Reviews
Schistosome Immunology:
More Questions than Answers
P. Hagan, P.D. Ndhlovu and D.W. Dunne
The past 30 years have seen research on the immunology of to many bacterial or viral infections, the development
schistosomiasis move to encompass studies of responses in of protective immunity does not seem to take place
naturally exposed human populations, in addition to the after a single exposure to infection; rather, it appears
studies in animal model systems. While animal systems that repeated exposures result in the accumulation of
still retain an important place in research on the immu- numbers of worms, with a decline in infection levels
nology of schistosomiasis, recent debate has centred on taking place only after several years of exposure14,15
aspects of human immunological responses that may or (Fig. 1). Convincing data to support such a view have
may not be associated with resistance or susceptibility to been obtained from a range of normal endemic foci
infection. In this article, Paul Hagan, Patricia Ndhlovu and and they indicate that the age at which infection
David Dunne take stock of the present state of knowledge prevalences and infection intensities peak is lower if
and offer their views on prospects for the future. transmission is high. The observed ‘peak shifts’ are
consistent with the predicted effects of acquired
The following description of the current understand- immunity produced by mathematical models16,17 (see
ing of schistosomiasis epidemiology, infection and M.E.J. Woolhouse, this issue).
disease offers one interpretation of the diverse data Apart from genetic factors, immunological re-
that have been collected, but many issues remain sponses and transmission levels, other factors might
unresolved. influence the pattern of prevalence and intensity of
infection that is observed in endemic and epidemic
Paradigm and problem foci. Principal among these are what might be consid-
In conditions of natural exposure to schistosome ered to be age-related factors, such as skin thickness
infection, many repeatedly exposed and infected indi- and hormones that make the adult host either more
viduals acquire a degree of resistance to infection1. At difficult to infect or a less conducive environment
the population level, this might contribute to a de- for parasite development, as has been discussed re-
cline in prevalence and intensity of infection with age cently18. However, the extent of the influence of these
in endemic areas2,3. The acquired immune responses and other physiological changes is keenly debated.
that have been associated with resistance to reinfec- The close association of schistosomiasis with water
tion are all of the Th2 type including interleukin 4
(IL-4) (Ref. 4), IL-5 (Refs 4, 5), IgE6–8 and eosinophils9.
The specific genetic elements that regulate the ca- 100
pacity to mount protective responses, which in turn
might serve to reduce the likelihood of infection, are
80
now being identified. The most striking evidence is
Prevalence (%)
provided from a study of a Brazilian population ex-
posed to Schistosoma mansoni infection. Segregation 60
analysis revealed a major gene or locus involved in
the control of infection intensities. This major gene, 40
designated SM1 (Ref. 10), has been located on chromo-
some 5q31–q33 (Ref. 11), in a region that encodes
some of the immunological factors putatively linked 20
to the development of resistance to schistosomiasis in
humans. Not all exposed humans develop a level of 0
resistance to infection that can protect them from the 0 20 40 60
consequences of the deposition of schistosome eggs in
their tissues, and so varying degrees of pathology can Age (years)
develop, with those most severely affected dying if Fig. 1. A typical schistosome age–prevalence curve, taken from
their infections are not treated in time12,13. an endemic focus of Schistosoma haematobium in The Gambia,
Here too, evidence is being gathered that appears with those passing >1 eggs per 10 ml urine (open circles), and
to support the view that a genetic predisposition to the those passing >1000 eggs per 10 ml urine (closed circles).
development of schistosome-associated pathology does Infection prevalence and intensity declines in older age groups.
exist (A. Dessein, pers. commun.). Unlike responses Heavy infections, which are associated with a high risk of sub-
sequent morbidity, are normally restricted to the younger age
groups, but the tissue damage might continue to affect individ-
Patricia Ndhlovu is at the Blair Research Institute, PO Box CY 573, uals for many years, even after their infection levels have de-
Causeway, Harare, Zimbabwe. David Dunne is at the Department clined. The decline in infection levels is thought to be a result
of Pathology, University of Cambridge, Cambridge, UK CB2 1QP. of a combination of factors including changes in acquired im-
Paul Hagan is at the Division of Infection and Immunity, IBLS, munity, reduced exposure to infection and alterations in host
University of Glasgow, Glasgow, UK G12 8QQ. physiology (see text and Box 1). Modified, with permission,
Tel: +44 141 330 2441, Fax: +44 141 330 2441, from Ref. 59.
e-mail:
Parasitology Today, vol. 14, no. 10, 1998 Copyright © 1998, Elsevier Science Ltd All rights reserved 0169–4758/98/$19.00 PII: S0169-4758(98)01325-8 407
, Reviews
Box 1. Factors Contributing to the Decline in Infection Levels with Age
Pathology
Eggs are produced by female worms. Many escape into the environment in urine or stools but a proportion lodge in
the tissues and continue to release antigens, which stimulate an intense immunological response. This results in the accu-
mulation of cells, predominantly eosinophils, macrophages and lymphocytes, around them: the classical schistosome
granuloma. Fibroblast activity might enhance tissue damage, leading to changes in blood flow and, in some situations,
compromised organ function. As with many parasitic infections, infection need not necessarily lead to disease. Chronic
disease with severe pathology is a relatively uncommon event in humans, affecting perhaps 10% of infected individuals.
Exposure to infection
Water contact might be domestic, recreational or occupational, and levels of contact of different individuals show great
variation. Contact might begin before children are one year old, and it tends to increase as children increase their recre-
ational activities, up to about ten years of age. In the early to middle teenage years, contact may start to decline, as children
take up other social responsibilities. But, for some, high levels of water contact might continue into adult life, usually for
domestic or occupational purposes. The relationship between water contact and exposure is influenced, among other
things, by seasonal factors, such as infected snail densities, the duration of contacts and cercarial densities. The relationship
between exposure to infection and acquisition of infection is one of the major issues in schistosome research.
Measuring infection
This is normally done by counting eggs in urine or faeces. However, to achieve any degree of accuracy, multiple sam-
ples are needed and even then the best that can be achieved is an estimate of infection levels. Low infection intensities can
be difficult to detect, and high infection intensities can be difficult to count accurately. The relationship between egg out-
put and numbers of worms has been examined in animals and in limited post-mortem studies, but remains uncertain
during the natural course of infection in repeatedly exposed individuals. Surrogate markers of worm burden have been
identified. These are antigens that are released from adult worms, circulate in the blood and are excreted in urine. Circu-
lating antigens can be detected in some egg-negative people. For Schistosoma haematobium but not S. mansoni, measure-
ments of circulating antigens together with measurements of egg outputs have helped provide evidence that worm
fecundity (egg output) might be depressed in an age-dependent manner in human populations, while worm numbers are
unaffected.
Physiological factors
One of the major complications in trying to tease apart the various factors that influence levels of infection, such as
exposure and acquired immunity, is that they tend to show variation with age. Physiological factors like skin thickness, lipid
content and hormone levels also vary with age, and might modify innate or acquired resistance to infection. The precise
nature of these interactions and their relative importance in determining levels of infection are still to be elucidated.
Immunology
The immune response to infection involves almost all of the components of the immune system. In terms of antibodies,
IgG1, IgG2, IgG3, IgG4, IgA, IgE and IgM have all been shown to be stimulated by schistosome infection. There is evi-
dence that some antibodies, notably IgG2 and IgG4, might block or compete with protective antibodies. Attempts to
relate immunological responses to resistance to reinfection after chemotherapy have provided correlative evidence that
IgG, IgE and IgA responses in particular might be important in protection. Cytokine profiles in humans appear to be
biased towards Th2.
Effector functions
A number of potentially functional immune reactivities have been described in which these antibodies participate in
antibody-dependent cellular cytotoxic mechanisms with a variety of cell types; these include eosinophils, neutrophils and
macrophages, which are effective in damaging the schistosomula stage of the schistosome in vitro. Other cell types such
as basophils and mast cells are thought to have an accessory role in the response to infection. However, the extent to
which any of these mechanisms operates during infection in humans is not clear. Animal studies have shown that
immune responses might act at several stages, preventing invasion, migration, development and egg production. Egg
hatching and infectivity of released miracidia for snail intermediate hosts might also be reduced.
sources means that environmental modifications de- least in some situations repeated treatments appear
signed to improve water supplies can have either to clear infection25. Mollusciciding is used less ex-
positive or negative impacts on the distribution of tensively and is now seen mainly as an adjunct to
infection and disease. In at least one case, a well- chemotherapy, providing a valuable additional di-
documented epidemic of schistosomiasis in the Richard mension to control in specific situations26. The view
Toll area of northern Senegal has occurred19. Data that the tools needed to control schistosomiasis are
from this study have shown that within a very few already available is gradually giving way to an aware-
years after the epidemic began, prevalence and inten- ness that, although existing tools could be used to
sity of infection profiles in relation to age were similar better effect, more are needed. As a consequence, the
to those observed in stable endemic foci20. development of a vaccine against schistosomes re-
Control of schistosomiasis in many endemic situ- mains a priority and studies on immunological re-
ations can be achieved through a number of interven- sponses to infection remain a key component of this
tions but, in general, the use of praziquantel is consid- effort27,28. As emphasized at the start, other interpre-
ered to be most effective21 (D. Cioli, this issue) (see tations of the data are possible, but the above presen-
also M.J. Doenhoff, this issue). Reports that have tation provides a reasonable synthesis of sometimes
raised the possibility of the development of drug conflicting data. The extent to which this paradigm is
resistance22–24 are increasing in frequency, but might the problem becomes clearer when the details of the
need to be reinterpreted given the evidence that at various contributing factors are examined (Box 1).
408 Parasitology Today, vol. 14, no. 10, 1998
Schistosome Immunology:
More Questions than Answers
P. Hagan, P.D. Ndhlovu and D.W. Dunne
The past 30 years have seen research on the immunology of to many bacterial or viral infections, the development
schistosomiasis move to encompass studies of responses in of protective immunity does not seem to take place
naturally exposed human populations, in addition to the after a single exposure to infection; rather, it appears
studies in animal model systems. While animal systems that repeated exposures result in the accumulation of
still retain an important place in research on the immu- numbers of worms, with a decline in infection levels
nology of schistosomiasis, recent debate has centred on taking place only after several years of exposure14,15
aspects of human immunological responses that may or (Fig. 1). Convincing data to support such a view have
may not be associated with resistance or susceptibility to been obtained from a range of normal endemic foci
infection. In this article, Paul Hagan, Patricia Ndhlovu and and they indicate that the age at which infection
David Dunne take stock of the present state of knowledge prevalences and infection intensities peak is lower if
and offer their views on prospects for the future. transmission is high. The observed ‘peak shifts’ are
consistent with the predicted effects of acquired
The following description of the current understand- immunity produced by mathematical models16,17 (see
ing of schistosomiasis epidemiology, infection and M.E.J. Woolhouse, this issue).
disease offers one interpretation of the diverse data Apart from genetic factors, immunological re-
that have been collected, but many issues remain sponses and transmission levels, other factors might
unresolved. influence the pattern of prevalence and intensity of
infection that is observed in endemic and epidemic
Paradigm and problem foci. Principal among these are what might be consid-
In conditions of natural exposure to schistosome ered to be age-related factors, such as skin thickness
infection, many repeatedly exposed and infected indi- and hormones that make the adult host either more
viduals acquire a degree of resistance to infection1. At difficult to infect or a less conducive environment
the population level, this might contribute to a de- for parasite development, as has been discussed re-
cline in prevalence and intensity of infection with age cently18. However, the extent of the influence of these
in endemic areas2,3. The acquired immune responses and other physiological changes is keenly debated.
that have been associated with resistance to reinfec- The close association of schistosomiasis with water
tion are all of the Th2 type including interleukin 4
(IL-4) (Ref. 4), IL-5 (Refs 4, 5), IgE6–8 and eosinophils9.
The specific genetic elements that regulate the ca- 100
pacity to mount protective responses, which in turn
might serve to reduce the likelihood of infection, are
80
now being identified. The most striking evidence is
Prevalence (%)
provided from a study of a Brazilian population ex-
posed to Schistosoma mansoni infection. Segregation 60
analysis revealed a major gene or locus involved in
the control of infection intensities. This major gene, 40
designated SM1 (Ref. 10), has been located on chromo-
some 5q31–q33 (Ref. 11), in a region that encodes
some of the immunological factors putatively linked 20
to the development of resistance to schistosomiasis in
humans. Not all exposed humans develop a level of 0
resistance to infection that can protect them from the 0 20 40 60
consequences of the deposition of schistosome eggs in
their tissues, and so varying degrees of pathology can Age (years)
develop, with those most severely affected dying if Fig. 1. A typical schistosome age–prevalence curve, taken from
their infections are not treated in time12,13. an endemic focus of Schistosoma haematobium in The Gambia,
Here too, evidence is being gathered that appears with those passing >1 eggs per 10 ml urine (open circles), and
to support the view that a genetic predisposition to the those passing >1000 eggs per 10 ml urine (closed circles).
development of schistosome-associated pathology does Infection prevalence and intensity declines in older age groups.
exist (A. Dessein, pers. commun.). Unlike responses Heavy infections, which are associated with a high risk of sub-
sequent morbidity, are normally restricted to the younger age
groups, but the tissue damage might continue to affect individ-
Patricia Ndhlovu is at the Blair Research Institute, PO Box CY 573, uals for many years, even after their infection levels have de-
Causeway, Harare, Zimbabwe. David Dunne is at the Department clined. The decline in infection levels is thought to be a result
of Pathology, University of Cambridge, Cambridge, UK CB2 1QP. of a combination of factors including changes in acquired im-
Paul Hagan is at the Division of Infection and Immunity, IBLS, munity, reduced exposure to infection and alterations in host
University of Glasgow, Glasgow, UK G12 8QQ. physiology (see text and Box 1). Modified, with permission,
Tel: +44 141 330 2441, Fax: +44 141 330 2441, from Ref. 59.
e-mail:
Parasitology Today, vol. 14, no. 10, 1998 Copyright © 1998, Elsevier Science Ltd All rights reserved 0169–4758/98/$19.00 PII: S0169-4758(98)01325-8 407
, Reviews
Box 1. Factors Contributing to the Decline in Infection Levels with Age
Pathology
Eggs are produced by female worms. Many escape into the environment in urine or stools but a proportion lodge in
the tissues and continue to release antigens, which stimulate an intense immunological response. This results in the accu-
mulation of cells, predominantly eosinophils, macrophages and lymphocytes, around them: the classical schistosome
granuloma. Fibroblast activity might enhance tissue damage, leading to changes in blood flow and, in some situations,
compromised organ function. As with many parasitic infections, infection need not necessarily lead to disease. Chronic
disease with severe pathology is a relatively uncommon event in humans, affecting perhaps 10% of infected individuals.
Exposure to infection
Water contact might be domestic, recreational or occupational, and levels of contact of different individuals show great
variation. Contact might begin before children are one year old, and it tends to increase as children increase their recre-
ational activities, up to about ten years of age. In the early to middle teenage years, contact may start to decline, as children
take up other social responsibilities. But, for some, high levels of water contact might continue into adult life, usually for
domestic or occupational purposes. The relationship between water contact and exposure is influenced, among other
things, by seasonal factors, such as infected snail densities, the duration of contacts and cercarial densities. The relationship
between exposure to infection and acquisition of infection is one of the major issues in schistosome research.
Measuring infection
This is normally done by counting eggs in urine or faeces. However, to achieve any degree of accuracy, multiple sam-
ples are needed and even then the best that can be achieved is an estimate of infection levels. Low infection intensities can
be difficult to detect, and high infection intensities can be difficult to count accurately. The relationship between egg out-
put and numbers of worms has been examined in animals and in limited post-mortem studies, but remains uncertain
during the natural course of infection in repeatedly exposed individuals. Surrogate markers of worm burden have been
identified. These are antigens that are released from adult worms, circulate in the blood and are excreted in urine. Circu-
lating antigens can be detected in some egg-negative people. For Schistosoma haematobium but not S. mansoni, measure-
ments of circulating antigens together with measurements of egg outputs have helped provide evidence that worm
fecundity (egg output) might be depressed in an age-dependent manner in human populations, while worm numbers are
unaffected.
Physiological factors
One of the major complications in trying to tease apart the various factors that influence levels of infection, such as
exposure and acquired immunity, is that they tend to show variation with age. Physiological factors like skin thickness, lipid
content and hormone levels also vary with age, and might modify innate or acquired resistance to infection. The precise
nature of these interactions and their relative importance in determining levels of infection are still to be elucidated.
Immunology
The immune response to infection involves almost all of the components of the immune system. In terms of antibodies,
IgG1, IgG2, IgG3, IgG4, IgA, IgE and IgM have all been shown to be stimulated by schistosome infection. There is evi-
dence that some antibodies, notably IgG2 and IgG4, might block or compete with protective antibodies. Attempts to
relate immunological responses to resistance to reinfection after chemotherapy have provided correlative evidence that
IgG, IgE and IgA responses in particular might be important in protection. Cytokine profiles in humans appear to be
biased towards Th2.
Effector functions
A number of potentially functional immune reactivities have been described in which these antibodies participate in
antibody-dependent cellular cytotoxic mechanisms with a variety of cell types; these include eosinophils, neutrophils and
macrophages, which are effective in damaging the schistosomula stage of the schistosome in vitro. Other cell types such
as basophils and mast cells are thought to have an accessory role in the response to infection. However, the extent to
which any of these mechanisms operates during infection in humans is not clear. Animal studies have shown that
immune responses might act at several stages, preventing invasion, migration, development and egg production. Egg
hatching and infectivity of released miracidia for snail intermediate hosts might also be reduced.
sources means that environmental modifications de- least in some situations repeated treatments appear
signed to improve water supplies can have either to clear infection25. Mollusciciding is used less ex-
positive or negative impacts on the distribution of tensively and is now seen mainly as an adjunct to
infection and disease. In at least one case, a well- chemotherapy, providing a valuable additional di-
documented epidemic of schistosomiasis in the Richard mension to control in specific situations26. The view
Toll area of northern Senegal has occurred19. Data that the tools needed to control schistosomiasis are
from this study have shown that within a very few already available is gradually giving way to an aware-
years after the epidemic began, prevalence and inten- ness that, although existing tools could be used to
sity of infection profiles in relation to age were similar better effect, more are needed. As a consequence, the
to those observed in stable endemic foci20. development of a vaccine against schistosomes re-
Control of schistosomiasis in many endemic situ- mains a priority and studies on immunological re-
ations can be achieved through a number of interven- sponses to infection remain a key component of this
tions but, in general, the use of praziquantel is consid- effort27,28. As emphasized at the start, other interpre-
ered to be most effective21 (D. Cioli, this issue) (see tations of the data are possible, but the above presen-
also M.J. Doenhoff, this issue). Reports that have tation provides a reasonable synthesis of sometimes
raised the possibility of the development of drug conflicting data. The extent to which this paradigm is
resistance22–24 are increasing in frequency, but might the problem becomes clearer when the details of the
need to be reinterpreted given the evidence that at various contributing factors are examined (Box 1).
408 Parasitology Today, vol. 14, no. 10, 1998
