IMMUNOLOGIC, GENETIC AND EXPOSURE-RELATED PATHWAYS TO CHILDHOOD ASTHMA

University Of Arizona, Tucson AZ

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Abstract

DESCRIPTION (provided by applicant): Asthma, the most common chronic disease of childhood in the US, originates in part in altered immune system development in early childhood. Both genetic and environmental factors influence asthma risk, and recent research suggests that the effect of particular gene variants on asthma risk may only be expressed in particular environments. Thus, the objective of this competitive renewal is to assess, prospectively, the roles of early life exposures, variation in innate immunity genes, immune system maturation, and their interactions on the development of asthma related phenotypes (i.e. persistent wheeze, bronchial responsiveness [BR] and lung function alterations) in childhood. Specific aims of the project are to: 1) Assess the influence of interactions between early life exposures and innate immunity gene variants on asthma-like symptoms, airway inflammation, BR and lung function in the first decade of life;2) Establish the relation between patterns of maturation of adaptive immune responses in early life and the development of persistent wheeze and lung function alterations at age 8;and 3) Determine the roles of IL-10 production, T regulatory cells, and monocytes in regulating development of immune responses early in life and in influencing susceptibility to asthma-related phenotypes. The proposed project will utilize an existing birth cohort of almost 500 children, the Infant Immune Study. When these children are 6-10 years old, we will assess baseline lung function, BR using cold dry air, and airway inflammation using exhaled nitric oxide;and obtain allergy skin prick tests, blood samples for cellular studies and IgE, and a questionnaire. These functional measurements of asthma status will be assessed for relation with a) interactions between common early life exposures, assessed prospectively, with innate immunity gene variants, b) characteristic patterns of immune system maturation in the first 5 years of life, and c) the development of T regulatory cell function. We propose a novel approach to identifying which components of complex exposures may be relevant to their protective effect against asthma, by identifying genetic modifiers of these relations. These studies, which have not yet been accomplished in a non-selected population followed from birth, will contribute substantially to our understanding of the relation of innate, regulatory, and adaptive immune responses over time to the subsequent development of asthma related outcomes, holding promise for the design of prevention strategies for this common and complex disease. The objective of this project is to assess the roles of early life exposures, variation in innate immunity genes, immune system maturation, and their interactions on the development of asthma-related outcomes in childhood. The project will be conducted in a birth cohort of almost 500 children, the Infant Immune Study, whose immune system development and respiratory health has been extensively characterized in the first 5 years of life. The study will advance our understanding of the relation of immune responses over time to the subsequent development of asthma and lung function alterations, and will thereby contribute to the design of appropriate prevention strategies for this common and complex disease.