Known Allergen Structures Predict Schistosoma mansoni IgE-Binding Antigens in Human Infection

This is the final published paper. The article was originally published in Frontiers in Immunology 6:26, 03 February 2015, doi: 10.3389/fimmu.2015.00026The IgE response has been associated with both allergic reactions and immunity to metazoan\ud parasites. Recently, we hypothesized that all environmental allergens bear structural\ud homology to IgE-binding antigens from metazoan parasites and that this homology defines\ud the relatively small number of protein families containing allergenic targets. In this study,\ud known allergen structures (Pfam domains) from major environmental allergen families were\ud used to predict allergen-like (SmProfilin, SmVAL-6, SmLipocalin, SmHSP20, Sm triosephosphate\ud isomerase, SmThioredoxin, Sm superoxide dismutase, SmCyclophilin, and Sm phosphoglycerate\ud kinase) and non-allergen-like [Sm dynein light chain (SmDLC), SmAldolase\ud SmAK, SmUbiquitin, and Sm14-3-3] proteins in Schistosoma mansoni. Recombinant antigens\ud were produced in Escherichia coli and IgG1, IgG4, and IgE responses against them\ud measured in a cohort of people (n = 222) infected with S. mansoni. All allergen-like antigens\ud were targeted by IgE responses in infected subjects, whilst IgE responses to the nonallergen-like\ud antigens, SmAK, SmUbiquitin, and Sm14-3-3 were essentially absent being of\ud both low prevalence and magnitude.Two new IgE-binding Pfam domain families, not previously\ud described in allergen family databases, were also found, with prevalent IgE responses\ud against SmDLC (PF01221) and SmAldolase (PF00274). Finally, it was demonstrated that\ud immunoregulatory serological processes typically associated with allergens also occurred\ud in responses to allergen-like proteins in S. mansoni infections, including the production of\ud IgG4 in people responding with IgE and the down-regulation of IgE in response to increased\ud antigen exposure from S. mansoni eggs. This study establishes that structures of known\ud allergens can be used to predict IgE responses against homologous parasite allergen-like\ud molecules (parallergens) and that serological responses with IgE/IgG4 to parallergens mirror\ud those seen against allergens, supporting our hypothesis that allergenicity is rooted in\ud expression of certain protein domain families in metazoan parasites.We would like to thank the people of Namoni Village for their\ud time and co-operation in the study as well as the field workers\ud of the Ugandan Virus Research Institute and the Kenyan Medical\ud Research Institute. Thanks go also to Shona Wilson, Joseph\ud Mwatha, and Timothy Kamau, for their knowledge and skill in\ud collecting and preparing samples for the study. We would also\ud like to thank Maureen Laidlaw of the Schistosomiasis Research\ud Group (University of Cambridge) for her expert technical assistance;\ud Undergraduate students Aws Sadik, Matthew J Murray,\ud Emma Robbins, and Emily Day for their hard work during final\ud year projects in the Schistosomiasis Research Group; and Prof.\ud Dame Janet Thornton at the European Bioinformatics Institute\ud for her continued help and support. This work was supported by\ud the Wellcome Trust via program WT 083931/Z/07/Z and project\ud WT 094317/Z/10/Z grants and by the European Commission via\ud FP7-CP-IP-SICA scheme grant 242107

The influence of early-life animal exposure on the risk of childhood atopic dermatitis, asthma and allergic rhinoconjunctivitis: findings from the Danish National Birth Cohort

BACKGROUND: Early-life animal exposure has been associated with both protective and harmful effects on asthma and allergic disease. We aimed to explore factors that may modify associations of early-life animal exposure with asthma and allergic disease, so as to better understand these differences in findings. METHODS: We used data from ≤84 478 children from the Danish National Birth Cohort recruited during pregnancy between 1996 and 2002, and linked registry data up to the child's 13th birthday. Adjusted Cox models were used to examine associations of early-life cat, dog, rabbit, rodent, bird and livestock exposure with atopic dermatitis, asthma and allergic rhinoconjunctivitis overall, and by source of exposure (domestic or occupation), parental history of asthma or allergy, maternal education level and timing of exposure. RESULTS: Overall, associations between animal exposure and the three outcomes of interest were weak. However, dog exposure was associated with marginally lower risk of atopic dermatitis and asthma [adjusted hazard ratio (aHR) = 0.81, 95% CI: 0.70-0.94 and 0.88, 95% CI: 0.82-0.94, respectively], whereas prenatal domestic bird exposure was associated with slightly increased risk of asthma (aHR = 1.18, 95% CI: 1.05-1.32). Source of exposure, parental history of asthma or allergy and timing of exposure modified associations. Early-life animal exposure did not appear to increase the risk of allergic rhinoconjunctivitis (aHR range = 0.88, 95% CI: 0.81-0.95 to 1.00, 95% CI: 0.91-1.10). CONCLUSIONS: The overall weak associations observed between animal exposure and atopic dermatitis, asthma and allergic rhinoconjunctivitis were modified by type of animal, source of exposure, parental history of asthma or allergy and timing of exposure, suggesting that these factors should be considered when assessing the risks associated with early-life animal exposure

Effects of treating helminths during pregnancy and early childhood on risk of allergy-related outcomes: Follow-up of a randomized controlled trial.

BACKGROUND: Helminth infections, common in low-income countries, may protect against allergy-related disease. Early exposure may be a key. In the Entebbe Mother and Baby Study, treating helminths during pregnancy resulted in increased eczema rates in early childhood. We followed the cohort to determine whether this translated to increased asthma rates at school age. METHODS: This randomized, double-blind, placebo-controlled trial, conducted in Entebbe, Uganda, had three interventions. During pregnancy, women were randomized, simultaneously, to albendazole vs placebo and to praziquantel vs placebo. Their children were independently randomized to quarterly albendazole vs placebo from age 15 months to 5 years. We here report follow-up to age 9 years. Primary outcomes at 9 years were recent reported wheeze, skin prick test positivity (SPT) to common allergens and allergen-specific IgE positivity to dust mite or cockroach. Secondary outcomes were doctor-diagnosed asthma and eczema rates between 5 and 9 years, recent eczema, rhinitis and urticaria at 9 years, and SPT and IgE responses to individual allergens. RESULTS: 2507 pregnant women were enrolled; 1215 children were seen at age nine, of whom 1188 are included in this analysis. Reported wheeze was rare at 9 years (3.7%) while SPT positivity (25.0%) and IgE positivity (44.1%) were common. There was no evidence of a treatment effect for any of the three interventions on any of the primary outcomes. CONCLUSIONS: Prenatal and early-life treatment of helminths, in the absence of change in other exposures, is unlikely to increase the risk of atopic diseases later in childhood in this tropical, low-income setting

Epidemiology and control of human schistosomiasis in Tanzania.

In Tanzania, the first cases of schistosomiasis were reported in the early 19th century. Since then, various studies have reported prevalences of up to 100% in some areas. However, for many years, there have been no sustainable control programmes and systematic data from observational and control studies are very limited in the public domain. To cover that gap, the present article reviews the epidemiology, malacology, morbidity, and the milestones the country has made in efforts to control schistosomiasis and discusses future control approaches. The available evidence indicates that, both urinary and intestinal schistosomiasis are still highly endemic in Tanzania and cause significant morbidity.Mass drug administration using praziquantel, currently used as a key intervention measure, has not been successful in decreasing prevalence of infection. There is therefore an urgent need to revise the current approach for the successful control of the disease. Clearly, these need to be integrated control measures.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Effects of treatment on IgE responses against parasite allergen-like proteins and immunit to reinfection in childhood schistosome and hookworm coinfections

Naturally occurring human immunity to both schistosomiasis and hookworm infection has been associated with IgE responses against parasite allergen-like proteins. Since the two helminths frequently coinfect the same individuals, there is growing advocacy for their concurrent treatment. However, both helminths are known to exert strong immunomodulatory effects; therefore, coinfected individuals could have immune responses different from those characteristically seen in monoinfected individuals. In this study, we measured changes in IgE, IgG1, and IgG4 responses to schistosome and hookworm antigens, including the allergen-like proteins Schistosoma mansoni tegumental-allergen-like 1 protein (SmTAL1), SmTAL2, and Necator americanus Ancylostoma-secreted protein-2 (Na-ASP-2), following concurrent treatment of schoolchildren coinfected withSchistosoma mansoni and hookworm. Antibody responses to schistosome egg (soluble egg antigen and SmTAL2) or somatic adult hookworm (AHW) antigens either decreased after treatment or were unchanged, whereas those to schistosome worm antigens (soluble worm antigen and SmTAL1) increased. The observed different effects of treatment likely reflect the different modes of drug action and sites of infection for these two helminths. Importantly, there was no evidence that the simultaneous treatment of coinfected children with praziquantel and albendazole affected schistosome- and hookworm-specific humoral responses differently from those characteristic of populations in which only one organism is endemic; schistosome- and hookworm-specific responses were not associated, and there was no evidence for cross-regulation. Posttreatment increases in the levels of IgE to schistosome worm antigens were associated with lower Schistosoma mansoni reinfection intensity, while no associations between humoral responses to AHW antigen and protection from hookworm reinfection were observed in this sample of school-aged children

Suppression of basophil histamine release and other IgE-dependent responses in childhood Schistosoma mansoni/hookworm coinfection.

BACKGROUND: The poor correlation between allergen-specific immunoglobulin E (asIgE) and clinical signs of allergy in helminth infected populations suggests that helminth infections could protect against allergy by uncoupling asIgE from its effector mechanisms. We investigated this hypothesis in Ugandan schoolchildren coinfected with Schistosoma mansoni and hookworm. METHODS: Skin prick test (SPT) sensitivity to house dust mite allergen (HDM) and current wheeze were assessed pre-anthelmintic treatment. Nonspecific (anti-IgE), helminth-specific, and HDM-allergen-specific basophil histamine release (HR), plus helminth- and HDM-specific IgE and IgG4 responses were measured pre- and post-treatment. RESULTS: Nonspecific- and helminth-specific-HR, and associations between helminth-specific IgE and helminth-specific HR increased post-treatment. Hookworm infection appeared to modify the relationship between circulating levels of HDM-IgE and HR: a significant positive association was observed among children without detectable hookworm infection, but no association was observed among infected children. In addition, hookworm infection was associated with a significantly reduced risk of wheeze, and IgG4 to somatic adult hookworm antigen with a reduced risk of HDM-SPT sensitivity. There was no evidence for S. mansoni infection having a similar suppressive effect on HDM-HR or symptoms of allergy. CONCLUSIONS: Basophil responsiveness appears suppressed during chronic helminth infection; at least in hookworm infection, this suppression may protect against allergy

Suppression of basophil histamine-release and other IgE-dependent responses in childhood Schistosoma mansoni hookworm co-infection

Background. The poor correlation between allergen-specific-IgE (asIgE) and clinical signs of allergy in helminth infected populations suggests that helminth infections could protect against allergy by uncoupling asIgE from its effector mechanisms. We investigated this hypothesis in Ugandan schoolchildren coinfected with Schistosoma mansoni and hookworm. Methods. Skin prick test (SPT) sensitivity to house dust mite allergen (HDM) and current wheeze were assessed pre-anthelmintic treatment. Non-specific (anti-IgE), helminth-specific and HDM-allergen-specific basophil histamine release (HR), plus helminth- and HDM-specific IgE and IgG4 responses were measured pre- and post-treatment. Results. Non-specific- and helminth-specific-HR, and associations between helminth-specific-IgE and helminth-specific-HR increased post-treatment. Hookworm infection appeared to modify the relationship between circulating levels of HDM-IgE and HR: a significant positive association was observed among children without detectable hookworm infection but no association was observed among infected children. In addition, hookworm infection was associated with a significantly reduced risk of wheeze, and IgG4 to somatic adult hookworm antigen with a reduced risk of HDM-SPT sensitivity. There was no evidence for S. mansoniinfection having a similar suppressive effect on HDM-HR or symptoms of allergy. Conclusions. Basophil responsiveness appears suppressed during chronic helminth infection; at least in hookworm infection, this suppression may protect against allergy

Suppression of basophil histamine release and other IgE-dependent responses in childhood Schistosoma mansoni/hookworm coinfection.

BACKGROUND: The poor correlation between allergen-specific immunoglobulin E (asIgE) and clinical signs of allergy in helminth infected populations suggests that helminth infections could protect against allergy by uncoupling asIgE from its effector mechanisms. We investigated this hypothesis in Ugandan schoolchildren coinfected with Schistosoma mansoni and hookworm. METHODS: Skin prick test (SPT) sensitivity to house dust mite allergen (HDM) and current wheeze were assessed pre-anthelmintic treatment. Nonspecific (anti-IgE), helminth-specific, and HDM-allergen-specific basophil histamine release (HR), plus helminth- and HDM-specific IgE and IgG4 responses were measured pre- and post-treatment. RESULTS: Nonspecific- and helminth-specific-HR, and associations between helminth-specific IgE and helminth-specific HR increased post-treatment. Hookworm infection appeared to modify the relationship between circulating levels of HDM-IgE and HR: a significant positive association was observed among children without detectable hookworm infection, but no association was observed among infected children. In addition, hookworm infection was associated with a significantly reduced risk of wheeze, and IgG4 to somatic adult hookworm antigen with a reduced risk of HDM-SPT sensitivity. There was no evidence for S. mansoni infection having a similar suppressive effect on HDM-HR or symptoms of allergy. CONCLUSIONS: Basophil responsiveness appears suppressed during chronic helminth infection; at least in hookworm infection, this suppression may protect against allergy