Epigenetic Trajectories to Childhood Asthma

Abstract

Asthma is the most common chronic disease of childhood and remains a public health concern in the United States and worldwide. Although it is characterized by recurrent, reversible bronchial obstruction, asthma is variable in its clinical expression and includes distinct cellular and molecular endotypes. In most cases, asthma manifestations (including subtle alterations to both adaptive and innate immunity) begin during the preschool years, even when chronic symptoms do not appear until adulthood. However, the lack of firm diagnostic criteria to distinguish children who will wheeze only transiently during early life viral illnesses from children who will wheeze persistently and then develop asthma prevents pinpointing the true inception of a child’s trajectory to the disease. Even though the evidence supporting the early origins of asthma is strong, the underlying mechanisms of asthma inception remain unknown. In this context, epigenetics is currently receiving much attention as a potential contributor to asthma pathogenesis in early life. To the extent that environmental and developmental factors are essential for asthma pathogenesis, epigenetic mechanisms are a plausible source of phenotypic variability because they mediate the responses to environmental stimuli and the timed unfolding of developmental programs. This work aims to better understand the roles of epigenetic and environmental mechanisms involved in asthma pathogenesis. The work presented herein shows that 1) an epigenetic trajectory to asthma is in place already at birth, at least in a subset of children, 2) distinct trajectories are evident in children born to asthmatic and non-asthmatic mothers, a finding that supports the importance of pre-natal exposure, and 3) in mice, protection from asthma conferred by exposure to products from traditional farming environments likely involves gammadelta17 T cells. Overall our data identify compelling candidates for future studies of the mechanisms underlying asthma development in humans and mouse models.