in vivo study follow-
ing treatment with praziquantel.
Trans R Soc Trop Med Hyg 2006; 100:
740–752.
88 Kjetland EF, Leutscher PDC & Ndhlovu
PD. A review of female genital schistosomi-
asis. Trends Parasitol 2012; 28: 59–66.
89 Kjetland EF, Ndhlovu PD, Mduluza T,
et al. Simple clinical manifestations of geni-
tal Schistosoma haematobium infection in
rural Zimbabwean women. Am J Trop
Med Hyg 2005; 72: 311–319.
90 Helling-Giese G, Sjaastad A, Poggensee G,
et al. Female genital schistosomiasis (FGS):
relationship between gynecological and his-
topathological findings. Acta Trop 1996; 62:
257–267.
438
91 Hegertun IEA, Sulheim Gundersen KM,
Kleppa E, et al. S. haematobium as a com-
mon cause of genital morbidity in girls: a
cross-sectional study of children in South
Africa. PLoS Negl Trop Dis 2013; 7: e2104.
92 Corachan M, Valls ME, Gascon J, Almeda
J & Vilana R. Hematospermia: a new etiol-
ogy of clinical interest. Am J Trop Med
Hyg 1994; 50: 580–584.
93 Farid Bassily S, Schulert AR, Zeind AS,
McConnell E, Abdel Wahab MF. Urinary
blood loss in Schistosoma haematobium
infection in Egyptian farmers. Trans R Soc
Trop Med Hyg 1968; 62: 496–500.
94 Tatala SR, Kihamia CM, Kyungu LH &
Svanberg U. Risk factors for anaemia in
schoolchildren in Tanga Region, Tanzania.
Tanzan J Health Res 2008; 10: 189–202.
95 The Partnership for Child Development.
The health and nutritional status of school-
children in Africa: evidence from school-
based health programmes in Ghana and
Tanzania. The Partnership for Child Devel-
opment. Trans R Soc Trop Med Hyg 1998;
92: 254–261.
96 Nmorsi OP, Kwandu UN & Ebiaguanye
LM. Schistosoma haematobium and urinary
tract pathogens co-infections in a rural
community of Edo State, Nigeria. J Com-
mun Dis 2007; 39: 85–90.
97 Kassim OO & Stek M Jr. Bacteriuria and
hematuria in infections due to Schistosoma
haematobium. J Infect Dis 1983; 147: 960.
98 Wilkins HA. Schistosoma haematobium in a
Gambian community. III. The prevalence
of bacteriuria and of hypertension.
Ann Trop Med Parasitol 1977; 71: 179–186.
99 Courtin D, Djilali-Sa€ıah A, Milet J, et al.
Schistosoma haematobium infection affects
Plasmodium falciparum-specific IgG
responses associated with protection against
malaria. Parasite Immunol 2011; 33: 124–
131.
© 2013 John Wiley & Sons Ltd, Parasite Immunology, 36, 428–438
Parasite Immunology
100 Diallo TO, Remoue F, Schacht AM, et al.
Schistosomiasis co-infection in humans
influences inflammatory markers in uncom-
plicated Plasmodium falciparum malaria.
Parasite Immunol 2004; 26: 365–369.
101 Cardoso LS, Oliveira SC & Araujo MI.
Schistosoma mansoni antigens as modula-
tors of the allergic inflammatory response
in asthma. Endocr Metab Immune Disord
Drug Targets 2012; 12: 24–32.
102 Medeiros M, Figueiredo JP, Almeida MC,
et al. Schistosoma mansoni infection is asso-
ciated with a reduced course of asthma. J
Allergy Clin Immunol 2003; 111: 947–951.
103 Araujo MI, Lopes AA, Medeiros M, et al.
Inverse association between skin response
to aeroallergens and Schistosoma mansoni
infection. Int Arch Allergy Immunol 2000;
123: 145–148.
104 Ara ujo MI, Hoppe BS, Medeiros M &
Carvalho EM. Schistosoma mansoni infec-
tion modulates the immune response
against allergic and auto-immune diseases.
Mem Inst Oswaldo Cruz 2004; 99: 27–32.
105 Lynch NR, Hagel I, Perez M, Di Prisco MC,
Lopez R, Alvarez N. Effect of anthelmintic
treatment on the allergic reactivity of chil-
dren in a tropical slum. Current Genomics
1993; 9: 290–300.
106 Grant AV, Araujo MI, Ponte EV, et al.
Polymorphisms in IL10 are associated with
total Immunoglobulin E levels and Schisto-
soma mansoni infection intensity in a Bra-
zilian population. Genes Immun 2011; 12:
46–50.
107 Larson D, H€ ubner MP, Torrero MN, et al.
Chronic helminth infection reduces basophil
responsiveness in an IL-10-dependent
manner. J Immunol 2012; 188: 4188–4199.