Asthma is a complex trait with an established genetic basis that represents a major public health burden. The usual source of the lower airway inflammation characteristic of asthma is a Th2-mediated reaction initiated by common environmental allergens which involves the production of antigen-specific IgE antibodies. An inverse relationship between allergic disease and helminthic infection, also characterized by elevated IgE, has long been observed, and individuals with a history of asthma appear to be 'protected' from helminthic parasites (i.e., Schistosoma mansoni). Many genes have been associated with asthma, but to date very few have replicated. Recently, three independent genome-wide association studies (GWAS) representing over 40,000 DNA samples have identified significant associations between polymorphisms in and flanking the Interleukin-33 (IL33) gene and asthma, rendering IL33 as one of the strongest candidate genes for asthma to date. We observed significant associations between the same IL33 'asthma risk' variants and outcomes associated with schistosomiasis in villagers living in an endemic region in Bahia, Brazil. IL-33 is a new member of the IL-1 family that induces Th2 cytokines. Its receptor, interleukin 1-like (or ST2) exists as membrane and circulating soluble proteins, and ST2 polymorphisms were also associated with asthma in one of the asthma GWAS's. The mechanism(s) by which IL-33 skews the Th2 response at the level of the mucosa, leading to asthma and immunity to parasites, is not known. Our ongoing genetic epidemiology studies in large cohorts characterized for risk of asthma and resistance to schistosomiasis provide a unique opportunity to test the hypothesis that IL33 polymorphisms contribute to both diseases by altering the function of IL-33. To accomplish our goals, we have amassed a multidisciplinary team of investigators from 6 institutions to: (i) quantify circulating IL-33 and its receptor, sST2, in serum from 500 asthma cases and controls using a mass spectrometry (MS)- based method called 'multiple reaction monitoring' (MRM) that provides absolute quantification of protein, and to test for association between IL-33 and sST2 concentrations and IL33 genotypes/haplotypes; (ii) characterize the effects of IL33 genetic variation on production of IL-33 and sST2, in response to Th2-promoting antigens (dust mite, schistosome) in human myeloid cells; (iii) test for co-associations between the IL33 variants/haplotypes that skew the Th2 response in asthma and a quantitative outcome representing resistance (S. mansoni antigen-specific IgE:IgG4 ratio) to schistosomiasis and serum levels of IL-33 and ST2 in samples from 500 villagers living in a region endemic for schistosomiasis in Bahia, Brazil; and (iv) develop a humanized murine model of IL33 haplotypes associated with risk/resistance to asthma/schistosomiasis to elucidate the functional role of the IL33 gene in these diseases. Results from this study will provide novel insights into the role of IL-33 in the pathogenesis of two diseases of high public health significance.
We will investigate the biological function of interleukin-33 (IL33), one of the most replicated candidate genes for asthma emanating from three genome-wide association studies (GWAS). Our multidisciplinary approach integrates proteomics, genetics, lung biology, and the development of an IL33 humanized mouse model. We will explore the dual function of IL33 in the pathogenesis of both asthma and resistance to schistosomiasis.
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