Role of Skin Barrier and Immune Alterations in Allergic Sensitization

PROJECT SUMMARY/ABSTRACT – PROJECT 3 Atopic dermatitis (AD) often begins in the first year of life and is a precursor of allergic diseases. It is often followed by food allergy (FA), with subsequent development of respiratory allergies. While the frequency of AD and FA are increasing in industrialized countries, posing a large burden on healthcare, primary prevention strategies are not yet successful. There is growing evidence that a farming lifestyle in early life in infants is associated with a diverse microbiome and a reduced risk of atopy. We have recently shown that Old Order Mennonites (OOM), a traditional single-family farming community, are significantly protected against early childhood atopic disease (3.8% AD and 0% FA) as compared to a high-risk Rochester Children cohort (ROC), born to atopic families, that show increased rates of AD (30%) and FA (15%). Consumption of unpasteurized farm milk, exposure to farm animals, and greater microbial diversity were proposed to be associated with the protective effects in OOM children. However, the protective mechanisms responsible for the attenuated development of atopy in OOM children are unknown. Understanding these factors is key for development of preventive strategies against AD and atopic conditions. Recent data suggest that epicutaneous allergen sensitization occurs more readily through a disturbed skin barrier, as in AD. Further, development of FA is highly associated with early, more severe AD, and skin colonization with S. aureus increases the risk to develop FA. The effects of a farming lifestyle on promoting a healthy, homeostatic epidermal skin barrier, diverse microbiome, and normal skin immunity, that prevent development of AD and allergic sensitization, have not yet been evaluated. We hypothesize that lifestyle impacts the development of a healthy infant skin barrier, immunity, and microbiome that may protect from allergic inflammation in the OOM infants or predispose towards development of a perturbed skin barrier function and an aberrant skin immune millieu and microbiome that induce AD and allergic sensitization in the ROC infants. We will test our hypothesis in a new longitudinal birth cohort of high (ROC)- vs. low (OOM)-risk for development of atopy (n=80 in ROC and n=40 in OOM group), in which we will collect lifestyle, environmental exposure, allergic sensitization, trans-epidermal-water loss/TEWL), skin tape strips samples and skin swabs for microbiome, with the following specific aims: Specific aim 1: To determine gene, protein, and microbiome skin biomarkers that modify the risk to develop AD or promote a healthy skin barrier. Specific aim 2: To determine cutaneous biomarkers that promote or protect from development of FA (and other atopic conditions), both with and without concomitant AD. Identification of the skin mechanisms, including specific genes and pathways, and microbiome that predispose to allergic conditions, as compared to those that may be associated with prevention of AD and atopy, can lead to novel prevention as well as therapeutic strategies for AD and the atopic march. This project will have significant impact on public health.