Tropical Medicine and International Health doi:10.1111/tmi.

13639

volume 26 no 9 pp 1098–1109 september 2021

Schistosoma mansoni infection is associated with decreased risk

of respiratory allergy symptoms and low production of CCL2
Cassia Giselle de Oliveira N
obrega1, Wheverton Ricardo Correia do Nascimento2,3,
Patr
ıcia d’Emery Alves Santos1, Virg
ınia Maria Barros de Lorena3, D

ecio Medeiros4,
audia Maria Assis Costa , Constancßa Clara Gayoso Sim~
Vl
1,2
oes Barbosa3, Dirceu Sol

e5,
4 1,6
Emanuel S
avio Cavalcanti Sarinho and Vald^ enia Maria Oliveira deSouza
1 Setor de Imunologia, Laborat
orio de Imunopatologia Keizo Asami, Universidade Federal de Pernambuco, Recife, Brasil
2 Departamento de Medicina Tropical, Universidade Federal de Pernambuco, Recife, Brasil
3 Instituto Aggeu Magalh~aes, Fundacß~ao Oswaldo Cruz, Recife, Brasil
4 Centro de Pesquisa em Alergia e Imunologia Cl
ınica, Hospital das Cl
ınicas, Universidade Federal de Pernambuco, Recife, Brasil
5 Divis~ao de Alergia, Imunologia Cl
ınica e Reumatologia, Departamento de Pediatria da Universidade Federal de S~ao Paulo, S~ao
Paulo, Brasil
6 Departamento de Ci^encias Farmac^euticas, Universidade Federal de Pernambuco, Recife, Brasil

Abstract objectives We measured the production of cytokines, chemokines and antibodies involved in
allergic responses and sCD23 levels during Schistosoma mansoni infection.
methods Individuals (n = 164) were selected using the ISAAC questionnaire and parasitological
exams. The subjects were divided as follows: those infected individuals with allergy-related symptoms
(A-I), those with allergy-related symptoms only (A-NI); those only infected (NA-I); and those non-
infected individuals without allergy-related symptoms (NA-NI). We used supernatants from cell
culture (mitogenic stimulation) to measure cytokine and chemokine levels using cytometric bead
arrays. Serum levels of anti-Ascaris lumbricoides (Asc) and anti-Blomia tropicalis IgE were measured
using ImmunoCAP, and sCD23 was measured using ELISA.
results Schistosoma mansoni infection was associated with a lower risk of allergy-related
symptoms. In A-I, there were higher levels of TNF-a, IL-10, IL-6, IFN-c and CXCL8 than in NA-NI
group, with TNF-a and IL-6 also at higher levels compared to A-NI group. Levels of IL-6, CXCL8,
total and anti-Asc IgE, as well as the numbers of eosinophils, were higher in NA-I than in NA-NI,
and the antibodies were also lower in A-NI than in NA-I group. In AI and NA-I, there was less
production of CCL2 than in NA-NI. There were no differences in the levels of IL-2, IL-4, IL-17,
CCL5, sCD23 and anti-Blomia IgE.
conclusions Patients with allergy-related symptoms and infected (simultaneously) had higher levels
of IL-10; due to the infection, there was increased production of IL-6 and CXCL8 and less CCL2.
These data may characterize deviation to Th1 or attenuation of the Th2 response in allergy sufferers
in areas endemic for schistosomiasis.

keywords CCL2, IL-10, immunomodulation, respiratory allergy, Schistosoma mansoni

Sustainable Development Goals: Good Health and Well-being.

skin tests [1, 2]. These findings suggest that infection by

Introduction
Helminth infection and allergies trigger Th2 immune
responses (IL-4, IL-5 and IL-13, with IgE production)
[1]. During Schistosoma mansoni infection, there is a
generation of Treg cells, production of IL-10 and TGF-b
related to the attenuation of the Th2 response, manifest-
ing as decreased production of IL-4 and IL-5, decreased
levels of anti-allergen IgE, and decreased positivity to
S. mansoni is associated with attenuation of the clinical
presentation in asthmatic patients, lower production of
IL-5 and IL-4, and higher IL-10 levels in response to
Dermatophagoides pteronyssinus [2, 3]. However, it is
necessary to determine whether membrane and cell acti-
vation molecules influence the dynamics of the immune
response by synthesizing and activating cytokines and
chemokines that influence the intensity of allergies,

1098 © 2021 John Wiley & Sons Ltd


Tropical Medicine and International Health
obrega et al. S. mansoni infection and respiratory allergy
C. G. de Oliveira N

in addition to IgE antibodies that cross-react with
allergens.
In Brazil, a high prevalence of anti-Ascaris lumbri-
coides (Asc) IgE has been demonstrated in patients with
respiratory allergies [4, 5]. Anti-Asc IgE is a risk factor
for allergic asthma and rhinitis symptoms, positive skin
tests for immediate hypersensitivity, increased levels of
total IgE, and eosinophils in peripheral blood [6–10].
Molecular mimicry and evidence of cross-reactions
between tropomyosin in A. lumbricoides and inverte-
brates such as mites have been reported [11, 12]. The
anti-tropomyosin IgE from Ascaris and Blomia tropicalis
was considered a risk factor for asthma [13]. For these
reasons, it is essential to assess the influence of these anti-
bodies (anti-Asc and anti-Blomia) on the association
between infection and allergy.
Soluble CD23 (sCD23), depending on its molecular
weight, is important because of its role in increasing
IgE synthesis by human B lymphocytes and clearing cir-
culating allergen-specific IgE as a decoy receptor [14,
15, 16]. Through the action of metalloproteases (pri-
marily ADAM10), membrane CD23 (mCD23) is cleaved
and soluble CD23 fragments (sCD23) are released [17,
18]. The fragments (trimers) of sCD23 can simultane-
ously bind to a membrane-bound IgE and CD21,
increasing the synthesis of this antibody. Meanwhile,
IgE binding to mCD23 prevents the cleavage and
release of soluble fragments of CD23 [15, 19] and can
prevent the increase in IgE via sCD23. In asthma,
higher levels of sCD23 have been described [20, 21]. In
S. mansoni infection, an increase in the frequency of
eosinophils and B cell expressing mCD23 has been
reported [22, 23]. Increased mCD23 expression in B
cells and high levels of sCD23 were shown to correlate
with eosinophilia and resistance to infection by S. man-
soni, but not with parasite-specific IgE [23]. Protease
from S. mansoni generated a sCD23 fragment of
15 kDa that acted as a decoy receptor by blocking IgE
from binding to mCD23 and FceRI, inhibiting allergic
responses in mice [16]. Although the increased sCD23
levels due to S. mansoni infection, as well as in asthma,
the relationship between sCD23 levels and allergy-
related symptoms in patients with schistosomiasis has
not yet been studied.
The chemokine CCL11, CCL5 and CCL2, participate
in the chemotaxis of eosinophils, basophils and mast cells
[24]. In children with asthma, there were increased serum
levels of CCL5 (Th2) and decreased CXCL9 (Th1) [25].
The airway epithelial cells of children with a history of
wheezing demonstrate reduced CCL5, CCL2 and IL-6
[26]. Recently, it was reported that, in the context of
infection with S. mansoni with or without allergic
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volume 26 no 9 pp 1098–1109 september 2021
reactivity (anti-allergen IgE in serum), there was no dif-
ference in the levels of the chemokines CCL3, CCL5,
CXCL10 or CCL11 [27, 28]; however, there was an
increase in plasma CXCL8 levels during acute S. man-
soni infection [29]. These studies showed no correlation
with allergy symptoms. In a previous study, we reported
for the first time an inverse association between S. man-
soni infection and CCL2 levels. There was less produc-
tion of CCL2 in individuals with schistosomiasis who
had a positive or negative skin test for allergy and higher
production of IL-10 in schistosomiasis with a negative
skin test without changes in the levels of CXCL8,
CXCL9, CXCL10 and CCL5 [30]. In light of these find-
ings, we investigated the association of chemokines with
respiratory allergy, along with sCD23 and possible con-
founding factors.
To better understand the effects mediated by S. man-
soni infection concerning the immune response to respira-
tory allergies, we investigated the influence of serum
levels of sCD23, cytokines (Th1, Th2, Th17, and IL-10),
chemokines (CCL2, CCL5 and CXCL8) and antibodies
known to be involved in the allergy-related responses (to-
tal, anti-Ascaris and anti-Blomia IgE).
Materials and methods
Selection of patients and formation of study groups
We enrolled individuals aged 5–60 years living in the
municipalities of Ilha de Itamarac
a, Cabo de Santo Agos-
tinho and Vit
oria de Santo Ant~ ao (Metropolitan Region
of Recife, Pernambuco, Brazil). Participants received
information about the study, and the participant or
responsible guardian provided informed consent. Pernam-
buco exhibited high rates of positivity for S. mansoni
[31]. According to data from the state health department
(2013), prevalence rates were 16.4% and 25.4% in the
endemic municipalities of Vit
oria de Santo Ant~
ao and
Cabo de Santo Agostinho, respectively [32]. Participants
were administered the ‘International Study of Asthma
and Allergies in Childhood’ questionnaire (ISAAC), vali-
dated in Brazil to identify asthmatic adults and those
with allergic rhinitis up to 65 years of age [33, 34]. On
subsequent days, stool samples were collected (three sam-
ples) for parasitological testing using the Kato–Katz
method (for each stool sample, two slides were analysed
by two independent technicians). According to ISAAC,
individuals who answered ‘yes’ to the second question of
the asthma module (presence of wheezing in the last year)
[35, 36] and/or answered ‘yes’ to the second question of
the rhinitis module (sneezing or runny nose, when they
did not have a cold or flu in the previous year) [34, 37]
1099

Tropical Medicine and International Health
obrega et al. S. mansoni infection and respiratory allergy
C. G. de Oliveira N

were considered to have allergy-related symptoms
(asthma and/or rhinitis, respectively). After administering
the ISAAC questionnaire and performing the parasitologi-
cal exam, four study groups were formed: those with
allergy-related symptoms who were infected with S. man-
soni (A-I); those with allergy-related symptoms who were
non-infected (A-NI); infected individuals without allergy-
related symptoms and infected (NA-I); and non-infected
individuals without allergy-related symptoms (NA-NI).
Uninfected individuals had negative stool parasitology.
Those positive for any other helminth or protozoan were
excluded, whether or not they were infected with S. man-
soni. The Research Ethics Committee of the Aggeu
Magalh~aes Institute/Oswaldo Cruz Foundation (IAM/Fio-
cruz) approved the study: CAAE,
22822813.3.0000.5190.
Cell culture and determination cytokine and chemokine
levels
Blood collection was performed at a family health unit
after administering ISAAC and parasitological examina-
tions. After collection, blood samples were automatically
analysed (Sysmex XS-1000i, Chuo-ku, Japan) to obtain
the absolute values of leukocyte counts. Cultures of
peripheral blood were performed in RPMI 1640 medium
(Sigma-Aldrich, St. Louis, USA) with foetal bovine serum.
Cells were stimulated with phytohemagglutinin (PHA,
10 µg/ml) (24 h, 37 °C, 5% CO2) as a mitogen. Culture
supernatants were collected and frozen at 80 °C until
the measurement of cytokines and chemokines.
Cytokines and chemokines were quantified from cul-
ture supernatants using the BD Cytometric Bead Array
Human Th1/Th2/Th17 Cytokine Kit and BD Cytomet-
ric Bead Array Human Chemokine Kit, according to
the manufacturer’s instructions (BD Pharmingen, San
Diego, USA). The results were expressed with the fol-
lowing detection thresholds (in pg/mL): IL-2 = 2.6; IL-
4 = 4.9; IL-6 = 2.4; IL-10 = 4.5; TNF-a = 3.8; IFN-
c = 3.7; IL-17 = 18.9; CXCL8 = 0.2; CCL5 = 1.0; and
CCL2 = 2.7.
Serum levels
Serum samples were used to measure levels of sCD23,
total IgE, IgE anti-Asc and IgE anti-Blomia. SCD23 was
measured by ELISA, using a specific kit (KAS0251),
according to the manufacturer’s instructions (Biosource,
San Diego, EUA), while antibody levels were measured
using a fluorescent immunoassay (ImmunoCAP—Phadia
AB, Uppsala, Sweden), according to the manufacturer’s
instructions. For specific antibodies (anti-Blomia and
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volume 26 no 9 pp 1098–1109 september 2021
anti-Asc IgE), results from ≥0.35 kU/l were categorized
as positive.
Statistical analysis
To measure associations between S. mansoni infection
and biological and social variables, with the presence of
symptoms related to respiratory allergy, we used odds
ratio (OR) and P-values using Wald’s test. Allergy-related
symptoms were considered a dependent variable, and
infection was an independent variable. The other vari-
ables (gender, age, family history of allergy, family
income, maternal education, active and passive smoking,
total IgE, anti-Asc and anti-Blomia) were tested as possi-
ble confounding factors, and those with P < 0.2 in uni-
variate analysis were entered into a logistic regression
model for adjustment [38]. The frequencies of asthma
and/or rhinitis symptoms in infected and uninfected peo-
ple were compared using the chi-square test. Analyses
were performed using RStudio 3.2.2 software.
Levels of cytokines and chemokines, absolute values of
peripheral blood cells (leukogram), and median age in the
A-I, A-NI, NA-I and NA-NI groups were compared using
the Kruskal–Wallis test and Dunn’s multiple comparison
test. The Mann–Whitney U test was used for single com-
parisons, as was the case with parasitic burden among
individuals with or without allergic symptoms. The anal-
yses were performed using GraphPad Prism, version 5.03.
In all analyses, P-values < 0.05 were considered signifi-
cant.
Results
The parasitological survey included 3816 individuals who
were 5–80 years of age. Of these, 2123 underwent para-
sitological examinations, and 1952 were excluded
because they were infected with geohelminths/protozoa,
presented with infectious or chronic diseases such as dia-
betes, hypertension, tuberculosis, tuberculosis, AIDS, or
leishmaniasis, or recently had been treated (less than
6 months) for these diseases, or there were losses of indi-
viduals (change of residence or refusal to participate in
the study) (Figure 1).
A total of 164 individuals, 5–60 years of age, were
selected to answer the ISAAC and provide blood samples
to measure cytokines. Of these, 45 (27.4%) reported
allergy-related symptoms, and 119 (72.6%) did not.
Among allergy sufferers, 18 (40%) individuals were
infected with S. mansoni (A-I), and 27 (60%) were unin-
fected (A-NI). Of those who had no allergy symptoms,
84 (70.6%) were infected (NA-I), and 35 (29.4%) were
not (NA-NI) (Figure 1). Regarding the frequency of
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Tropical Medicine and International Health volume 26 no 9 pp 1098–1109 september 2021

obrega et al. S. mansoni infection and respiratory allergy

C. G. de Oliveira N

3816 individuals included in the parasitological survey

2123 underwent parasitological examinations

1952 excluded

164 selected to answer the ISAAC and

collect blood samples

45 with allergy 119 no allergy

symptoms symptoms

18 infected 18 infected
27 non-infected 35 non-infected
(A-I) (NA-I)
(A-NI) (NA-NI)
Median: 48 epg Median: 24 epg

Asthma: 7 Asthma: 4
Rhinitis: 7 Rhinitis: 10
Asthma and Rhinitis: 4 Asthma and Rhinitis: 13

Figure 1 Flowchart for the selection of infected individuals with allergy-related symptoms.

asthma or rhinitis symptoms among allergy sufferers, in
the infected group, seven had isolated asthma, seven had
rhinitis, and four had both; in the non-infected group,
there were four, ten and 13, respectively. The median
parasitic load was 24 eggs per gram of faeces (epg) (P25–
P75: 24–48 epg). In allergic and non-allergic patients, the
medians were 48 (24–72 epg) and 24 (24–48 epg),
respectively. There was no significant difference in the
frequency of asthma, rhinitis or parasitic load between
the groups.
The median age in the study population was 30.5 years
(P25-P75: 16–45). In the groups, the medians were as fol-
lows: A-I = 29.5 (19.75–41.0); A-NI = 20.0 (10.25–
44.75); NA-I = 28.0 (18.75–46.25) and NA-
NI = 39.0 years (14.0–51.0). There was no statistical dif-
ference among the groups. Regarding gender, the fre-
quencies of male and females were as follows: A-I = 8
(44.4%) vs 10 (55.6%); A-NI: 13 (48.1%) vs 14
(51.9%); NA-I: 43 (51.2%) vs 41 (48.8%); NA-NI: 12
(34.3%) vs 23 (65.7%). The chi-square test revealed no
difference in frequency among groups (P = 0.407).
Univariate and multivariate logistic regression analyses
were performed to investigate the interaction between
allergy-related symptoms and infection, excluding possi-
ble confounding variables (Table 1). In the univariate
analysis, the mother’s history of allergy was a risk factor
for allergy-related symptoms (OR = 4.16, CI
95% = 1.66–10.46; P < 0.002). Conversely, infection by
S. mansoni was negatively associated with allergy symp-
toms (OR = 0.28, CI 95% = 0.14–0.57; P < 0.001). In
multivariate logistic regression, when adjusted for anti-
Blomia IgE and age (variables with P < 0.2), only
S. mansoni infection (adjusted OR = 0.42, 95%
CI = 0.18–0.97; P = 0.042) remained negatively associ-
ated with allergy symptoms, and mother’s allergy history
was no longer significantly associated.
Levels of cytokines TNF-a, IL-6, IL-2, IFN-c, IL-4, IL-
10 and IL-17A (Figure 2 and Table 2) and the chemoki-
nes CXCL8, CCL2, and CCL5 (Figure 3 and Table 2)
were measured from peripheral blood. In the AI group,
there were significantly higher levels of TNF-a (Fig-
ure 2a), IL-10 (Figure 2b), IL-6 (Figure 2c) and IFN-c
(Figure 2d) than in the NA-NI group, with TNF-a and
IL-6 also at higher levels compared to A-NI group.
Group NA-I had higher levels of IL-6 than did group
NA-NI. Among groups, there were no significant differ-
ences in levels of IL-4 (Figure 2e), IL-2 (Figure 2f), or IL-
17A (Figure 2g).
As for chemokines, in the A-I and NA-I groups, levels
of CXCL8 (Figure 3a) were significantly higher, while
there was less production of CCL2 (Figure 3b) than in
the NA-NI. In the NA-I group, there were also higher

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obrega et al. S. mansoni infection and respiratory allergy

C. G. de Oliveira N

Table 1 Univariate and multivariate analysis of the association between respiratory allergy and biological, socioeconomic and environ-
mental variables

Univariate analysis Multivariate analysis‡

Allergic Non-allergic
45 (27.4%) 119 (72.6%) Crude OR (CI 95%) P Adjusted OR (CI 95%) P

Gender
Male 21 55 1.02 (0.51–2.03) 0.959
Female 24 64
Age
≤18 years 17 31 1.72 (0.77–3.85) 0.165 1.27 (0.51–3.16) 0.602
≥19 years 28 88
Mother’s family history of allergy
Yes 12 11 4.16 (1.66–10.46) 0.002** 2.27 (0.76–6.79) 0.144
No 27 103
S. mansoni infection
Yes 18 84 0.28 (0.14–0.57) <0.001*** 0.42 (0.18–0.97) 0.042*
No 27 35
Maternal education
Education I† 26 82 0.59 (0.27–1.29) 0.309
Education II† 13 25
Family income
≤1 minimum wage 21 61 0.95 (0.44–2.02) 0.887
>1 minimum wage 16 44
Active smoking
Yes 2 10 0.63 (0.13–3.03) 0.560
No 43 109
Passive smoking
Yes 18 47 1.2 (0.58–2.48) 0.620
No 22 69
Anti-Blomia IgE§
Yes 24 49 1.87 (0.91–3.86) 0.089 1.97 (0.88–4.41) 0.098
No 17 65
Anti-Asc IgE§
Yes 21 71 0.64 (0.31–1.31) 0.218
No 20 43

*P < 0.05.
**P < 0.01.
***P < 0.001. Bold values indicates P-values with statistical significance.
†Education I: Illiterate until complete primary education; Education II: Incomplete high-school until complete graduation.
‡The variables with P < 0.2 in univariate analysis were tested as possible confounding factors.
§Anti-Blomia and anti-Asc IgE results ≥0.35 kU/l were categorized as positive.

levels of CXCL8 and lower levels of CCL2 compared to
NA-NI. There were no significant differences in levels of
CCL5 among groups (Figure 3c).
Regarding antibody levels, total IgE (Figure 4a) and
anti-Asc IgE (Figure 4b) were significantly lower in the
A-NI group than in the NA-I and higher in NA-I than in
the N-NI group. There was no difference in the levels of
anti-Blomia IgE (Figure 4c) among the groups. Regarding
the leukogram, a more significant absolute number of
eosinophils (Figure 4d) was observed in the NA-I group
than in the NA-NI group (Table 2).
Levels of sCD23 (U/ml) between the groups were not
significantly different. The medians (P25–P75) were as
follows: A-I = 1.25 (0.97–1.46); NA-I = 1.25 (0.98–
1.40); A-NI = 1.26 (1.11–1.55); and NA-NI = 1.14
(0.96–1.45).
Discussion
Schistosoma mansoni modulates the host’s immune
response and induces protection against allergic diseases
[1, 39]. By contrast, anti-Asc IgE presence is associated
with asthma and rhinitis symptoms [6, 40]. The ability of
S. mansoni infection to decrease atopy and asthma symp-
toms is mediated by the negative regulation of the Th2
immune response that is mediated predominantly by

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obrega et al. S. mansoni infection and respiratory allergy

C. G. de Oliveira N

(a) ** (b)
*
4000
3500 2600 *
3000 2400
2000 2200
1800 2000

TNF-α (pg/mL)
1600 1800

IL-10 (pg/mL)
1400 1600
1200 1400
1000 1200
1000
800
800
600 600
400 400
200 200
0 0
A-I A-NI NA-I NA-NI A-I A-NI NA-I NA-NI

(c) (d) 800 *

***
750
* *** 700
650
18000 600
16000 550

IFN-γ (pg/mL)
14000 * 500
450
IL-6 (pg/mL)

12000 400
10000 350
8000 300
250
6000 200
4000 150
100
2000 50
0 0
A-I A-NI NA-I NA-NI A-I A-NI NA-I NA-NI

(e) (f) 40
35
40
35 30
IL-2 (pg/mL)

30 25
IL-4 (pg/mL)

25
20
20
15 15
10 10
5 5
0
A-I A-NI NA-I NA-NI 0
A-I A-NI NA-I NA-NI
(g) 200
120
110
100
IL-17 (pg/mL)

90
80
70
60
50
40
30
20
10
0
A-I A-NI NA-I NA-NI

Figure 2 Cytokine levels: TNF-a (a), IL-10 (b), IL-6 (c), IFN-c (d), IL-4 (e), IL-2 (f) and IL-17A (g) in the supernatant of peripheral
blood culture, stimulated with PHA (24 h), of those individuals infected with S. mansoni and with allergy-related symptoms (A–I),
those with allergy-related symptoms only (A-NI); those only infected (NA-I); and those non-infected individuals without allergy-related
symptoms (NA-NI). The results were expressed in pg/ml with the following detection thresholds: IL-2 = 2.6; IL-4 = 4.9; IL-6 = 2.4;
IL-10 = 4.5; TNF-a = 3.8; IFN-c = 3.7; IL-17 = 18.9. The medians were compared using the Kruskal–Wallis test and Dunn’s multiple
comparison test. *P < 0.05. **P < 0.01. ***P < 0.001.

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obrega et al. S. mansoni infection and respiratory allergy

C. G. de Oliveira N

Table 2 Numerical results of Figures 2–4, grouped according to the immune response profile

AI (n = 18) A-NI (n = 27) NA-I (n = 84) NA-NI (n = 35)

Median (P25–P75) Median (P25–P75) Median (P25–P75) Median (P25–P75)

Treg/Th2-related responses
IL-10a 54.28* (30.66–465.5) 27.92 (6.38–107.8) 27.88 (11.85–81.66) 25.86 (9.36–46.01)
Th2-related responses
IL-4a 0.0 (0.0–6.75) 0.0 (0.0–1.65) 0.0 (0.0–0.09) 0.0 (0.0–0.0)
CCL2b 8203.0* (1910–8998) 11 232.0 (2700–14437) 8529.0* (6918–9739) 15724.0 (7937–21128)
CCL5b 2174.0 (1578–2280) 2116.0 (1755–2396) 1877.0 (1662–2105) 2031.0 (1849–2266)
Total IgEc 300.0 (134.6–2946) 111.0*** (55.5–679.0) 865.0* (274.5–2403) 190.0 (47.7–1061)
Anti-Asc IgEc 0.74 (0.1–5.31) 0.30*** (0.02–0.67) 1.19* (0.19–4.21) 0.21 (0.03–1.768)
Anti-Blomia IgEc 0.66 (0.02–1.70) 0.52 (0.03–8.55) 0.27 (0.08–1.43) 0.24 (0.02–3.16)
Eosinophilsd 315.0 (208.5–565.5) 460.0 (128.0–776.0) 409.5* (223.8–617.8) 237.0 (118.0–408.5)
Th1-related responses
TNF-aa 40.55*,** (22.83 – 1413.0) 11.91 (0.0–84.45) 39.54 (8.18–163.6) 14.67 (4.94–39.75)
a
IL-6 6337.0*,** (4214–14087) 4037.0 (1314–8901) 5597.0* (3073–12207) 2649.0 (1607–5103)
IFN-ca 72.31* (10.75–113.7) 11.35 (1.99–38.38) 17.51 (2.375–50.83) 8.46 (0.0–22.66)
IL-2a 0.35 (0.0–4.96) 0.0 (0.0–3.70) 0.0 (0.0–3.56) 0.0 (0.0–1.85)
CXCL8b 13250.0* (9971 – 15346) 10564.0 (6952–13287) 12519.0* (10344–14093) 9889.0 (8301–12467)
Th17-related responses
IL-17a 0.0 (0.0–0.0) 0.0 (0.0–0.0) 0.0 (0.0–0.0) 0.0 (0.0–0.0)

a—Cytokines and b—chemokines (pg/mL) measured in the peripheral blood culture supernatant under phytohemagglutinin stimulation
by cytometric bead array; c—antibodies (KUI/l) and d—eosinophils (Cells/mm3) measured in plasma.
*P < 0.05 compared to NA-NI group.
**P < 0.05 compared to A-NI group.
***P < 0.05 compared to NA-I group.

IL-10 [2]. Corroborating these findings, in this study, we
observed a lower frequency of asthma/rhinitis symptoms
in infected individuals, even in the presence of anti-Asc
IgE. It is important to note that the confounding factors
commonly associated with allergy did not alter our
results after adjustment using multivariate analysis. For
example, the mother’s family history of allergy is an
essential risk factor [41]; however, was no longer a risk
factor in our study. Nevertheless, variables such as occu-
pational exposures and pets at home were not evaluated.
Among soluble molecules that can affect the outcome
of asthma, in S. mansoni-infected individuals, is sCD23
that simultaneously binds to membrane IgE and CD21,
increasing the synthesis of this antibody, but can also
clearing allergen-specific circulating IgE as a decoy recep-
tor [16, 19]. In our study, low levels of sCD23 were
detected among the groups. It is possible that mild-to-
moderate allergy symptoms and infection with low loads
of S. mansoni [42] do not favour the detection of sCD23.
Indeed, a study reported higher levels of sCD23 in
asthma patients who sought hospital care suffering
asthma attacks, bronchiolitis or bronchial pneumonia
[21]. In S. haematobium infection, sCD23 levels
increased significantly with the intensity of the infection
[43]. Regarding S. mansoni infection, Mwinzi et al
(2009) related high levels of sCD23 in infected patients,
but the parasitic burden has not been established [23].
We are aware that molecular biology techniques or
immunoassays have replaced parasitological stool exami-
nations. Nevertheless, we believe this limitation was min-
imized by collecting three samples and the analysis of
two slides for each sample by two independent techni-
cians [44].
In this study, we evaluated the stimulation of blood
cultures under polyclonal activation (mitogen) to know
the broader and background cellular immune response
(cytokine and chemokines production) of the individuals
from endemic areas. In this way, our results suggest that
individuals only when allergic and infected showed a
mixed immune response profile with higher levels of
TNF-a, IL-6, IFN-c (Th1 response), and IL-10 (Th2/Treg
cytokine).
Regarding the participation of the infection, under sim-
ilar conditions of mitogenic stimulus, Ondigo et al.
(2018) related that peripheral blood mononuclear cells of
S. mansoni-infected individuals from endemic areas, after
Treg cell depletion (CD4+, CD25hi, CD127low), pro-
duced higher levels of IFN-c, compared to cell cultures
without depletion [45]. Here, we also observed IFN-c in
peripheral blood of A-I patients, without increase in IL-

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obrega et al. S. mansoni infection and respiratory allergy

C. G. de Oliveira N

(a) * 4, IL-2 and IL-17 and low loads of infection common in

* an endemic area secondary to reinfection [46]. In the pre-
20000 sent study, this phenomenon cannot be directly attributed
18000
to S. mansoni or allergens despite the immune response
16000
profile. However, the broad stimulus of the mitogen may
CXCL8 (pg/mL)

14000
12000
recover the cellular memory immune response generated
10000 during the larval (acute) and egg (chronic) deposition
8000 phases. The production of type 1 cytokines, TNF-a, IL-6,
6000 IFN-c, with or without IL-10, by whole blood or
4000 mononuclear cells, has been reported in loads parasites
2000 above 100 epg faeces, present in the acute phase [27, 46–
0
48], whereas, the IL-10 is marker of the Th2/Treg profile
A-I A-NI NA-I NA-NI
induced by soluble antigens of S. mansoni eggs [49, 50].
**
In addition to IL-10, infection by S. mansoni induces reg-
(b)
ulatory factors such as Tregs cells, TGF-b and CTLA-4 in
***
30000 the modulation of the inflammatory response in allergy
28000 [2, 51].
26000
24000 Concerning respiratory allergies, the Th1 profile with
22000 the participation of the pro-inflammatory cytokine profile
20000
CCL2 (pg/mL)

18000
(IFN-c, TNF-a and IL-6) involved in the immunopathol-
16000 ogy of severe allergic asthma has been reported [52-54].
14000 However, the individuals with allergy-related symptoms
12000
10000 in our study demonstrated mild-to-moderate symptoms
8000 (according to symptoms reported in ISAAC—data not
6000 shown) and without high levels of total and anti-blomia
4000
2000 IgE. This may be associated with higher production of
0 intrinsic IL-10 in these individuals [55] and the presence
A-I A-NI NA-I NA-NI of IL-10 may reflect control of the exacerbation of the
(c) immune response because the infection and the allergy
4000
3750 increased IL-10 levels concerning the absence of allergy
3500 and infection.
3250
3000 Chemokines participate in developing and maintaining
2750 allergic inflammation by modulating recruitment and
CCL5 (pg/mL)

2500
2250 coordinating cell activation through their receptors [56–
2000 58]. Respiratory allergy and Schistosoma infections mod-
1750
1500 ulate the production of chemokines [59]. Schistosomal
1250 individuals who had no respiratory allergy symptoms in
1000
750 this study had a characteristic Th2 profile (eosinophils
500 and total IgE) but with low levels of CCL2. Those with
250
0 allergy-related symptoms only, although there was no
A-I A-NI NA-I NA-NI increase in the studied Th2 parameters, had a decrease in
pro-inflammatory cytokines (IL-6 and TNF), but without
Figure 3 Chemokines levels: CXCL8 (a), CCL2 (b), CXCL5 (c) changes in chemokines.
in the supernatant of peripheral blood culture, stimulated with Studies that evaluated only the infection, or infection
PHA (24 h), of those individuals infected with S. mansoni and associated with allergy, did not show any difference in
with allergy-related symptoms (A-I), those with allergy-related terms of levels of CCL5 [27, 28]. In a previous study, we
symptoms only (A-NI); those only infected (NA-I); and those demonstrated that in infected individuals and with posi-
non-infected individuals without allergy-related symptoms (NA- tive or negative skin allergy tests, there was no alteration
NI). The results were expressed in pg/ml with the following
in CCL5 and CXCL8, but the infection was compro-
detection thresholds: CXCL8 = 0.2; CCL5 = 1.0; and
CCL2 = 2.7. The medians were compared using the Kruskal–
mised with the reduction of CCL2 levels [30]. In the cur-
Wallis test and Dunn’s multiple comparison test. *P < 0.05. rent study, in which we included twice as many infected
**P < 0.01. ***P < 0.001. patients, we corroborated the finding of CCL5 (without

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obrega et al. S. mansoni infection and respiratory allergy

C. G. de Oliveira N

(b) **
45
**
(a)
40
**
6000 35

Anti-Asc IgE (KUI/L)

5500
5000 30
Total IgE (KUI/mL)

4500
25
4000
3500 20
3000
2500 15
2000
10
1500
1000 5
500
0 0
A-I A-NI NA-I NA-NI A-I A-NI NA-I NA-NI

**
(c) 100 (d) 3000
90 2750
2500
80
Anti-BIomia IgE (KUI/L)

Number of Eosinophils

2250
70
2000
(células/mm3)

60 1750
50 1500
40 1250
1000
30
750
20
500
10 250
0 0
A-I A-NI NA-I NA-NI A-I A-NI NA-I NA-NI

Figure 4 Levels of total IgE (a), anti-Asc IgE (b) and anti-Blomia IgE (c) in serum and the absolute number of eosinophils (d) in
peripheral blood of those individuals infected with S. mansoni and with allergy-related symptoms (A-I), those with allergy-related
symptoms only (A-NI); those only infected (NA-I); and those non-infected individuals without allergy-related symptoms (NA-NI). The
medians were compared using the Kruskal–Wallis test and Dunn’s multiple comparison test. *P < 0.05. **P < 0.01. ***P < 0.001.

alteration) and the tendency to decreased CCL2 levels smCKBP peptide secreted by the eggs of S. mansoni [60].
(due to infection). However, there were increasing In this manner, the systemic pro-inflammatory type 1
CXCL8 in those infected and with symptoms related to response can be controlled in the presence of infection.
respiratory allergy or only infected. In conclusion, patients with allergy-related symptoms
High levels of pro-inflammatory cytokines (IL-6) in the and S. mansoni infected (simultaneously) had higher
infected group may explain the increase in CXCL8. Aller- levels of IL-10, TNF-a and IFN-c; due to the infection,
gic and infected individuals also had higher levels of there was increased production of IL-6 and CXCL8 and
CXCL8, suggesting the influence of parasitosis on this less CCL2. Therefore, our findings suggest that these indi-
parameter. This chemokine is involved in chemotaxis and viduals have a modified immune response background
neutrophil activation [60]; however, we did not observe when rescued the immune cells expansion. These data
an increase in the number of neutrophils in peripheral may characterize deviation to Th1 or attenuation of the
blood (data not shown). It is important to note that the Th2 response in allergy sufferers in areas endemic for
action of this chemokine can be blocked, in vivo, by the schistosomiasis.

1106 © 2021 John Wiley & Sons Ltd


Tropical Medicine and International Health
obrega et al. S. mansoni infection and respiratory allergy
C. G. de Oliveira N

Acknowledgements
This work was supported by Conselho Nacional de
Desenvolvimento Cient
ıfico e Tecnol

ogico (CNPq—pro-
cess number: 404413/2012.9).
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Corresponding author Vald^enia Maria Oliveira de Souza, Universidade Federal de Pernambuco. Av. Prof. Moraes Rego, s/n.
Cidade Universit
aria, Z 50.670-901 Recife-PE, Brazil. Tel.: + 55 81 2126 8484; E-mail: valdenia.souza@ufpe.br

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