Helminth-allergy associations in rural and urban Uganda: insights from antibody studies

Abstract

Background: Allergy-related disease (ARD) is a major cause of morbidity in high-income countries (HICs). Although populations in tropical low-income countries (LICs), and in rural (compared to urban) settings, seem to be remarkably protected, the trends are fast changing as these communities undergo an epidemiological transition exemplified by changing helminth exposure patterns. Helminth exposure is of particular interest in understanding the epidemiology of ARD because of the homology between several helminth antigens and allergens, and the many similarities between helminth- and allergen-specific immune responses. Antibodies, especially IgE, are key constituents of the analogous immune responses to helminths and allergens, and are among the chief mediators of the effector cell activation underlying ARDs. While mindful of effects of other environmental exposures on epidemiological trends of ARDs in LICs, this PhD project postulated a crucial role for helminth-induced antibody profiles. Methods: This research project obtained data on current helminth infections and allergy-related outcomes, and measured helminth- and allergen-specific antibody profiles, with immunoassays that included allergen and carbohydrate microarrays. Samples used were collected from Ugandan participants of three cross-sectional surveys: the baseline and outcome surveys of a cluster-randomised trial of intensive versus standard anthelminthic treatment in rural Schistosoma mansoni (Sm)-endemic islands, and a parallel survey in proximate urban communities with lower helminth exposure. A casecontrol study on asthma among schoolchildren enabled assessment of a role for antibodies in allergic disease. Results: Cross-sectional analyses showed that setting (rural vs. urban) was an effect modifier for risk factors (such as location of birth, current helminth [Sm] infection and other helminthrelated factors) for atopy and clinical allergy outcomes, and for atopy–clinical allergy associations. Although Sm infection was an important risk factor for skin prick test (SPT) reactivity and allergen-specific (as) IgE sensitisation (inversely or otherwise), definitive statistical proof for a role of helminth exposure in the observed effect modification between the two settings was not evident: helminths alone may not fully explain the differences observed. To obtain further insight into helminth-allergy associations, this project assessed total, Sm- and asIgE and asIgG4 and found strong positive associations with current Sm infection and atopic sensitisation (but not with ARD), but inverse associations between total IgE/ asIgE ratios, asIgG4/ asIgE ratios and SPT reactivity and asthma. This supported a role for helminth-induced antibodies in individual positive helminth-atopy associations, and for the IgG4–IgE balance and the total IgE–allergen-specific IgE balance in the low overall prevalence of clinical allergies in such settings. Helminths have a range of antigens that are strikingly homologous to common allergens, including cross-reactive carbohydrate determinant (CCD) N-glycans carrying core b-1,2- xylose and a-1,3-fucose epitopes. Analyses showed distinctive relationships between IgE/IgG reactivity to these motifs and Sm infection intensity and the rural (versus urban) environment, and implied that they are abundant on common allergen extracts (such as house dust mite, German cockroach and peanut extracts used in standard ImmunoCAP assays), which likely results in false diagnosis of allergic sensitisation in tropical helminth-endemic settings. Microarray component-resolved IgE analyses showed that rural participants had lower responses to non-glycosylated, established major allergenic protein components, but higher reactivity to CCDs, than urban participants. Elevated anti-CCD IgE did not translate into clinical allergy. Indeed, an inverse association between asthma and reactivity to core a-1,3-fucose substituted N-glycans suggested that reactivity to specific (but not all) CCD epitopes might contribute to protection against clinical allergy. Conclusions: The current PhD research provides important insight into mechanisms underlying the complex epidemiological helminth-allergy trends in LICs. Notably, this work highlights the importance of balance in IgG4–IgE and total IgE–asIgE in inhibition of clinical allergy. This work also demonstrates strong associations between Sm exposure and anti-CCD IgE, which complicates atopy assessment, with implications for understanding the contribution of atopy to ARD in tropical LICs. The finding that schistosomiasis-associated core a-1,3-fucose-specific IgE is inversely associated with asthma is suggestive of a potential role of specific carbohydrate epitopes in protection against clinical allergy, which merits further investigation.