The hygiene hypothesis and atopy: Bring back the parasites?
2005; Elsevier BV; Volume: 54; Issue: 1 Linguagem: Inglês
10.1016/j.jaad.2005.09.020
ISSN1097-6787
Autores Tópico(s)Allergic Rhinitis and Sensitization
ResumoAtopy has been increasing in prevalence in the industrialized world for at least two decades, but the same increase has not been noted in the developing world.1Romagnani S. The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both?.Immunology. 2004; 112: 352-363Crossref PubMed Scopus (352) Google Scholar, 2Ndiaye M. Bousquet J. Allergies and parasitoses in sub-Saharan Africa.Clin Rev Allergy Immunol. 2004; 26: 105-113Crossref PubMed Google Scholar The hygiene hypothesis suggests that lack of exposure to infectious agents during childhood results in a balance of T helper 1 (Th1) and T helper 2 (Th2) type immune responses that favor atopy. Typical Th1 cytokines include IL-12 and interferon (IFN)-γ, whereas Th2 cytokines include IL-4, IL-5, IL-9, and IL-13. Most antimicrobial responses are Th1 responses, whereas atopy is associated with a Th2 pattern of cytokines.The hygiene hypothesis has gained significant credibility, but is not universally accepted. It should be noted that most of the evidence in favor of the hypothesis is in the form of population-based studies of incidence and association, but there is currently no proof of causation. Studies have varied in their methods, with some relying on historic data, and some using skin test positivity rather than clinical disease manifestations as a measured outcome.There are prospective data supporting an inverse relationship between atopic dermatitis and endotoxin exposure, early day care, and animal exposure, but other data suggest a positive association between infections in early life and atopic dermatitis.3Flohr C. Pascoe D. Williams H.C. Atopic dermatitis and the 'hygiene hypothesis': too clean to be true?.Br J Dermatol. 2005; 152: 202-216Crossref PubMed Scopus (159) Google Scholar, 4Eder W. von Mutius E. Hygiene hypothesis and endotoxin: what is the evidence?.Curr Opin Allergy Clin Immunol. 2004; 4: 113-117Crossref PubMed Scopus (80) Google Scholar, 5Ramsey C.D. Celedon J.C. The hygiene hypothesis and asthma.Curr Opin Pulm Med. 2005; 11: 14-20Crossref PubMed Scopus (74) Google Scholar Infections that have been negatively associated with atopy include geohelminths in warmer climates and hepatitis A, Helicobacter pylori, and toxoplasma in temperate climates.6Sheikh A. Strachan D.P. The hygiene theory: fact or fiction?.Curr Opin Otolaryngol Head Neck Surg. 2004; 12: 232-236Crossref PubMed Scopus (93) Google Scholar Mycobacteria have been hypothesized to play a role in a range of climates.7Smit J.J. Folkerts G. Nijkamp F.P. Mycobacteria, genes and the 'hygiene hypothesis'.Curr Opin Allergy Clin Immunol. 2004; 4: 57-62Crossref PubMed Scopus (27) Google ScholarUniversal acceptance of the hygiene hypothesis would require proof from prospective clinical trials, and explanations for some apparent paradoxes. First is the apparent paradox that although helminthic infections are potent stimuli for Th2 responses, many populations with high endemic levels of helminth infections have a low incidence of atopy. Another paradox is the increase in asthma among inner-city populations in the United States, an observation that appears to contradict the hygiene hypotheses, as these populations presumably live in a less sterile environment than more affluent populations.8Matricardi P.M. Bouygue G.R. Tripodi S. Inner-city asthma and the hygiene hypothesis.Ann Allergy Asthma Immunol. 2002; 89: 69-74Abstract Full Text PDF PubMed Scopus (29) Google Scholar In addition, the prevalence of Crohn's disease, widely regarded a Th1-dominant inflammatory disease, is increased in industrialized societies, and parallels the increase in Th2-dominant atopic responses.9Wells R.W. Blennerhassett M.G. The increasing prevalence of Crohn's disease in industrialized societies: the price of progress?.Can J Gastroenterol. 2005; 19: 89-95PubMed Google Scholar, 10Danese S. Sans M. Fiocchi C. Inflammatory bowel disease: the role of environmental factors.Autoimmun Rev. 2004; 3: 394-400Crossref PubMed Scopus (303) Google Scholar, 11Feillet H. Bach J.F. Increased incidence of inflammatory bowel disease: the price of the decline of infectious burden?.Curr Opin Gastroenterol. 2004; 20: 560-564Crossref PubMed Scopus (31) Google Scholar The incidence of insulin-dependent diabetes mellitus, also mediated by a type 1 response, has increased in parallel with that of childhood asthma.In this article, I review recent evidence for and against the hygiene hypothesis and examine the role of helminthic pathogens, as they may represent a plausible link. Immune responses to early infection are complex, and the timing and intensity of exposure to pathogens appear to influence the immune response, and the risk of atopy. These factors may explain some of the apparent paradoxes presented by the hygiene hypothesis.Evidence for and against the hygiene hypothesisChildren who grow up on farms have a lower incidence of atopy and other allergic manifestations as compared with children who do not grow up on farms, but there is a paradoxically high prevalence of asthma. The prevalence of asthma is highest among children living on farms that raise swine and those that add antibiotics to animal feed.12Merchant J.A. Naleway A.L. Svendsen E.R. Kelly K.M. Burmeister L.F. Stromquist A.M. et al.Asthma and farm exposures in a cohort of rural Iowa children.Environ Health Perspect. 2005; 113: 350-356Crossref PubMed Scopus (108) Google Scholar Similarly, a questionnaire-based study in Hanoi, Vietnam, found a positive relationship between allergic conditions and pig ownership.13Chai S.K. Nga N.N. Checkoway H. Takaro T.K. Redding G.J. Keifer M.C. et al.Comparison of local risk factors for children's atopic symptoms in Hanoi, Vietnam.Allergy. 2004; 59: 637-644Crossref PubMed Scopus (19) Google Scholar It is possible that the beneficial immune priming of a farm environment is outweighed by the addition of antibiotics to animal feed. Other evidence also suggests an association between antibiotic administration to children early in life and an increased risk of asthma.14Cohet C. Cheng S. MacDonald C. Baker M. Foliaki S. Huntington N. et al.Infections, medication use, and the prevalence of symptoms of asthma, rhinitis, and eczema in childhood.J Epidemiol Community Health. 2004; 58: 852-857Crossref PubMed Scopus (118) Google Scholar The association between pig farming and asthma deserves further study.A case control study of 313 pairs of children living in Sao Paulo, Brazil, suggests that household crowding increases the risk of acute lower respiratory infection, and is inversely associated with asthma.15Cardoso M.R. Cousens S.N. de Goes Siqueira L.F. Alves F.M. D'Angelo L.A. Crowding: risk factor or protective factor for lower respiratory disease in young children?.BMC Public Health. 2004; 4: 19Crossref PubMed Scopus (109) Google Scholar Epidemiologic evidence supports a birth order effect, and an increased risk of atopy in children born into small, affluent households. A case control study of 602 children in the United Kingdom found a reduction in atopy with increasing birth order, but no specific measure of infection reduced the odds significantly.16Gibbs S. Surridge H. Adamson R. Cohen B. Bentham G. Reading R. Atopic dermatitis and the hygiene hypothesis: a case-control study.Int J Epidemiol. 2004; 33: 199-207Crossref PubMed Scopus (46) Google Scholar A questionnaire-based study of 34,362 individuals from 26,100 households found a 19.3% incidence of hay fever. The odds of having hay fever were less for individuals with two or more siblings.17Marshall A.H. Owen V. Jones N.S. More siblings, less hay fever: more evidence.Clin Otolaryngol. 2002; 27: 352-358Crossref PubMed Scopus (8) Google Scholar Recall bias could have influenced the results. In a European cohort study, atopy, defined by prick tests to common aeroallergens, was less common among those from larger families. A higher number of brothers appeared to offer the best protection. (Having grown up with two brothers, I can appreciate a plausible link with the hygiene hypothesis.) In this study, gastrointestinal infections had a strong negative association with atopy, but the protective effect did not correlate with either hepatitis A or Helicobacter pylori infection, or with the total number of documented infections or antibiotic prescriptions.18Cullinan P. Harris J.M. Newman Taylor A.J. Jones M. Taylor P. Dave J.R. et al.Can early infection explain the sibling effect in adult atopy?.Eur Respir J. 2003; 22: 956-961Crossref PubMed Scopus (51) Google ScholarA cohort study of 835 children from suburban Detroit, Mich, found that those with fevers before age 1 year had a lower incidence of atopy. Each additional febrile episode in the first year was associated with reduced odds for allergic sensitization. Upper respiratory tract infections showed a particularly strong effect.19Williams L.K. Peterson E.L. Ownby D.R. Johnson C.C. The relationship between early fever and allergic sensitization at age 6 to 7 years.J Allergy Clin Immunol. 2004; 113: 291-296Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar In a population-based study in Guinea-Bissau, measles infection was negatively associated with house dust mite skin-prick test positivity, even after adjustment for variables such as breast-feeding.20Shaheen S.O. Aaby P. Hall A.J. Barker D.J. Heyes C.B. Shiell A.W. et al.Measles and atopy in Guinea-Bissau.Lancet. 1996; 347: 1792-1796Abstract PubMed Scopus (475) Google Scholar Although most current evidence suggests no association between childhood vaccination and allergic disease,21Koppen S. de Groot R. Neijens H.J. Nagelkerke N. van Eden W. Rumke H.C. No epidemiological evidence for infant vaccinations to cause allergic disease.Vaccine. 2004; 22: 3375-3385Crossref PubMed Scopus (75) Google Scholar a questionnaire-based Danish study of 9744 children found that the incidence of atopic dermatitis increased after measles, mumps, and rubella vaccination.22Olesen A.B. Juul S. Thestrup-Pedersen K. Atopic dermatitis is increased following vaccination for measles, mumps and rubella or measles infection.Acta Derm Venereol. 2003; 83: 445-450Crossref PubMed Scopus (46) Google ScholarThere is evidence that endotoxin exposure in early life is negatively associated with atopic manifestations. Specifically, it may down-regulate airway eosinophilia and hyperreactivity.23Douwes J. Le Gros G. Gibson P. Pearce N. Can bacterial endotoxin exposure reverse atopy and atopic disease?.J Allergy Clin Immunol. 2004; 114: 1051-1054Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar Endotoxin levels in dust from infant mattresses in East German homes are significantly higher than those in the West. The levels correlate with pet ownership, close contact with pets, and the number of persons living in the home.24Gehring U. Bischof W. Borte M. Herbarth O. Wichmann H.E. Heinrich J. LISA. Study Group Levels and predictors of endotoxin in mattress dust samples from East and West German homes.Indoor Air. 2004; 14: 284-292Crossref PubMed Scopus (63) Google ScholarThe prenatal and neonatal immune responseThe neonatal immune response is weighted toward a Th2 response, and the observation that cord blood mononuclear cells proliferate in response to food and inhalant allergens suggests that T-cell priming already occurs in utero.25Prescott S.L. Macaubes C. Yabuhara A. Venaille T.J. Holt B.J. Habre W. et al.Developing patterns of T cell memory to environmental allergens in the first two years of life.Int Arch Allergy Immunol. 1997; 113: 75-79Crossref PubMed Scopus (82) Google Scholar The Th2 bias of neonatal T cell–dependent responses is heavily dependent on the level of CD28 costimulation. When CD28 cosignal is minimal, IL-12 can prime neonatal CD4+ T cells to produce both IL-4 and IFN-γ. In contrast, strong CD28 costimulation results in production of high levels of type 1 (IL-2, IFN-γ, and tumor necrosis factor beta) and low levels of type 2 (IL-4 and IL-13) cytokines by neonatal T cells.26Delespesse G. Yang L.P. Ohshima Y. Demeure C. Shu U. Byun D.G. et al.Maturation of human neonatal CD4+ and CD8+ T lymphocytes into Th1/Th2 effectors.Vaccine. 1998; 16: 1415-1419Crossref PubMed Scopus (118) Google ScholarMaternal peripheral blood mononuclear cells synthesize greater amounts of IL-12 than neonatal cells, and reduced IL-12 production in the perinatal period is associated with stronger neonatal Th2 responses in the postnatal period.27Prescott S.L. Taylor A. King B. Dunstan J. Upham J.W. Thornton C.A. et al.Neonatal interleukin-12 capacity is associated with variations in allergen-specific immune responses in the neonatal and postnatal periods.Clin Exp Allergy. 2003; 33: 566-572Crossref PubMed Scopus (69) Google Scholar There is also evidence of a Th2 bias after in vitro stimulation of cord blood mononuclear cells from children with a family history of atopy.28Gabrielsson S. Soderlund A. Nilsson C. Lilja G. Nordlund M. Troye-Blomberg M. Influence of atopic heredity on IL-4-, IL-12- and IFN-gamma-producing cells in in vitro activated cord blood mononuclear cells.Clin Exp Immunol. 2001; 126: 390-396Crossref PubMed Scopus (42) Google Scholar Animal data suggest that strong maternal Th2 immune responses influence the neonatal response, favoring a Th2-type immune response to a novel antigen.29Herz U. Ahrens B. Scheffold A. Joachim R. Radbruch A. Renz H. Impact of in utero Th2 immunity on T cell deviation and subsequent immediate-type hypersensitivity in the neonate.Eur J Immunol. 2000; 30: 714-718Crossref PubMed Scopus (45) Google ScholarNewborn CD4/CD45RA+ T cells are highly responsive to IL-4, IL-4 plus anti-CD2 monoclonal antibodies, and IL-4 plus phytohemagglutinin. In contrast, adult CD4/CD45RA+ T cells are unresponsive to the same stimulation. This sensitivity to IL-4 could also promote a Th2 immune response in the newborn.30Early E.M. Reen D.J. Antigen-independent responsiveness to interleukin-4 demonstrates differential regulation of newborn human T cells.Eur J Immunol. 1996; 26: 2885-2889Crossref PubMed Scopus (37) Google ScholarMaternal helminthic infection can affect both the humoral and cellular responsiveness of newborn children, with production of both Th1- and Th2-type cytokines.31Soboslay P.T. Geiger S.M. Drabner B. Banla M. Batchassi E. Kowu L.A. et al.Prenatal immune priming in onchocerciasis-Onchocerca volvulus-specific cellular responsiveness and cytokine production in newborns from infected mothers.Clin Exp Immunol. 1999; 117: 130-137Crossref PubMed Scopus (42) Google Scholar Proliferative responses of umbilical cord mononuclear cells to helminthic antigens generally parallel those of maternal peripheral blood mononuclear cells. In the setting of maternal infection, neonate's cells do not present a dominant expression of immunity of either Th1 or Th2 in response to helminthic antigens.32Pit D.S. Polderman A.M. Schulz-Key H. Soboslay P.T. Prenatal immune priming with helminth infections: parasite-specific cellular reactivity and Th1 and Th2 cytokine responses in neonates.Allergy. 2000; 55: 732-739Crossref PubMed Scopus (53) Google ScholarA study of cord blood lymphocytes from neonates from a highly endemic area for schistosomiasis, filariasis, and tuberculosis in Kenya showed that the cord blood cells mimicked the response by maternal peripheral blood mononuclear cells. Both produced helminthic antigen-specific IL-5 and/or IFN-γ and purified protein derivative-induced IFN-γ, but little or no IL-4 or IL-5. In contrast, no Ag-specific IL-4, IL-5, or IFN-γ release was detected from cord blood cells of children in the United States. These findings suggest that prenatal exposure does not lead to immune tolerance, but rather primes the immune response in the same fashion as exposure in adults.33Malhotra I. Ouma J. Wamachi A. Kioko J. Mungai P. Omollo A. et al.In utero exposure to helminth and mycobacterial antigens generates cytokine responses similar to that observed in adults.J Clin Invest. 1997; 99: 1759-1766Crossref PubMed Scopus (142) Google Scholar Thus, prenatal exposure and neonatal exposure can produce very different immune responses.Prevalence of geohelminthic infestationMore than 3.5 billion people worldwide are infested with intestinal worms, and the worm burden correlates with poor sanitation and hygiene.34Luong T.V. De-worming school children and hygiene intervention.Int J Environ Health Res. 2003; 13: S153-S159Crossref PubMed Scopus (40) Google Scholar In addition to the presence of latrines and sewage systems, the practice of washing with soap and water is independently associated with a lower risk of helminthic infestation.35Olsen A. Samuelsen H. Onyango-Ouma W. A study of risk factors for intestinal helminth infections using epidemiological and anthropological approaches.J Biosoc Sci. 2001; 33: 569-584Crossref PubMed Scopus (68) Google ScholarIn a study of 1000 children in India, the incidence of helminthic infection was 68.0%. In urban children, the rate of infestation was 56.8%, compared with 79.2% in the rural group. In both populations, Ascaris lumbricoides was the single predominant species. The most common mixed infestation was a combination of A lumbricoides and Trichuris trichiura.36Chandrasekhar M.R. Nagesha C.N. Intestinal helminthic infestation in children.Indian J Pathol Microbiol. 2003; 46: 492-494PubMed Google Scholar Mixed infections with A lumbricoides and Trichuris trichiura are also common in parts of Africa.37Legesse M. Erko B. Medhin G. Comparative efficacy of albendazole and three brands of mebendazole in the treatment of ascariasis and trichuriasis.East Afr Med J. 2004; 81: 134-138PubMed Google Scholar Trichiura whipworm infestation is thought to affect 800 million people throughout tropical and temperate areas.38Cooper E.S. Bundy D.A. Trichuris is not trivial.Parasitol Today. 1988; 4: 301-306Abstract Full Text PDF PubMed Scopus (57) Google ScholarThe immune response against geohelminthic infestationHelminths, unlike most bacteria and viruses, selectively stimulate Th2 function and are among the most potent stimulators of mucosal Th2 responses.39Palmas C. Gabriele F. Conchedda M. Bortoletti G. Ecca A.R. Causality or coincidence: may the slow disappearance of helminths be responsible for the imbalances in immune control mechanisms?.J Helminthol. 2003; 77: 147-153Crossref PubMed Scopus (17) Google Scholar In general, induction of type 2 cytokine responses imparts resistance to intestinal nematodes, whereas type 1 responses can exacerbate the infection. In a study of IL-10-, IL-10/IL-4-, IL-10/IL-12-, IL-4-, and IL-12-deficient mice infected with Trichuris muris, the IL-10-, IL-4-, and IL-10/IL-4-deficient mice were most susceptible to infection. IL-10-deficient mice demonstrated an increase in morbidity and mortality. The increased susceptibility was attributed to a marked increase in type 1 cytokine production. In contrast, those mice deficient in both IL-10 and IL-12 were completely resistant to the infestation. The doubly deficient mice mounted a highly polarized type 2 cytokine response. This suggests that the increased susceptibility of the IL-10-deficient mice was dependent the presence of normal IL-12 with production of a Th1 response.40Schopf L.R. Hoffmann K.F. Cheever A.W. Urban Jr., J.F. Wynn T.A. IL-10 is critical for host resistance and survival during gastrointestinal helminth infection.J Immunol. 2002; 168: 2383-2392PubMed Google ScholarResistance to murine larval Trichuris infestation is mediated by development of a strong Th2 response. A humoral response is not required for effective immunity. The immune response appears to be directed against the worm itself and is unlikely to involve killing of infected gut epithelial cells, as Fas and Fas ligand-deficient mice (which are unable to mount a CD4-mediated cytotoxic response) can readily expel Trichuris muris.41Betts J. deSchoolmeester M.L. Else K.J. Trichuris muris: CD4+ T cell-mediated protection in reconstituted SCID mice.Parasitology. 2000; 121: 631-637PubMed Google Scholar In human Trichuris trichiura infections, excretory and secretory products of the worms preferentially induce IL-10 and tumor necrosis factor-alpha, whereas IL-4 and IL-13 responses are noted with whole worm extracts. Similar responses are seen with Trichuris muris antigens, suggesting similarities in the response to different species of geohelminth.42Turner J. Faulkner H. Kamgno J. Else K. Boussinesq M. Bradley J.E. A comparison of cellular and humoral immune responses to trichuroid derived antigens in human trichuriasis.Parasite Immunol. 2002; 24: 83-93Crossref PubMed Scopus (15) Google ScholarThe immune response to massive helminth infestation differs from the response to trickle (repeated low-dose) infestationIn general, low-level worm infestations tend to be tolerated, and an effective immune response against the worms requires a threshold dose. In human beings, low-dose hookworm exposure results in maturation to egg formation. Patients who are infected develop marked blood eosinophilia but low-level infection does not induce much in the way of T cell– and B cell–dependent immune responses.43Maxwell C. Hussain R. Nutman T.B. Poindexter R.W. Little M.D. Schad G.A. et al.The clinical and immunologic responses of normal human volunteers to low dose hookworm (Necator americanus) infection.Am J Trop Med Hyg. 1987; 37: 126-134Crossref PubMed Scopus (120) Google Scholar In a mouse model, antigen dose also affected the outcome of infection. Low antigen doses favored type 1 responses and susceptibility to the infestation, whereas high antigen doses favored a type 2 response and resistance. High-level challenge infection could only be established after priming of the immune response by a low-level infection. Once type 2 responses were initiated, it was impossible to induce a type 1 response, even using IL-12 (a potent stimulus of type 1 responses).44Bancroft A.J. Else K.J. Humphreys N.E. Grencis R.K. The effect of challenge and trickle Trichuris muris infections on the polarization of the immune response.Int J Parasitol. 2001; 31: 1627-1637Crossref PubMed Scopus (61) Google Scholar In a lamb model, challenge doses of Trichostrongylus colubriformis result in increased antibody titers and eosinophil numbers in control animals but not those that had received previous trickle infection.45Sutherland I.A. Leathwick D.M. Green R. Brown A.E. Miller C.M. The effect of continuous drug exposure on the immune response to Trichostrongylus colubriformis in sheep.Vet Parasitol. 1999; 80: 261-271Crossref PubMed Scopus (18) Google Scholar In mice, an effective immune response to Trichinella spiralis also requires a threshold level of infection.46Bell R.G. Liu W.M. Trichinella spiralis: quantitative relationships between intestinal worm burden, worm rejection, and the measurement of intestinal immunity in inbred mice.Exp Parasitol. 1988; 66: 44-56Crossref PubMed Scopus (9) Google Scholar Active down-regulation of the immune response may occur with trickle infections. In a cattle model that found trickle infection with Fasciola hepatica not to be protective against infection, gamma delta + T cells appeared to down-regulate alpha beta + T-cells.47McCole D.F. Doherty M.L. Baird A.W. Davies W.C. McGill K. Torgerson P.R. T cell subset involvement in immune responses to Fasciola hepatica infection in cattle.Parasite Immunol. 1999; 21: 1-8Crossref PubMed Scopus (16) Google ScholarIn some animal models, repeated low-level infection can produce an immune response. In a mouse model, frequently infected mice demonstrated greater protective immunity against Heligmosomoides polygyrus than mice infected with the same total number of larvae in fewer doses.48Brailsford T.J. Behnke J.M. The dynamics of trickle infections with Heligmosomoides polygyrus in syngeneic strains of mice.Int J Parasitol. 1992; 22: 351-359Crossref PubMed Scopus (27) Google Scholar In sheep, immunity induced by trickle infection results in significant differences in adult female worm length and egg counts.49Sutherland I.A. Brown A.E. Green R.S. Miller C.M. Leathwick D.M. The immune response of sheep to larval challenge with Ostertagia circumcincta and O ostertagi.Vet Parasitol. 1999; 84: 125-135Crossref PubMed Scopus (17) Google Scholar In a porcine model, strong resistance to reinfection was induced by trickle inoculations with Trichuris suis (250 infective eggs twice weekly for 4 weeks). After induction of immunity, there was a 96% reduction in the mean number of established infestations after a challenge dose of 4000 ova.50Pedersen S. Saeed I. Acquired immunity to Trichuris suis infection in pigs.Parasitology. 2001; 123: 95-101Crossref PubMed Scopus (25) Google Scholar In mice, immunization with trickle doses of subcutaneous Wuchereria bancrofti larvae was effective in inducing a protective immune response against W bancrofti.51Rajasekariah G.R. Monteiro Y.M. Netto A. Deshpande L. Subrahmanyam D. Protective immune responses with trickle infections of third-stage filarial larvae of Wuchereria bancrofti in mice.Clin Exp Immunol. 1989; 78: 292-298PubMed Google Scholar In cattle experimentally infected with F hepatica, both single dose and trickle infection promote a type 2 response. Single-dose infection resulted in greater humoral and cellular immunity than trickle infection, but the mean number of flukes recovered was similar in the two groups.52Bossaert K. Farnir F. Leclipteux T. Protz M. Lonneux J.F. Losson B. Humoral immune response in calves to single-dose, trickle and challenge infections with Fasciola hepatica.Vet Parasitol. 2000; 87: 103-123Crossref PubMed Scopus (49) Google Scholar, 53Bossaert K. Jacquinet E. Saunders J. Farnir F. Losson B. Cell-mediated immune response in calves to single-dose, trickle, and challenge infections with Fasciola hepatica.Vet Parasitol. 2000; 88: 17-34Crossref PubMed Scopus (27) Google Scholar Cows with an existing chronic F hepatica infection that are subject to further trickle infection demonstrate tolerance to the organism and moderate superinfection, suggesting that the prevailing immune response was a nonprotective Th2 response.54Clery D. Torgerson P. Mulcahy G. Immune responses of chronically infected adult cattle to Fasciola hepatica.Vet Parasitol. 1996; 62: 71-82Crossref PubMed Scopus (142) Google ScholarInfestation with one worm alters the immune response to a second type of worm, and the immune response to other infectious agentsIn mice, large, single-pulse laboratory infections with Trichuris muris are cleared, but low-level infections of fewer than 20 worms survive for long periods. The number of worms required to induce an immune response is significantly higher in mice concurrently infected with Nematospiroides dubius, allowing trickle infections to survive to the point of egg production.55Behnke J.M. Ali N.M. Jenkins S.N. Survival to patency of low-level infections with Trichuris muris in mice concurrently infected with Nematospiroides dubius.Ann Trop Med Parasitol. 1984; 78: 509-517PubMed Google Scholar In pigs, trickle infection with either Oesophagostomum dentatum or A suum did not influence total worm burdens after challenge infection with the other species, but an effect on worm length was demonstrated.56Helwigh A.B. Christensen C.M. Roepstorff A. Nansen P. Concurrent Ascaris suum and Oesophagostomum dentatum infections in pigs.Vet Parasitol. 1999; 82: 221-234Crossref PubMed Scopus (14) Google ScholarIn mice, persistent infection with Taenia crassiceps cysticerci affects the immune response to subsequent Trypanosoma cruzi infection. In the early stages of the helminth infection, there is a delay in the onset of Trypanosoma cruzi parasitemia, early specific production of IFN-γ, and high specific production of IL-4. Increased susceptibility to Trypanosoma cruzi was observed only when mice were coinfected in late stages of the helminth infection when the immune response against it is predominantly a Th2 type response. The response to Trypanosoma cruzi antigens was then characterized by low levels of both IFN-γ and IL-4.57Rodriguez M. Terrazas L.I. Marquez R. Bojalil R. Susceptibility to Trypanosoma cruzi is modified by a previous non-related infection.Parasite Immunol. 1999; 21: 177-185Crossref PubMed Scopus (45) Google ScholarMost areas of the world with high rates of chronic helminthic infection also have a high incidence of mycobacterial diseases. Low efficacy of BCG has been described in these regions. The immunomodulatory effects of trickle infection may offer an explanation for this phenomenon. Mice with subclinical Schistosoma mansoni infection show an impaired ability to induce an effective Th1 immune response against mycobacteria.58Elias D. Akuffo H. Thors C. Pawlowski A. Britton S. Low dose chronic Schistosoma mansoni infection increases susceptibility to Mycobacterium bovis BCG infection in mice.Clin Exp Immunol. 2005; 139: 398-404Crossref PubMed Scopus (72) Google ScholarEvidence suggesting a negative association between geohelminthic infestation and atopic manifestationsGeohelminths infestation during childhood may contribute to the low prevalence of allergic disease reported from rural areas of the tropics. In a study of 2865 school-aged Ecuadorian children, active geohelminth infection (eggs in stool) and chronic geohelminth infection (≥3564 IU/mL total serum IgE or the presence of anti-A lumbricoides IgG4 antibodies) were negatively associated with allergen skin test reactivity.59Cooper P.J. Chico M.E. Rodrigues L.C. Ordonez M. Strachan D. Griffin G.E. et al.Reduced risk of atopy among school-age children infected with geohelminth parasites in a rural area of the tropics.J Allergy Clin Immunol. 2003; 111: 995-1000Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar In a study of 4433 school-aged children in a rural tropical area of Ecuador, the prese
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