Interleukin-13 in the skin and interferon-gamma in the liver are key players in immune protection in...

Interleukin-13 in the skin and

interferon-g in the liver are key

players in immune protection in

human schistosomiasis

Alain Dessein

Bourema Kouriba

Carole Eboumbou

Helia Dessein

Laurent Argiro

Sandrine Marquet

Nasr-Eldin M. A. Elwali

Virmondes Rodrigues

Yuesheng Li

Ogobara Doumbo

Christophe Chevillard

Authors’ addresses

Alain Dessein1, Bourema Kouriba1, Carole Eboumbou1,Helia Dessein1, Laurent Argiro1, Sandrine Marquet1,Nasr-Eldin M. A. Elwali2, Virmondes Rodrigues3,Yuesheng Li4, Ogobara Doumbo5, Christophe Chevillard1

1Immunology and Genetics of Parasitic Diseases,

INSERM, Faculte de Medecine, Marseille, France.2Institute of Nuclear Medicine and Molecular

Biology, University of Gezira, Wad Medani, Sudan.3Laboratory of Immunology, University of

Medicine, Triangulo Miniero, Uberaba, Brazil.4Hunan Institute of Parasitic Diseases, Huabanqiao

Road, Yueyang, Hunan, China.5DEAP – Center de Recherche sur les Maladies

Tropicales, Faculte de Medecine, Bamako, Mali.

Correspondence to:

Dr Alain J. DesseinFaculte de Medecine

27 bd Jean Moulin

13385 Marseille cedex 5

France

Tel.: þ33 491324453

Fax: þ33 491796063

E-mail: [email protected]

Acknowledgements

Thisworkwas fundedbygrants fromthe InstitutNationalde la

Sante et de la Recherche Medicale, France, the World Health

Organization (ID096546), the European Economic

Community (TS3CT940296, IC18CT970212), the Scientific

and Technical Cooperation with Developing Countries

(IC18CT980373), the French Ministry of research and

technology (PRFMMIP), Conseil General Provence Alpes Cote

d’Azur, and Conseil Regional Provence Alpes Cote d’Azur.

Summary: Immunity against schistosomes includes anti-infection immu-nity, which is mainly active against invading larvae in the skin, and anti-disease immunity, which controls abnormal fibrosis in tissues invaded byschistosome eggs. Anti-infection immunity is T-helper 2 (Th2) cell-dependent and is controlled by a major genetic locus that is located near theTh2 cytokine locus on chromosome 5q31-q33. Mutations in the geneencoding interleukin (IL)-13 that decrease or increase IL-13 productionaccount, at least in part, for that genetic control. In contrast, protection againsthepatic fibrosis is dependent on interferon (IFN)-g and is controlled by a majorgenetic locus that is located on 6q23, near the gene encoding the IFN-greceptor b chain. Mutations that modulate IFN-g gene transcription areassociated with different susceptibility to disease. These data indicate thatIL-13 in the skin and IFN-g in the liver are key players in protective immunityagainst schistosomes. These roles relate to the high anti-fibrogenic activities ofIFN-g and to the unique ability of IL-13 in Th2 priming in the skin and inthe mobilization of eosinophils in tissues. The coexistence of strong IFN-g andIL-13-mediated immune responses in the same subject may involve thecompartmentalization of the anti-schistosome immune response between theskin and the liver.

Introduction

Schistosomiasis is caused by worms of various species that

have different geographic distributions, vectors, and tissue

tropisms, and these worms cause different diseases. Schistosoma

mekongi, Schistosoma japonicum, and Schistosoma mansoni live in the

mesenteric and the portal veins and cause intestinal and hepa-

tosplenic diseases; Schistosoma hematobium lives in the vessels of

the urinary system and causes disease of the urinary tract,

ultimately leading to hydronephrosis (1–3). All schistosomes

can be lethal. Adult schistosomes are little affected by the

immune response of their host. Young larvae, however, are

targets of immunity when they invade the skin and when they

migrate through the lungs (4). The eggs laid by female worms

also stimulate a strong immune response in the organs in

Immunological Reviews 2004Vol. 201: 180–190Printed in Denmark. All rights reserved

Copyright � Blackwell Munksgaard 2004

Immunological Reviews0105-2896

180

which they are deposited and induce the formation of granu-

loma (reviewed in 5). Most eggs cross the intestinal and

bladder walls and are eliminated in feces or urine. Eggs induce

persistent granulomatous reactions in intestinal and bladder

tissues. The blood also carries some eggs to other locations, in

particular to the liver where they remain blocked in the

sinusoidal veins. In this location, the egg granuloma is essen-

tial to prevent eggs from digesting hepatocytes (6–8). The

granuloma leads to the formation of a scar. The scarring

process resulting from this inflammation may escape regula-

tory control and cause organ fibrosis. Pathological alterations

in subjects infected by schistosomes are principally the con-

sequence of uncontrolled extracellular matrix protein (ECMP)

deposition in periportal spaces and in the walls of the urinary

tract (reviewed in 9–11). In endemic regions, 5–20% of the

population is affected by severe schistosomiasis. The annual

number of deaths attributable to schistosomes is 250 000–

300 000 worldwide (12).

Epidemiological studies have identified two types of protect-

ive immunity in subjects living in regions of high schistosome

transmission. (i) Immunity that is directed toward schistosome

larvae and that reduces worm load is referred to as ‘sterile

immunity’. There are two sources of epidemiological evidence

supporting the existence of sterile immunity in endemic

regions: first, prevalence and infection curves show a clear

reduction in infection in adults that cannot be accounted for

by changes in exposure; second, reinfection intensities after

treatment vary markedly between individuals with similar expos-

ure and are correlated with preinfection level (13–16). Never-

theless, most subjects living in endemic areas are infected even

after many years of exposure and become reinfected after para-

sitological cure with praziquantel. Thus, sterile immunity is

almost never complete, even in the most resistant subjects. (ii)

Immunity that limits the pathological consequences of infection

is referred to as ‘clinical immunity’. Clinical immunity can be

observed both in urinary and in hepato-intestinal schistosomi-

asis. Unlike sterile immunity, clinical immunity can be very

strong and provide full protection against clinical disease (17).

Nevertheless, in highly exposed populations, most individuals

are affected by a mild or intermediate disease that does not

endanger their life but, in the long term, may be aggravated by

bacterial or viral infections.

Larvae that invade the skin are the target of Th2-

dependent protective immunity

Studies in experimental models have identified several immuno-

logical mechanisms of protection against schistosome infec-

tion; various effector cells, including macrophages (18–23)

and eosinophils (24–26), damage larvae through antibody-

dependent or antibody-independent mechanisms. Young

larvae are also damaged by the membrane attack complex

resulting from complement pathway activation. Mice and

rats injected with antibodies directed against larval antigens

are semi-protected against live cercariae (27). The earlier the

transfer, the better the protection, which suggests that larvae

become refractory to antibody-dependent attack within a few

days of penetrating the skin. Indeed, 24–48 h after transform-

ation into schistosomula, larvae lose a number of surface

antigens and are surrounded by a tegument that is resistant

to toxic oxygen radicals and basic proteins, such as those

released by eosinophils (28–30).

In vitro studies confirmed that antibody-dependent cellular

cytotoxicity (ADCC) is most efficient against larvae. Eosino-

phils, monocytes, and neutrophils are capable of killing schis-

tosomula. Eosinophils and macrophages exhibit the strongest

killing capacity. In vivo studies have been carried out to identify

immunological responses predictive of resistance to reinfec-

tion after praziquantel treatment. We conducted such a study

in a Brazilian population of a region endemic for S. mansoni;

Hagan and colleagues (31) carried out similar work in The

Gambia on a population infected by S. hematobium. As work on

experimental models and in vivo with human cells indicated

that the most efficient immune mechanisms involve antibody,

it was hypothesized that certain isotypes are associated with

resistance. A multivariate analysis, including all isotypes and

epidemiological variables that could influence reinfection,

showed that immunoglobulin (Ig) E and IgG4 are associated

with resistance/susceptibility to reinfection (31, 32). High

IgE levels are associated with protection against reinfection,

and elevated IgG4 levels are associated with increased suscept-

ibility to reinfection (31–33). The effects of these isotypes

were best demonstrated when both were present in the

analysis, indicating that they balance out each other’s effects.

IgG4 was subsequently shown to compete with IgE for

schistosomula antigens, suggesting that the balancing effect

results from competition for antigen binding (34). These

results were confirmed in later studies by Dunn and colleagues

(35).

As IgE and eosinophils are highly dependent on interleukin

(IL)-4, IL-13, and IL-5, it is implied that protection against

larvae involves a T-helper 2 (Th2) response. This conclusion

was confirmed by the demonstration that larvae-specific

T-cell clones from resistant subjects are Th2 or Th0/2,

whereas those from susceptible subjects are Th1 or Th0/1

(36, 37) (Fig. 1).

Dessein et al � IFN-g and IL-13 in protection against schistosomiasis

Immunological Reviews 201/2004 181

Resistance to infection is controlled by genes from the

5q31-q33 chromosomal region

In endemic populations, high infection levels are clustered in

certain families. This observation led us to postulate that some

inherited factors might determine infection (15). We tested

this hypothesis in the Brazilian population where the immuno-

logical studies described above were carried out. First, we used

segregation analysis to look for the evidence of a strong,

major, genetic effect (38). This analysis showed that the dis-

tribution of infection levels in families was best explained by a

model that included age, gender, exposure, and a major codom-

inant gene effect (38). Genetic control accounted for half of

the variance of infection levels, indicating that infection is

subject to strong genetic control, as expected from family

data. The frequency of the deleterious allele was estimated to

be around 0.25: 5% of the population was predisposed to a

high level of infection, 60% was resistant, and 35% had an

intermediate level of resistance. This finding was reproduced

in Kenya (Dessein and Gachuhi, unpublished data). We thus

attempted to map this gene in the human genome.

Linkage analysis using data from a whole genome scan was

used to map the major gene. The linkage analysis was con-

ducted on 142 Brazilian subjects from 11 informative families.

The genome was scanned with 246 polymorphic microsatel-

lite markers, corresponding to a 15 cM map. Only one region

on chromosome 5 (5q31-q33) showed suggestive linkage:

two adjacent markers provided maximum lod scores of 3.18

and 3.06. To investigate this region further, 11 additional

markers were analyzed and significant linkage (lod score

>3.3) was observed for two close markers (39, 40). The

maximum two-point lod score was observed for markers

near the colony stimulating factor-1 receptor gene (CSF1R)

and near the IL-4, IL-13, IL-5 gene cluster. Multipoint linkage

analysis including five markers for this region indicated that

the most likely location of this major gene, called SM1, was

close to the CSF1R marker, with a maximum lod score of 5.45

(39, 40). This result was later confirmed in an independent

study in Senegal by Muller–Myshsock and colleagues (41).

The 5q31-q33 region contains a cluster of cytokines that

play a central role in the immune response, including in Th2/

Th1 differentiation. These cytokines include the granulocyte–

macrophage CSF (GM-CSF/CSF2), several interleukins (IL-3,

IL-4, IL-5, IL-9, IL-12, and IL-13), the interferon regulatory

factor 1, and CSF-1R. This cluster also contains genes

controlling total serum IgE levels and familial hypereosino-

philia (42–44).

IL-13 alleles determine susceptibility to infection

We tested whether any known polymorphisms in these genes

could modulate susceptibility to infection. This study could

not be performed in the initial Brazilian population, because

we did not recruit enough subjects before curing the whole

population with oxamniquine. This study was therefore

carried out in subjects recruited in two Dogon villages in

Mali who were highly exposed to S. hematobium. We directly

tested whether any polymorphisms in the IL-4, IL-5, or IL-13

genes were associated with the control of infection. We first

focused on mutations in promoter regions: no associations

were found with mutations in the IL-4 and IL-5 promoters.

Analysis of the transmission of the alleles of IL13-1055C/T

and IL-13–591A/G polymorphisms showed that IL13-1055C

and IL-13-591A alleles were transmitted more frequently in

the 10% of patients with the highest infections, compared to

Fig. 1. Production of interleukin (IL)-4, IL-5, and interferon (IFN)-gby schistosomula-specific T-cell clones. Production of IL-4, IL-5, andIFN-g by parasite-specific CD4þ T-cell clones from (A) resistant and (B)susceptible individuals. Boxes represent 25–75 percentiles, and verticalbars represent 10–90 percentiles of the mean of one or two duplicatedeterminations performed on culture supernatants of each T-cell cones

stimulated by anti-CD3 plus phorbol myristate acetate. Horizontal linesare the median values. The numbers of clones were 7, 11, 7, 13, 11, and9 for subjects R1, R2, R3, S1, S2, and S3, respectively. In (B), IL-4/IFN-g(left) and IL-5/IFN-g (right) ratios of Schistosoma mansoni-specific CD4þ

T-cell clones derived from resistant and susceptible individuals areindicated.


182 Immunological Reviews 201/2004

the expected values based on the hypothesis of there being no

association between the allele and the phenotype (Kouriba et al.,

manuscript submitted). Others have shown that IL13-1055T/T

is associated with altered regulation of IL-13 (45), with elevated

IgE levels (46), and with sensitization to food and outdoor

allergens (47). These findings together with the data showing

the importance of the Th2 response in protection (31–37,

48–50) strongly suggested that differences in susceptibility to

infection could be due in part to these alleles. This possibility

was further evaluated in the whole population. IL13-1055

genotypes were found to affect infection levels markedly in

this population in all age classes (Kouriba et al., manuscript in

preparation) (Fig. 2). This result demonstrated (i) the genetic

control by the 5q31-q33 region originally described in a

Brazilian population infected by S. mansoni was confirmed in

Kenyan, Malian, and Senegalese populations, (ii) this locus

controlled both S. mansoni and S. hematobium infections, and (iii)

this control at least in part was accounted for by allelic variants

in the IL-13 gene.

IL-13 may increase protection in several manners. First, IL-

13 induces germline epsilon transcription and IgE switching

(51) and stimulates IgE production, especially in situations

when IL-4 is produced at low levels (52). Second, IL-13

induces the expression of the low affinity Fc"eRII (CD23)

(53–55), which leads to IgE-dependent destruction of schisto-

some larvae by monocytes and eosinophils (26, 56–58).

Unlike IL-4, IL-13 is unable to drive T-cell differentiation

into Th2. However, it may indirectly affect T-cell function

and differentiation by downregulating IL-12 production,

which directs Th1 development. It, therefore, could play a

role in the selection of Th2 or Th1 phenotypes of CD4þ

T-lymphocytes observed in Brazilian subjects. Eosinophils are

also central in protection against helminths; IL-13 increases

vascular cellular adhesion molecule (VCAM)-1 on endothelial

cells (59), thus increasing the recruitment of eosinophils

through VCAM-1-a4b1 interaction (60). Furthermore, IL-13

increases CD69 expression on eosinophils (61) and GM-CSF

production by several cell types including epithelial cells (62).

Therefore, it could prolong the life of eosinophils in dermal

tissue near the entry site of invading cercariae. IL-13 also has

strong anti-inflammatory properties (53, 63) that are probably

not directly relevant to sterile immunity but that are discussed

in the context of clinical immunity later in this article.

Anti-disease immunity in chronic schistosome infections

Eggs trapped in tissues are responsible for the most severe

clinical complications observed in chronically infected sub-

jects. In particular, they cause advanced fibrosis in periportal

spaces in subjects infected by S. mansoni or S. japonicum, leading

to portal hypertension (PH). PH causes collateral circulation,

varicose veins, and ascites in the abdominal cavity. The

accumulation of fibrotic granulomas in the ureters and

bladder wall causes severe bleeding and obstructs urine flow,

which in turn causes hydronephrosis in patients infected with

S. hematobium.

Some subjects who have lived in endemic areas all their life

and frequently come into contact with infected water show no

clinical manifestations of the disease. Thus, anti-disease immun-

ity is complete in certain subjects. Fig. 3 shows two families of

fishermen living on boats on the Dongting Lake in the Hunan

province of China. Both families comprised a number of cases

of severe periportal and parenchymal fibrosis; several adults

have bled from esophageal varicose veins and have had to be

splenectomized. In contrast, other families, who live in the

same boat cluster with the two most affected families, show

very little periportal fibrosis (PPF) and no parenchymal fibro-

sis. All subjects were born on a boat and have lived on a boat

ever since. They have daily contacts with infected water, and

men bathe almost daily in the lake in summer time.

Clinical immunity in S. mansoni and S. japonicum infections is

not correlated with immunity to infection. This finding was

first suggested by a number of clinical studies that failed to

find a clear correlation between PPF and infection levels. It has

been suggested that disease in adults is the consequence of

severe infections in children. However, PPF seldom occurs

before puberty, and the reduction in water contacts at adult

200A B

150

100

50

0

200

200

150

IL13-1055C/TC/CC/TT/T

100

50

0

Age (years)

Egg

s/20

ml

Egg

s/20

ml

0–7

8–10

11–1

3

14–1

7

18–2

0

21–3

5

>35C/C C/T T/T

IL13-1055C/T

Fig. 2. (A) Infection intensities according to interleukin (IL)13-1055genotypes. Genotypes at the IL13-1055 locus were determined in 462subjects. Infection intensities are represented as the number of eggsexcreted per 20 ml of urine (arithmetic mean of seven determinations).(B) Infection intensities according to IL13-1055 genotypes and ageclasses. Multivariate analysis of the association between IL13-1055genotypes and infection levels in the presence of age, gender, and villageof origin has confirmed that IL13-1055T/T protects against infectionacross all age classes, genders, and villages (Kouriba et al., manuscript inpreparation).



age prevents advanced PPF, even in subjects who were highly

exposed as children. However, disease in children with

S. hematobium infections is correlated with egg excretion in

urine (bladder disease) and circulating worm antigens (kidney

disease).

Anti-disease immunity in subjects with chronic S. mansoni

infections is associated with high interferon (IFN)-gproduction

Eggs trapped in host tissues secrete a number of substances

including proteolytic enzymes that are toxic for the surround-

ing cells. Damaged endothelial cells release inflammatory sub-

stances, as do activated platelets. These mediators initiate an

inflammatory reaction that involves the infiltration of eosino-

phils (64), macrophages, T-lymphocytes, and B-lymphocytes.

This periovular reaction, which persists for several weeks due

to the resistance of the eggshell to immune attack, is referred

to as a granuloma (65, 66). During early stages, the granuloma

is inflammatory necrotic. It then becomes a fibrotic granu-

loma. These changes are regulated by a variety of cytokines

and lipid-derived mediators (67, 68) produced by hepato-

cytes, endothelial cells, or Kupffer cells and by inflammatory

cells like eosinophils, monocytes/macrophages, T-lympho-

cytes, and tissue mast cells (69–72). In acute infections,

the granuloma is downregulated 8 weeks after the beginning

of oviposition, probably by the anti-inflammatory cytokine

IL-10 (73–75). In experimental models, the cytokine profile

of the periovular cellular reaction is Th1-like in the early stages

and Th2-like in the late stage. At least two important regula-

tory events affect the granuloma: one regulates the progression

from the inflammatory stage to the fibrotic stage and the other

occurs when the initially acute infection becomes chronic.

Alterations in either one or both of these regulatory mechan-

isms can cause the abnormal accumulation of ECMPs into a

dense and cross-linked network in tissues. The deposition

of ECMPs at the site of inflammation, like the granuloma, is

a normal part of the scarring process that aims to repair tissues

damaged by the toxic products released by inflammatory cells.

ECMPs are normally turned over and replaced by healthy

dividing cells. Fibrosis is the result of the abnormal accumula-

tion of ECMPs in tissues. ECMPs (e.g. laminin, collagen, and

connectin) are produced by stellate cell (Ito-cells)-derived

myofibroblasts. Stellate cells are activated by substances

like PDGF, released by damaged hepatocytes, endothelial

cells, and activated platelets. Myofibroblasts are regulated by

Family 1Age > 70W.C. = 2

Age 35–50W.C. ≥ 4

Age > 20W.C. variable

Age 35–50W.C. ≥ 4

Age > 20W.C. variable

Age > 70W.C. = 2

Family 2

Fig. 3. Distribution of severe schistosomiasis cases in two families of

fishermen from the Dongting Lake, Hunan, China. Patients’ ages areindicated on the right. All subjects were born and lived on boats. Adults>35 years of age had come into frequent contact with the water in the lakeduring their whole life. Subjects <25 years of age were born on boats butlived on shore for 10–15 years for their studies. Closed symbols representsubjects with severe periportal fibrosis (PPF) and parenchymal fibrosis(PaF). These subjects have already bled from esophageal varicose veins orwere at high risk of bleeding. Half-closed symbols represent subjects with

advanced disease characterized by advanced but not severe PPF andpossibly with a milder stage of PaF. Open symbols represent subjects withno or very mild PPF and no PaF. Note that five of the 13 subjects aged over35 years had severe disease, whereas the frequency of severe disease in thewhole fishermen population is around 15%. Note also the correlationbetween the clinical phenotype of parents and offspring and betweensiblings and the striking lack of correlation between those of the twoparents. This association suggests that the risk factors that increase diseasesusceptibility are not environmental. W.C., water contacts.



cytokines such as IFN-g, which inhibits their multiplication

and the production of ECMPs (76–79). Conversely, IL-13,

transforming growth factor (TGF)-b, and IL-4 stimulate

fibroblast division and ECMP production (80–82). Tissue

fibrosis results from the excessive production of ECMP and

the insufficient turnover of the fibrotic tissue, which depends

on the action of metalloprotease (MP)/metalloproteases

inhibitors (MPI), the synthesis and activities of which are

also regulated by the above-mentioned cytokines, i.e. IFN-gstimulates the production of MP and inhibits the synthesis of

MPI (83).

To determine which cytokines are involved in fibrosis in

S. mansoni-infected subjects, we conducted an immunological

study in a Sudanese village that is surrounded by a dense

network of water canals that are populated by Biophalaria

glabrata snails, a vector of S. mansoni. This parasite is endemic

in the whole province of Gezira. No mass treatments have

been carried out for 30–40 years, and the prevalence of

infection was over 70% in the village (17). To evaluate

PPF, abdominal ultrasonography was performed on the

whole population (750 subjects). PPF was observed in a

large number of subjects. Evidence of severe disease

(PPFþPH) (grade III fibrosis) was recorded in 2.5% of

the study population, and advanced fibrosis (grade II fibro-

sis) was observed in 12% of adults. Twenty-eight percent

showed no signs of PPF, and 59% had either mild fibrosis

or focal periportal inflammation (grade I disease).

Advanced PPF was only observed in adults, whereas grade

I disease was observed in subjects of all ages and in a large

number of children (17). This finding indicates that

disease is not the result of a linear cumulative process

and that some critical factors are probably responsible

for the progression of disease to the severe clinical stages.

We evaluated cytokine production by the blood mono-

nuclear cells of these subjects. The study included all cyto-

kines involved in ECMP synthesis and degradation, except

TGF-b. Univariate analysis showed that IFN-g and IL-1b are

associated with severe fibrosis. Multivariate analysis of the

cytokine data, including epidemiological covariates such as

age, gender, and infection levels, indicated that IFN-g was

the only cytokine that is strongly associated with PPF (84):

the risk of severe PPF was about 10-fold higher in the low

IFN-g-producer group than in the high IFN-g-producer

group (Fig. 4) (median IFN-g levels were used to define

low and high producers). Furthermore, when the effects of

IFN-g were accounted for, tumor necrosis factor (TNF)-awas shown to be associated with increased susceptibility to

PPF (84).

PPF is controlled by a major locus that maps near

IFNGR1

Severe PPF was more prevalent in certain families. Further-

more, the risk of PPF was higher in children born to parents

with the disease, even though the clinical phenotypes of the

parents varied independently of each other (17). These obser-

vations suggested that PPF is under strong genetic control.

Segregation analysis provided evidence for a major codom-

inant gene controlling PPF (85). The frequency of the deleteri-

ous allele A was estimated to be 0.16. Consequently, the

proportions of AA, Aa, and aa subjects were 0.03, 0.27, and

0.70, respectively. The penetrance of the three genotypes is a

function of duration of exposure. For AA males, penetrance is

almost complete after 12 years, and for AA females, penetrance

is almost complete after 17 years. For Aa males, penetrance is

0.73 after 20 years of exposure. For aa males, penetrance

reaches 0.02 after 20 years of exposure and is lower than

0.01 beforehand; for Aa and aa females, penetrance remains

lower than 0.001 after 20 years of exposure.

To map the gene responsible for developing sever hepatic

fibrosis, called SM2, linkage analysis was conducted in four

candidate regions: (i) the 5q31-q33 region, where SM1 and

several candidate genes are located (see above); (ii) the human

leukocyte antigen (HLA)-TNF region (6p21), containing the

HLA locus and the TNF-a and TNF-b genes; (iii) the 12q15

region, including the IFN-g gene and a gene controlling total

Age (années)

>3516–356–15

70

60

50

40

30

20

10

0

low

high

Subj

ects

with

adv

ance

d fi

bros

is (

%)

IFN- γ

Fig. 4. Proportion of grade II or III fibrosis in high and lowinterferon (IFN)-g classes in the different age groups. The levels ofcytokine produced by soluble egg antigen-stimulated peripheral bloodmononuclear cells of FII-III subjects (24) and F0-I subjects (75) weredetermined by enzyme-linked immunosorbent assay. The association ofperiportal fibrosis with low interferon (IFN)-g production is illustratedon this figure, which shows the percentage of subjects with FII-III in highand low IFN-g classes in age groups. Median INF-g levels were used todefine low and high producers. Age groups have been defined as tocorrespond to the three principal periods of disease progression.



serum IgE levels; and (iv) the 6q22-q23 region, containing the

IFN-g receptor 1 (IFNGR1) gene. No significant linkage was

observed with any markers in regions 5q31-q33, 6p21, and

12q15. In contrast, significant linkage was observed with

markers of the 6q22-q23 region, including a marker in

IFNGR1 that encodes the g chain of the IFN-g receptor (85).

This result shows that the major locus controlling fibrosis is

not linked to chromosome 5q31-33. Thus, anti-disease immun-

ity and anti-infection immunity are controlled by distinct

major genes (86). Obviously this finding does not rule out

an interaction between SM1 and SM2. It is reasonable to pos-

tulate that disease development is accelerated in SM2 subjects

predisposed to high infections. Our analysis also indicated that

the major locus SM2 is very unlikely to be located within the

HLA-TNF region, whereas associations have been reported

between some HLA class I alleles (A1 and B5) and hepato-

splenomegaly in Egypt (87–91) and an HLA class II allele

(DQB1*0201) and biopsy-confirmed hepatic schistosomiasis

in Brazil (92). However, we cannot rule out the possibility that

additional polymorphisms, such as HLA polymorphisms, play

a role in PPF.

Given the results of multipoint linkage analysis, which

mapped the susceptibility locus close to the IFNGR1 gene,

polymorphism(s) in the IFN-g receptor gene may account for

increased susceptibility to severe fibrosis. This hypothesis is

consistent with various reports showing the strong anti-fibro-

genic activity of IFN-g and with the results of immunological

studies carried out on the same population that found an

association between PPF and reduced production of IFN-g (84).

Given that this study indicated that allelic variants of IFNGR1

might account for differences in susceptibility to PPF, we

analyzed polymorphisms in that gene and in the gene encod-

ing IFN-g in the original Sudanese population and in a case/

control cohort recruited in the same region. This study identi-

fied new variants of IFN-g gene (93, 94). Association studies

indicated that two polymorphisms were associated with severe

fibrosis (95)(Table 1). These alleles more frequent in subjects with

severe fibrosis are associated with reduced gene transcription.

Conclusion

The findings that IL-13 and IFN-g both play critical roles

in protective immunity against schistosomes raises several

questions: (i) why does IL-13 play such a unique role, given that

IL-4 and IL-13 share many biological activities; (ii) how do IL-13

and IFN-g synergize in protective immunity against schisto-

somes, given that Th2 and Th1 responses mutually inhibit each

other; and (iii) does this model make biological sense?

Why does IL-13 play such a unique role in protection, given that

IL-4 and IL-13 are thought to share many biological activities?

IL-13 and IL-4 share several biological activities such as

regulating IgE synthesis (52). However, a detailed analysis

revealed important differences in the biological activities of

these two cytokines. We discuss here the activities of IL-13 that

could be most relevant to protective immunity to schisto-

somes. First, IL-13 is the principal cytokine involved in the

recruitment of eosinophils in tissues. This involvement was

clearly demonstrated in lungs, but these observations are

probably applicable to other tissues such as the skin. This effect

results from the action of IL-13 on VCAM-1 receptors on

endothelial cells (59), on CD69 receptors on eosinophils

(61), and on the production of GM-CSF by epithelial cells

(62). These activities promote the recruitment and survival

of eosinophils in tissues. Second, IL-13 is required for Th2

Table 1. Association of severe fibrosis with interferon (IFN)-g polymorphisms

Clinical groups

Polymorphisms Genotypes F0, FI, and FII subjects FIII subjects P value

IFN-gþ2109 A/A 60/76*(78.9y) 17/29 (58.6) 0.035A/G or G/G 16/76 (21.1) 12/29 (41.4)

IFN-gþ3810 G/G 60/73 (82.2) 25/25 (100) 0.035G/A or A/A 13/73 (17.8) 0/25 (0)

The entire IFN-g gene was thoroughly examined for polymorphisms by single strand conformational polymorphism and by the digestion of polymerasechain reaction product with restriction enzymes. This identified five single nucleotide polymorphisms. One hundred and five unrelated subjects werestudied: 76 individuals who exhibited no (F0) or mild (FI) or advanced (FII) fibrosis and 29 individuals characterized by severe (FIII) fibrosis. The tablesummarizes the genotype distributions of the two polymorphisms in the F0-I-II and FIII clinical groups. Significant associations (Fisher’s exact test) weredetected between FIII fibrosis and IFN-gþ 2109 A (P¼ 0.035) and IFN-gþ 3810 G (P¼ 0.035). The frequency of the IFN-gþ 2109A/A genotype washigher (78.9 vs. 58.6) in the F0-I-II group than in subjects with severe fibrosis (FIII). The IFN-gþ 2109 G allele was associated with a higher risk of PPF[Odds Ratio¼ 2.6; 95 confidence interval: 0.15–0.95]. Thus, subjects carrying the IFN-gþ 2109A/G genotype have a 2.6-fold higher risk of severe fibrosisthan subjects with the IFN-gþ 2109 G/G genotype. The frequency of the IFN-gþ 3810 G/G genotype was lower (82.2 vs. 100) in the F0-I-II clinicalgroup than in subjects with severe fibrosis (FIII). The IFN-gþ 3810 A allele was associated with a reduced risk of periportal fibrosis.*Number of subjects with the indicated genotype/number of subjects genotyped.yPercentage of subjects with the indicated genotype.



priming by soluble antigens in the skin. IL-13–/– mice, unlike

IL-4–/– animals, fail to mount a Th2 response upon skin

immunization with soluble antigens (96). In contrast,

intraperitoneal immunization induces a strong Th2 response

in IL-13–/– mice. Schistosome larvae enter their mammalian

hosts through the skin and remain in the epidermis and dermis

for 24–48 h before migrating in the vascular system. There-

fore, Th2 immunization against early schistosomula-specific

antigens occurs in the skin, as migrating larvae lose most of

these early antigens when they enter the blood stream.

How do IL-13 and IFN-g synergize in protective immunity

against schistosomes, given that Th2 and Th1 responses

mutually inhibit each other?

Although IFN-g can inhibit Th2 differentiation, a strong Th1

response does not always downregulate an ongoing Th2

response in vivo (97). Furthermore, mixed (Th2 and Th1)

T-cell responses have been frequently described in the lungs of

subjects with asthma and in the mouse model of eosinophilic

airway inflammation (98, 99). Such mixed T-cell responses are

close to what is observed in subjects resistant and susceptible to

schistosomiasis. In mouse models of airway inflammation,

IFN-g was shown to inhibit some and potentiate other IL-13

activities (100). However, in the situation of a strong polarized

T-cell response, as obtained with the injection of IL-12, IFN-g-

dependent suppression of Th2 responses was observed (101,

102). Conversely, a strong Th2 response may bias T-cell differ-

entiation toward Th2 by a mechanism known as ‘collateral

priming’ (103). IL-4 is thought to play a key role in this

mechanism. Unlike IL-4, IL-13 is not active on mature lympho-

cytes and is unable to inhibit an established Th1 response; it may

delay, however, the development of such a response by acting

on naıve T cells and by inhibiting IL-12 production. The T-cell

response in schistosome-infected subjects is not fully polarized.

Hence, the view that IFN-g and IL-13 are mutually exclusive in

human schistosomiasis is probably too simplistic; in addition,

the compartmentalization of the immune response between the

skin and the liver allows for a specialization of the immune

response.

Does it make biological sense for IL-13 and IFN-g to have

central roles in protection?

A large number of animal and human studies have shown that

the targets of anti-infection immunity are young larvae, when

they are in the skin and possibly the lungs. When they leave

the skin, most larvae are already refractory to immune attacks.

Thus, the rapid mobilization of immune defenses in the skin is

critical. Th2-mediated immunity is well suited for a rapid and

massive reaction to invading larvae, as IgE-sensitized mast cells

are positioned in the dermis and epidermis at the site of entry

of the parasite, and as eosinophils, which are very efficient

larval killers, can be recruited in the skin extremely rapidly.

We have seen that IL-13 has a unique role in the skin: priming

a Th2 response to larval antigens, recruiting eosinophils in the

skin, prolonging eosinophil survival, and increasing eosino-

phil receptors for ADCC. IL-13 also enhances tissue repair

activities that normally occur after parasite destruction; it

also stimulates angiogenesis in scar tissues (104). This activity

further contributes to host protection against infection and its

damaging effects. However, the profibrogenic activity of IL-13

may contribute to liver fibrosis in subjects with PPF, as is the

case in S. mansoni-infected mice (74, 105, 106) or in asthma

(107). These studies clearly indicate that IL-13, but not IL-4,

enhances collagen deposition in the granuloma. Studies in

other models of fibrosis have also demonstrated the profibro-

genic effect of this cytokine. Excess production of IL-13 may

contribute to hepatic fibrosis in human infected by schisto-

somes. As IL-13 is critical in the control of invading larvae,

mutations or down-regulating mechanisms that reduce IL-13

production would increase susceptibility to infection and in

turn increase the number of eggs in the liver. In this biological

context, IFN-g appears to be the logical and best-suited

response to excessive ECMP deposition. IFN-g is the most

potent anti-fibrogenic cytokine produced in the granuloma

and is not linked with Th2 cytokines. The IL-13- and IFN-g-

dependent protective immune response probably takes advan-

tage of the compartmentalization of the immune response

between the skin and the liver and of the different properties

of larval and egg antigens. These aspects, however, have not

yet been investigated in detail.

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