335

Review Article
Interrelationship among asthma, atopy, and helminth infections*
Eduardo Vieira Ponte1, José Ângelo Rizzo2, Álvaro Augusto Cruz3

Abstract
To describe the principal evidence in the literature regarding the interrelationship among helminth infections, atopy, and asthma, a
nonsystematic review of the literature was conducted. Among the publications on the subject, we found a number in which there was
controversy regarding the capacity of geohelminth infections to inhibit responsiveness to skin allergy tests and to minimize the symptoms
of allergic diseases. However, although small in number, studies of patients infected with Schistosoma spp. suggest that these helminths
can inhibit the responsiveness to skin allergy testing and minimize asthma symptoms. Evidence provided by in vitro studies suggests that
helminthiases inhibit T helper 1- and T helper 2-type immune responses. This opens new therapeutic possibilities for the treatment of
immune system diseases.
Keywords: Asthma; Helminths; Hypersensitivity; Epidemiology.

* Study carried out as part of the Programa para o Controle da Asma e Rinite Alérgica na Bahia – ProAR, Bahia State Asthma and Allergic Rhinitis Control
Program – Universidade Federal da Bahia – UFBA, Federal University of Bahia – Salvador (BA) Brazil.
1. PhD Student in the Postgraduate Program in Medicine and Health at the Hospital Universitário Professor Edgard Santos – HUPES, Professor Edgar Santos
University Hospital – Universidade Federal da Bahia – UFBA, Federal University of Bahia – Salvador (BA) Brazil.
2. PhD in Medicine; Adjunct Professor at the Universidade Federal de Pernambuco – UFPE, Federal University of Pernambuco – School of Medicine, Recife (PE)
Brazil.
3. PhD in Medicine; Adjunct Professor at the Universidade Federal da Bahia – UFBA, Federal University of Bahia – School of Medicine; General Coordinator of the
Programa para o Controle da Asma e Rinite Alérgica na Bahia – ProAR, Bahia State Asthma and Allergic Rhinitis Control Program – Salvador (BA) Brazil.
Correspondence to: Eduardo Vieira Ponte. Programa de Controle da Asma e da Rinite Alérgica na Bahia. Rua Carlos Gomes, 270, 7º andar, Centro Médico Carlos
Gomes, CEP 40060-330, Salvador, BA, Brasil.
Phone 55 71 3321-8467. E-mail: [email protected]
Submitted: 8 October 2006. Accepted, after review: 15 October 2006.

J Bras Pneumol. 2007;33(3):335-342

336 Ponte EV, Rizzo JA, Cruz AA

Introduction In the Th2 immune response, allergens or

helminth antigens stimulate T lymphocytes
Despite the great scientific advances in the area to produce Th2 cytokines, such as interleukin
of immunology and the new therapeutic options (IL)‑4 and IL‑5, IL-4 inducing B lymphocytes
available, the prevalence of allergic diseases, such to produce immunoglobulin E (IgE), whereas
as asthma and rhinitis, has increased in developed IL‑5 attracts and activates eosinophils. Eosinophilia
countries.(1,2) However, the prevalence of asthma is and an increased serum level of IgE are, there-
low in developing countries.(3) It is important to find fore, characteristics of the Th2 response. A portion
explanations for this fact, which is possibly related of the IgE produced during the Th2 response is
to the influence of the environment on the immune antigen-specific. When specific IgE binds to high-
system. affinity receptors on the surface of mastocytes
In rich countries, the reduced exposure to infec- and basophils, it primes the immune system for
tious agents is among the environmental factors allergic reactions to any exposure to the allergen.
that can modify the immune system of human The Th2 immune response is reinforced whenever
beings and contribute to the increase in the preva- the antigen binds to specific IgE on the surface of
lence of allergic diseases. Helminth infections, for mastocytes, which undergo degranulation, releasing
example, are rare in developed countries. In view of mediators of the immediate allergic reaction (hista-
this, various studies have been conducted in recent mine, prostaglandins, and leukotrienes) as well as
years in attempts to ascertain whether the absence proinflammatory cytokines (IL-4, IL-13, and the
of exposure to helminth infections can contribute to regulated upon activation, normal T-cell expressed
the appearance of allergic diseases. In addition, there and secreted cytokine).(4,5)
is the need to reveal the immunopathological mech- Not all Th2 responses are equal. In the immune
anisms that could determine the inhibition of allergic response to helminth infections, such as those caused
responses in individuals infected with helminths. by Schistosoma mansoni,(6,7) S. haematobium,(8) and
A more in-depth investigation of the subject Onchocerca volvulus,(9) in addition to the increased
could identify alternatives for new treatments for production of IL-4 and IL-5, there is also increased
immune system diseases. One of these alternatives production of IL-10. Since IL-10 is a cytokine with
is the use of helminth antigens in the develop- immunosuppressive action, it seems to be important
ment of vaccines for the treatment of allergic and in the establishment of the immunological toler-
autoimmune diseases. The objective of this article is ance of the host to these helminths, which, in some
to describe the principal evidence in the literature cases, survive for up to 30 years.(10) However, in other
regarding the interrelationship among helminth helminth infections, as in the case of infection with
infections and allergy. Ascaris lumbricoides, the production of IL-10 is
not increased.(11-13) In the Th2 response observed in
Immune response in allergic diseases allergic diseases, IL-10 production is decreased,(14,15)
and helminth infections and the haplotype that determines the increased
production of this cytokine is less common in patients
One of the functions of the immune system is with asthma than in patients without asthma.(16)
to protect the individual against infectious agents. It is considered plausible that production of IL-10
However, dysfunction of this system can be the decreases in allergic diseases, since it is likely that the
cause of diseases such as allergies and autoim- anti-inflammatory effect of this cytokine prevents
mune diseases. The immune system acts through the progression of the allergic inflammation.
two patterns of acquired immune response:
the T helper 1 (Th1) immune response; and the Epidemiology of allergic diseases and
T helper 2 (Th2) immune response. The Th1 immune the hygiene hypothesis
response occurs in autoimmune diseases, as well as
in reaction to viral and bacterial infections. The Th2 A study entitled The International Study of
immune response occurs in the reaction to helminth Asthma and Allergies in Childhood carried out a
infections and in allergic diseases, such as asthma, lengthy investigation of the prevalence of asthma
rhinitis, and eczema. worldwide. In that study, the prevalence of

J Bras Pneumol. 2007;33(3):335-342

Interrelationship among asthma, atopy, and helminth infections 337

wheezing in 13- and 14-year-old children in the suggesting that this helminth can inhibit allergic airway
last year varied considerably, ranging from 2.1% in inflammation. Population studies have demonstrated
Indonesia to 32.2% in England. In Brazil, the preva- that infections with geohelminths (A. lumbricoides,
lence was 23.3%. In industrialized Western countries Trichuris trichiura, and Ancylostomidae) also inhibit
where English is the official language, as well as allergy skin test reactivity and the prevalence of
in some countries in Latin America, the prevalence wheezing, which is an indicator of asthma.(24-26) In a
of asthma is higher than in most developing coun- clinical trial, treatment with albendazole and prazi-
tries.(3) Although genetic factors are known to play quantel was shown to increase skin reactivity to
an important role in the variability of the preva- aeroallergens in a population of individuals infected
lence of asthma worldwide, genetic factors cannot with geohelminths,(27) suggesting that it is the infec-
account for the recent sharp increase in the preva- tion that inhibits the allergy, and not the allergy that
lence of asthma, allergic rhinitis, eczema, and allergy protects against the infection.
skin test reactivity seen in various countries.(1,2) This Some studies, however, have demonstrated
increase is probably related to the environmental that patients infected with geohelminths present a
changes that have occurred in recent decades. higher frequency of allergy skin test reactivity.(28,29)
Among the environmental factors that can In addition, a clinical trial with patients residing in
influence the appearance of allergic diseases are slums demonstrated that treatment with albenda-
childhood infections. In neonates, the immunolog- zole reduces asthma symptoms,(30) suggesting that
ical activity in the population of T lymphocytes in geohelminth infection could worsen the allergic
the umbilical core is predominantly Th2, similar to airway inflammation in these patients. Furthermore,
what happens in allergic individuals.(17) It is possible a cross-sectional study and a clinical trial,(31,32) both
to suppose that there is a natural predisposition to of which were published recently, suggest that
the development of allergic diseases in childhood, geohelminth infections have no effect on asthma
and that the infectious diseases acquired at this age symptoms or on allergy skin test reactivity (Table 1).
contribute the development of balanced immuno- Some explanations for these conflicting results
logical activity, thereby preventing the appearance have been proposed. Since many helminths have a
of allergies. This is the hygiene hypothesis,(18) which pulmonary cycle in the acute phase of the infection,
has the support of publications that have demon- it is possible that, during this phase, there is a wors-
strated an inverse correlation between allergy and ening of asthma symptoms, and that, during the
exposure to viral, bacterial, and helminth infec- chronic phase of infection, the symptoms improve.
tions.(20-24) According to the hygiene hypothesis, the Another potential explanation is related to the
vaccination and sanitation policies implemented parasite load of the population. It is possible that
in recent decades in developed countries prevent inhibition of allergic manifestations occurs only in
infectious diseases in childhood, which hinders infected individuals with a high parasite load. Some
the immunological balance, thereby explaining the studies indicate that the allergy skin test reac-
increased prevalence of allergic diseases. tivity is not inhibited, or is only slightly inhibited,
in individuals with a low parasite load,(13,31) thereby
Helminth infections and allergy supporting this hypothesis. However, other studies
have demonstrated that inhibition of allergy skin
Studies evaluating the interrelationship among test reactivity,(24) as well as amelioration of asthma
helminth infection, allergy skin test reactivity, and symptoms,(33) occur with equal frequency in individ-
symptoms of allergic diseases have provided contro- uals with a high parasite load and in those with a low
versial results. In cross-sectional studies involving parasite load. Another possible explanation is that
allergy skin tests, it has been shown that, among the lower capacity of geohelminths for stimulating
individuals infected with the helminths S. mansoni or the production of immunosuppressive cytokines,
S. haematobium, a small proportion test positive for such as IL-10, results in a lower capacity for inhib-
aeroallergens.(8,23) In a retrospective study, one group iting the allergic inflammation.(11-13) The helminths
of authors demonstrated that the frequency of symp- S. mansoni and S. haematobium induce increased
toms indicative of asthma, a disease associated with IL-10 production,(6-8) which could make them more
atopy, is lower in patients infected with S. mansoni,(25) capable of inhibiting allergic inflammation.

J Bras Pneumol. 2007;33(3):335-342

338 Ponte EV, Rizzo JA, Cruz AA

Table 1 - Studies evaluating the influence of geohelminth infections and infection with Schistosoma spp. on allergy
skin test reactivity and on asthma symptoms.
Study design Reference Helminth Effect
Clinical trial Am J Respir Crit Care Med 156:50-4, 1997 Geohelminths Induce
Prospective study J Allergy Clin Immunol 102:414-20, 1998 Geohelminths Induce
Cross-sectional study Int Arch Allergy Immunol 123:145-8, 2000 Schistosoma spp. Inhibit
Cross-sectional study Lancet 356:1723-7, 2000 Schistosoma spp. Inhibit
Cross-sectional study Lancet 358:1493-9, 2001 Geohelminths Induce
Cross-sectional study Am J Respir Crit Care Med 165:1489-93, 2002 Geohelminths Induce
Cross-sectional study J Allergy Clin Immunol 111:995-1000, 2003 Geohelminths Inhibit
Cross-sectional study Am J Respir Crit Care Med 167:1369-73, 2003 Geohelminths Inhibit
Prospective study J Allergy Clin Immunol 111:947-51, 2003 Schistosoma spp. Inhibit
Prospective study J Infect Dis 190:1797-803, 2004 Schistosoma spp. Inihibit
Clinical trial J Infect Dis 189:892-900, 2004 Geohelminths Inhibit
Cross-sectional study Clin Exp Allergy 35:301-7, 2005 Geohelminths No influence
Cross-sectional study Ann Asthma Allergy Immunol 96:713-8, 2006 Geohelminths No influence
Clinical trial Lancet 13;367:1598-603, 2006 Geohelminths No influence
Meta-analysis Am J Respir Crit Care Med 174:514-23, 2006 Geohelminths No influence
Cross-sectional study Allergy 61:996-1001, 2006 Geohelminths No influence
Cross-sectional study Clin Exp Allergy 36:640-8, 2006 Geohelminths Induce
Cross-sectional study Int Arch Allergy Immunol 139:317-24, 2006 Geohelminths Induce

Mechanisms by which by helminth (Th2), and that helminth infections (Th2) would
infections inhibit allergies stimulate the appearance of the allergic inflamma-
tion. However, this polarized form of classifying the
Despite the current controversy regarding the immune response is too simplistic to be applied to
subject, some hypotheses have been formulated to human beings, in whom the Th1 cytokines partici-
explain the potential mechanism by which allergy
pate in the inflammatory process of allergic diseases
skin test reactivity is inhibited and symptoms are
(Th2), (35,36) as well as in the inflammatory process
minimized in individuals infected with helminths.
Initially, it was believed that the Th1 immune of autoimmune diseases (Th1).(37,38) In addition, as
response had an antagonistic action to that of the described previously, some studies have suggested
T2 immune response, one inhibiting the other.(34) that helminth infections (Th2 response) inhibit the
Therefore, it would be expected that viral and appearance of allergies (also Th2 response), which is
bacterial infections, which trigger a Th1 immune incompatible with the polarized model of immune
response, would inhibit the allergic inflammation response (Table 2).

Table 2 - Characteristics of T helper 1 and T helper 2 immune responses.

Th1 immune response Th2 immune response
Cytokines involved Interferon gamma Interleukin-4 and interleukin-5
Participation of IgE Absent Present
Participation of IgG Present Absent
Participation of eosinophils Absent Present
Participation of mastocytes Absent Present
Participation of lymphocytes Present Present
Participation of neutrophils Present Absent

Pathologies Autoimmune diseases and response Allergic diseases and response to

to viral and bacterial infections helminth infections
Th1: T helper 1 lymphocytes; Th2: T helper 2 lymphocytes; IgE: immunoglobulin E; IgG: immunoglobulin G.

J Bras Pneumol. 2007;33(3):335-342

Interrelationship among asthma, atopy, and helminth infections 339

Currently, one of the most widely accepted tion,(7) as well as an increase in the skin response to
pathophysiological models to explain how helminth aeroallergens,(27) thereby underscoring evidence that
infections inhibit allergy involves the induction of IL-10 plays an important role in the inhibition of
regulatory mechanisms capable of limiting exacer- allergic inflammation in individuals with helminth
bated Th1 and Th2 immune responses, which would infection.
prevent the appearance not only of allergic diseases, Another mechanism by which allergic responses
but also of autoimmune diseases. This would be are inhibited in patients with helminth infection is
achieved by regulatory cells,(39) as well as by immu- related to increased production of nonspecific IgE
nosuppressive cytokines such as IL-10.(40,41) in infected patients. The nonspecific IgE saturates
The regulatory cells are lymphocytes and can the IgE receptors on the surface of mastocytes,
be grouped into two main categories: CD4/CD25+ thereby preventing the specific IgE from binding
regulatory cells and antigen-specific regulatory T- with the allergens. Consequently, the allergens do
cells, both of which are important in the control of not cause degranulation of mastocytes, and allergic
the allergic inflammation. The immunosuppressive inflammation is thus prevented. In one study, it was
effect of CD4/CD25+ is exerted primarily through demonstrated that inhibition of the skin response
cell-cell contact, whereas that of antigen-specific to aeroallergens in individuals with helminth infec-
regulatory cells occurs as a result of the secretion of tion is associated with increased production of
IL-10 and of transforming growth factor beta.(42) total IgE, thereby strengthening this hypothesis.(24)
The role of regulatory cells in the inhibition of However, there are arguments against this model.
the Th2 immune response has been demonstrated Epidemiological studies have indicated that inhi-
in vitro: CD4/CD25+ regulatory cells were shown to bition of the skin response to aeroallergens in
inhibit the proliferation of CD4+/CD25− cells, as well individuals infected with geohelminths is not asso-
as the production of IL-4 and IL-5, in atopic and ciated with high serum levels of total IgE.(8,33) In
nonatopic individuals.(43) In vivo, immunotherapy with addition, there is evidence that the concentration
grass pollen has been shown to induce the production of nonspecific IgE necessary to saturate the recep-
of CD4/CD25+ cells, which possibly contributes to tors on the surface of the mastocytes is very high,
the improvement of symptoms in allergic individuals considerably higher than that found in most patients
who are submitted to this therapy.(41) In individuals with helminth infection.(46) This occurs because the
infected with helminths, regulatory T-cells promote concentration of IgE receptors is regulated at the
a state of immunosuppression,(44) leading to inhibi- surface of the mastocytes, where higher serum levels
tion of the allergic inflammation. of IgE induce an increase in the concentration of
Studies indicate that IL-10 also plays an impor- receptors, making it possible for the specific IgE to
tant role in the inhibition of allergic inflammation in find receptors available for binding.(47)
individuals with helminth infection. Individuals with
allergic diseases have a decreased production of this Exposure to infections also protects
cytokine,(14,15) whereas certain helminth infections, against autoimmune diseases
in turn, are highly likely to induce IL-10 produc-
tion.(6-9) Some authors have demonstrated that, in Since the regulatory mechanisms induced by
individuals infected with S. haematobium, IL-10 infectious agents also inhibit the exacerbated Th1
inhibits the proliferation of peripheral blood mono- immune response,(48-50) it is expected that infec-
nuclear cells, which induces a state of anergy and tions are capable of preventing the appearance of
contributes to controlling the allergic inflamma- autoimmune diseases. Similar to what has occurred
tion.(45) In other studies, it has been shown that, in with allergic diseases, the prevalence of autoimmune
individuals infected with S. haematobium, increased diseases has increased in developed countries,(51-55)
IL-10 production is associated with lower allergy reflecting the influence of environmental factors.
skin test reactivity,(8) and that, in individuals infected There is evidence that individuals who live in envi-
with S. mansoni, IL-10 inhibits peripheral blood ronments where there is a greater risk of infection
mononuclear cell production of Th2 cytokines.(7) In are less likely to develop autoimmune diseases.(56,57)
addition, the treatment of individuals infected with In addition, a clinical trial has demonstrated that
helminths promotes a decrease in IL-10 produc- exposure to helminths inhibits the clinical manifes-

J Bras Pneumol. 2007;33(3):335-342

340 Ponte EV, Rizzo JA, Cruz AA

tations of Crohn’s disease and ulcerative rectocolitis, schoolchildren between 1979 and 1991. Clin Exp Allergy.
both of which are autoimmune diseases.(58) 1995;25(9):815-9.
2. Von Mutius E, Weiland SK, Fritzsch C, Duhme H, Keil U.
Increasing prevalence of hay fever and atopy among children
Therapeutic potential of IL-10 and in Leipzig, East Germany. Lancet. 1998;351(9106):862-6.
helminth antigens in the treatment of 3. Worldwide variation in prevalence of symptoms of
asthma, allergic rhinoconjunctivitis, and atopic eczema:
immune system diseases ISAAC. The International Study of Asthma and Allergies
in Childhood (ISAAC) Steering Committee. Lancet.
Based on the knowledge obtained through the 1998;351(9111):1225-32.
study of the influence of infections on allergic and 4. Busse WW, Lemanske RF Jr. Asthma. N Engl J Med.
2001;344(5):350-62.
autoimmune manifestations, new options for the 5. Kay AB. Allergy and allergic diseases. First of two parts. N
treatment of immune system diseases have been Engl J Med. 2001;344(1):30-7.
proposed. Among future prospects is the use of IL‑10 6. Malaquias LC, Falcao PL, Silveira AM, Gazzinelli G, Prata A,
and helminth antigens as treatment modalities. Coffman RL, et al. Cytokine regulation of human immune
response to Schistosoma mansoni: analysis of the role of
Clinical trials have already been conducted in IL-4, IL-5 and IL-10 on peripheral blood mononuclear cell
order to evaluate the safety and efficacy of using responses. Scand J Immunol. 1997;46(4):393-8.
IL-10 in the treatment of autoimmune diseases. In 7. Araujo MI, Hoppe B, Medeiros M Jr, Alcantara L, Almeida
MC, Schriefer A, et al. Impaired T helper 2 response to
a study of 46 patients with Crohn’s disease refrac-
aeroallergen in helminth-infected patients with asthma. J
tory to treatment with corticosteroids, intravenous Infect Dis 2004;190(10):1797-803.
administration of IL-10 was found to be safe and 8. van den Biggelaar AH, van Ree R, Rodrigues LC, Lell B,
clinically efficacious when compared to that of the Deelder AM, Kremsner P, et al. Decreased Atopy in Children
infected with Schistosoma haematobium: a role for parasite
placebo.(59) In a study of 10 patients with psoriasis, induced interleukin 10. Lancet. 2000;356(9243):1723-7.
IL-10 proved safe and appeared to be efficacious in 9. Doetze A, Sotoquina J, Burchard G, Rau T, Löliger C, Fleischer
the control of symptoms.(60) In another study, the B, et al. Antigen-specific cellular hyporesponsiveness in a
administration of Trichuris suis eggs in patients chronic human helminth infection is mediated by T(h)3/
T(r)1-type cytokines IL-10 and transforming growth
with Crohn’s disease and ulcerative rectocolitis led factor-beta but not by a T(h)1 to T(h)2 shift. Int Immunol.
to remission in 86% of the cases.(58) 2000;12(5):623-30.
10. Klion AD, Nutman TB. The role of eosinophils in host
Conclusions defense against helminth parasites. J Allergy Clin Immunol.
2004;113(1):30-7.
Despite the numerous publications on the subject, 11. Cooper PJ, Chico ME, Sandoval C, Espinel I, Guevara
A, Kennedy MW, et al. Human infection with Ascaris
there is still controversy regarding the capacity of lumbricoides is associated with a polarized cytokine response.
geohelminth infections to inhibit allergy skin test J Infect Dis. 2000;182(4):1207-13.
reactivity and minimize the symptoms of allergic 12. Geiger SM, Massara CL, Bethony J, Soboslay PT, Carvalho OS,
Correa - Oliveira R. Cellular Responses and cytokine profiles
diseases, such as asthma. Although there have been
in Ascaris lumbricoides and Trichuris trichiura infected
few studies of patients infected with helminths that patients. Parasite Immunol. 2002;24(11-12):499-509.
induce IL-10 production (e.g., Schistosoma spp.), 13. Ponte EV, Lima F, Araújo MI, Oliveira RR, Cardoso LS, Cruz
the results obtained to date suggest that these AA. Skin test reactivity and Der p-induced interleukin 10
production in patients with asthma or rhinitis infected with
helminths can inhibit allergy skin test reactivity and Ascaris. Ann Asthma Allergy Immunol. 2006;96(5):713-8.
minimize asthma symptoms. Evidence from in vitro 14. Takanashi S, Hasegawa Y, Kanehira Y, Yamamoto K, Fujimoto
studies suggests that helminthiases inhibit Th1 and K, Satoh K, et al. Interleukin-10 level in sputum is reduced
Th2 immune responses by increasing IL-10 produc- in bronchial asthma, COPD and in smokers. Eur Respir J.
1999;14(2):309-14.
tion. This opens new therapeutic possibilities for the 15. van der Velden VH, Laan MP, Baert MR, de Waal Malefyt R,
treatment of immune system diseases. Studies eval- Neijens HJ, Savelkoul HF.. Selective development of a strong
uating the use of IL-10 and helminth antigens in Th2 cytokine profile in high-risk children who develop atopy:
the treatment of autoimmune diseases have already risk factors and regulatory role of IFN-gamma, IL-4 and IL-
10. Clin Exp Allergy. 2001;31(7):997-1006.
been carried out, with promising initial results. 16. Lim S, Crawley E, Woo P, Barnes PJ. Haplotype associated
with low interleukin-10 production in patients with severe
References asthma. Lancet. 1998;352(9122):113.
17. Prescott SL, Macaubas C, Smallacombe T, Holt BJ, Sly PD, Holt
1. Aberg N, Hesselmar B, Aberg B, Eriksson B. Increase PG. Development of Allergen-specific T-cell memory in atopic
of asthma, allergic rhinitis and eczema in Swedish and normal children. Lancet. 1999;353(9148):196-200.

J Bras Pneumol. 2007;33(3):335-342

Interrelationship among asthma, atopy, and helminth infections 341

18. Strachan DP. Hay fever, hygiene and household size. BMJ. 34. Matricardi PM, Bonini S. High microbial turnover
1989;299(6710):1259-60. rate preventing atopy: a solution to inconsistencies
19. Shaheen SO, Aaby P, Hall AJ, Barker DJ, Heyes CB, Shiell impinging on the Hygiene hypothesis? Clin Exp Allergy.
AW, et al. Measles and atopy in Guinea-Bissau. Lancet. 2000;30(11);1506-10.
1996;347(9018):1792-6. 35. John M, Lim S, Seybold J, Jose P, Robichaud A, O´Connor
20. Shirakawa T, Enomoto T, Shimazu S, Hopkin JM. The B, et al. Inhaled corticosteroids increase interleukin-10
inverse association between tuberculin responses and atopic but reduce macrophage inflammatory protein-1alpha,
disorder. Science. 1997;275(5296):77-9. granulocyte-macrophage colony-stimulating factor, and
21. Matricardi PM, Rosmini F, Ferrigno L, Nisini R, Rapicetta interferon-gamma release from alveolar macrophages in
M, Chionne P, et al. Cross sectional retrospective asthma. Am J Respir Crit Care Med. 1998;157(1):256-62.
study of prevalence of atopy among Italian military 36. Cho SH, Stanciu LA, Holgate ST, Johnston SL. Increased
students with antibodies against hepatitis A virus. BMJ. interleukin-4, interleukin-5, and interferon-gamma in airway
1997;314(7086):999-1003. CD4+ and CD8+ T cells in atopic asthma. Am J Respir Crit
22. Ball TM, Castro-Rodriguez JA, Griffith KA, Holberg CJ, Care Med. 2005;171(3):224-30.
Martinez FD, Wright AL. Siblings, day-care attendance, and 37. Hesse M, Bayrak S, Mitchison A. Protective major
the risk of asthma and wheezing during childhood. N Engl J histocompatibility complex genes and the role of
Med. 2000;343(8):538-43. interleukin-4 in collagen-induced arthritis. Eur J Immunol.
23. Araujo MI, Lopes AA, Medeiros M, Cruz AA, Souza-Atta L, 1996;26(12):3234-7.
Sole D, et al. Inverse association between skin response to 38. Wakelkamp IM, Gerding MN, Van Der Meer JW, Prummel
aeroallergens and Schistosoma mansoni infection.. Int Arch MF, Wiersinga WM. Both Th1- and Th2-derived cytokines
Allergy Immunol. 2000;123(2):145-8. in serum are elevated in Graves‘ ophthalmopathy. Clin Exp
24. Cooper PJ, Chico ME, Rodrigues LC, Ordonez M, Strachan D, Immunol. 2000;121(3):453-7.
Griffin GE, et al. Reduced risk of atopy among school-age 39. Groux H, O´Garra A, Bigler M, Rouleau M, Antonenko S,
children infected with geohelminth parasites in a rural area of de Vries JE, et al. A CD4+ T-cell subset inhibits antigen-
the tropics. J Allergy Clin Immunol. 2003;111(5):995-1000. specific T-cell responses and prevents colitis. Nature.
25. Medeiros M, Figueiredo JP, Almeida MC, Matos MA, 1997;389(6652):737-42.
Araújo MI, Cruz AA, et al. Schistosoma mansoni infection
40. Asano M, Toda M, Sakaguchi N, Sakaguchi S. Autoimmune
is associated with a reduced course of asthma. J Allergy Clin
disease as a consequence of developmental abnormality of a
Immunol. 2003;111(5):947-51.
T cell subpopulation. J Exp Med. 1996;184(2):387-96.
26. Dagoye D, Bekele Z, Woldemichael K, Nida H, Yimam M,
41. Francis JN, Till SJ, Durham SR. Induction of IL-
Hall A, et al. Wheezing, allergy, and parasite infection in
10+CD4+CD25+ T cells by grass pollen immunotherapy. J
children in urban and rural Ethiopia. Am J Respir Crit Care
Allergy Clin Immunol. 2003;111(6):1255-61.
Med. 2003;167(10):1369-73.
42. Hawrylowicz CM. Regulatory T cells and IL-10 in allergic
27. van den Biggelaar AH, Rodrigues LC, van Ree R, van der
inflammation. J Exp Med. 2005;202(11):1459-63.
Zee JS, Hoeksma-Kruize YC, Souverijn JH, et al. Long-term
43. Bellinghausen I, Klostermann B, Knop J, Saloga J. Human
treatment of intestinal helminths increases mite skin-
CD4+CD25+ T cells derived from the majority of atopic
test reactivity in Gabonese schoolchildren. J Infect Dis.
2004;189(5):892-900. donors are able to suppress TH1 and TH2 cytokine
28. Dold S, Heinrich J, Wichmann HE, Wjst M. Ascaris-specific production. J Allergy Clin Immunol. 2003;111(4):862-8.
IgE and allergic sensitization in a cohort of school children 44. Satoguina J, Mempel M, Larbi J, Badusche M, Löliger C, Adjei
in the former East Germany. J Allergy Clin Immunol. O, et al. Antigen-specific T regulatory-1 cells are associated
1998;102(3):414-20. with immunosuppression in a chronic helminth infection
29. Palmer LJ, Celedón JC, Weiss ST, Wang B, Fang Z, Xu X. (onchocerciasis). Microbes Infect. 2002;4(13):1291-300.
Ascaris lumbricoides infection is associated with increased 45. King CL, Medhat A, Malhotra I, Nafeh M, Helmy A, Khaudary
risk of childhood asthma and atopy in rural China. Am J J, et al. Cytokine control of parasite-specific anergy in
Respir Crit Care Med. 2002;165(11):1489-93. human urinary schistosomiasis. IL-10 modulates lymphocyte
30. Lynch NR, Palenque M, Hagel I, DiPrisco MC. Clinical reactivity. J Immunol. 1996;156(12):4715-21.
improvement of asthma after anthelminthic treatment 46. Mitre E, Norwood S, Nutman TB. Saturation of
in a tropical situation. Am J Respir Crit Care Med. immunoglobulin E (IgE) binding sites by polyclonal IgE
1997;156(1):50-4. does not explain the protective effect of helminth infections
31. Davey G, Venn A, Belete H, Berhane Y, Britton J. Wheeze, against atopy. Infect Immunol. 2005;73(7):4106-11
allergic sensitization and geohelminth infection in Butajira, 47. Saini SS, MacGlashan DW, Sterbinsky SA, Togias A, Adelman
Ethiopia. Clin Exp Allergy. 2005;35(3):301-7 DC, Lichtenstein LM, et al. Down-regulation of human
32. Cooper PJ, Chico ME, Vaca MG, Moncayo AL, Bland JM, basophil IgE and FC epsilon RI alpha surface densities and
Mafla E, et al. Effect of albendazole treatments on the mediator release by anti-IgE-infusions is reversible in vitro
prevalence of atopy in children living in communities and in vivo. J Immunol. 1999;162(9):5624-30.
endemic for geohelminth parasites: a cluster-randomised 48. Qin HY, Sadelain MW, Hitchon C, Lauzon J, Singh B.
trial. Lancet. 2006;367(9522):1598-603. Complete Freund’s adjuvant-induced T cells prevent the
33. Scrivener S, Yemaneberhan H, Zebenigus M, Tilahun development and adoptive transfer of diabetes in nonobese
D, Girma S, Ali S, et al. Independent effects of intestinal diabetic mice. J Immunol. 1993;150(5):2072-80.
parasite infection and domestic allergen exposure on risk 49. Berg DJ, Kuhn R, Rajewsky K, Muller W, Menon S, Davidson
of wheeze in Ethiopia: a nested case-control study. Lancet. N, et al. Interleukin-10 is a central regulator of the response
2001;358(9292):1493-9 to LPS in murine models of endotoxic shock and the

J Bras Pneumol. 2007;33(3):335-342

342 Ponte EV, Rizzo JA, Cruz AA

Shwartzman reaction but not endotoxin tolerance. J Clin 56. McKinney PA, Okasha M, Parslow RC, Law GR, Gurney KA,
Invest. 1995;96(5):2339-47. Williams R, et al. Early social mixing and childhood type
50. Carvalho EM, Bacellar O, Brownell C, Regis T, Coffman 1 diabetes mellitus: a case-control study in Yorkshire, UK.
RL, Reed SG. Restoration of IFN-gamma production and Diabet Med. 2000;17(3):236-42.
lymphocyte proliferation in visceral leishmaniasis. J Immunol. 57. Leibowitz U, Antonovsky A, Medalie JM, Smith HA, Halpern
1994;152(12):5949-56. L, Alter M. Epidemiological study of multiple sclerosis in
51. Rosati G, Aiello I, Mannu L, Pirastru MI, Agnetti V, Sau G, Israel. II. Multiple sclerosis and level of sanitation. J Neurol
et al. Incidence of multiple sclerosis in the town of Sassari, Neurosurg Psychiatry. 1966;29(1):60-8.
Sardinia, 1965 to 1985: evidence for increasing occurrence 58. Summers RW, Elliott DE, Qadir K, Urban JF Jr, Thompson R,
of the disease. Neurology 1998;38(3):384-8. Weinstock JV. Trichuris suis seems to be safe and possibly
52. Poser S, Stickel B, Krtsch U, Burckhardt D, Nordman B. effective in the treatment of inflammatory bowel disease.
Increasing incidence of multiple sclerosis in South Lower Am J Gastroenterol. 2003;98(9):2034-41.
Saxony, Germany. Neuroepidemiology. 1989;8(4):207-13. 59. Van Deventer SJ, Elson CO, Fedorak RN. Multiple doses
53. Variation and trends in incidence of childhood diabetes of intravenous interleukin 10 in steroid-refractory Crohn’s
in Europe. EURODIAB ACE Study Group. Lancet. disease. Crohn’s Disease Study Group. Gastroenterology.
2000;355(9207):873-6. 1997;113(2):383-9.
54. Elliott DE, Urban JF Jr, Argo CK, Weinstock JV. Does the 60. Asadullah K, Docke WD, Ebeling M, Friedrich M, Belbe
failure to acquire helminthic parasites predispose to Crohn’s G, Audring H, et al. Interleukin 10 treatment of psoriasis:
disease? FASEB J. 2000;14(12):1848-55. clinical results of a phase 2 trial. Arch Dermatol.
55. Farrokhyar F, Swarbrick ET, Irvine EJ. A critical review of 1999;135(2):187-92.
epidemiological studies in inflammatory bowel disease.
Scand J Gastroenterol. 2001;36(1):2-15.

J Bras Pneumol. 2007;33(3):335-342