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Identification of Candidate Genes for Specific Immune Responsiveness to Cockroach

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Sensitization and exposure to cockroach allergen is one of the strongest predictors of asthma morbidity, especially among African Americans, yet its underlying mechanisms and the genetic etiology for allergenicity specific to cockroach antigen are largely unknown. We hypothesize that there are distinct genes controlling susceptibility to cockroach allergen which subsequently contribute to the added risk of asthma. In particular, cockroach antigen may confer susceptibility to dendritic cell (DC) dysfunction and lead to a polarized Th2 response, a pattern which we hypothesize is (1) unique among cockroach sensitized asthmatic individuals compared to atopic asthma subjects without cockroach, and (2) distinct from a specific immune response to other common aeroallergens. Our hypothesis is based on the following observations in preliminary studies: (1) cockroach allergen is capable of activating DCs, leading to a Th2-type cytokine production, (2) using high- throughput expression profiling, we have already observed specific "transcriptional signatures" in ex vivo plasmacytoid DCs (pDCs) and CD4+ T cells from cockroach-sensitized patients in response to cockroach allergen;and (3) Initial analyses from two ongoing genome-wide association study (GWAS) on asthma in the African American population provided significant evidence for association between cockroach sensitization and several loci. In this application, we will expand our previous study to include a sufficiently powered sample size of human subjects, focus on 2 major purified human DC subtypes [pDCs and myeloid DCs (mDCs)] as opposed to previous cocultured pDCs and CD4+ T cells, and control for important confounders (endotoxin contamination, sensitization to irrelevant allergens, and the potential impact of ethnicity). Our specific aims are: (1) To characterize the specific effects of cockroach extract on DC functions in well-characterized atopic asthma subjects with and without cockroach sensitization by evaluating DC maturation, cytokine production and APC function in T cell polarization ex vivo;and (2) To utilize high-throughput gene expression profiling of isolated DCs for prioritization of candidate genes for cockroach sensitization. Given our findings from this proposal, combined with the immediate availability of raw genetic data from 2 datasets of African ancestry as part of an ongoing GWAS, we believe we are exceptionally positioned to identify candidate genes responsible for specific immune responsiveness to cockroach allergen. These candidates will provide the foundation for a future, NIH-supported application focused on genetic association studies in populations of African descent, and studies on interrogating the role of relevant polymorphisms and risk of cockroach sensitization. Ultimately, these collective studies will result in the characterization of the molecular and genetic mechanisms associated with cockroach-induced Th2-mediated immune responses and allergic diseases, including asthma, with a specific focus on an ethnic minority population (e.g., African Americans) at greatest risk of disease, and lead to better targets of therapy.

PUBLIC HEALTH RELEVANCE: Sensitization and exposure to cockroach allergen is one of the strongest risk factors of asthma morbidity and has a strong genetic basis. We will study the effect of cockroach allergen exposure on dendritic cell function and identify candidate genes for cockroach-induced specific immune response using whole genome expression studies. This will generate a reliable list of candidate genes for future studies in populations of African descent.

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