aSaffrey R, bRead J, bHolt PG, bStrickland DH
aMurdoch Children’s Research Institute and Dept Paediatrics, University Melbourne
bThe Kids Research Institute Australia, The University of Western Australia, Perth Australia
The most common chronic inflammatory disorders afflicting humans are allergic diseases. Genetically susceptible individuals have dysfunctional immune responses that cumulatively result in the adaptive generation of IgE to specific environmental antigen(s). Defining the molecular pathways that are disrupted in IgE mediated antigen sensitization has proven to be one of the most elusive aspects in our understanding of how to better direct approaches towards preventive or improved treatment strategies targeting allergic disease. The development of allergic disease appears to involve a complex interplay between genetic susceptibility and environmental exposure. Recent findings suggest a role for epigenetic change, in particular DNA methylation, in the causal pathway. The central aim of this study is to identify differences in epigenetic profiles of specific immune cell populations specifically associated with environmentally induced allergen sensitization in humans, using allergic asthma as an archetypal allergic disease. Recent unequivocal data in inducible mouse models of asthma have demonstrated specific disruption of DNA methylation profile in the peripheral T cell compartment. The equivalent data is lacking in humans due to the difficulties associated with teasing out the relative roles of genes and environment in the modulation of epigenetic state. To overcome such issues associated with population diversity, we have chosen the elegant approach of studying human twins in childhood. This study aims to definitively test the link between altered DNA methylation in isolated subpopulations of immune cells and allergy in genetically identical twins discordant for allergic sensitization to house dust mite. The first aim is to Identify methylation sensitive genes (MSG) associated with gene expression differences in monozygotic twins discordant for house dust mite (HDM) sensitization (SPT+ and SPT-) through a within-pair comparison of the epigenetic and gene expression profiles of cells of the adaptive immune system (CD4+ T and APC cells). We have used flow cytometry to sort purify subsets of immune cells from PBMC of twin pairs and are currently in the process of examining genome wide methylation profiles. Additionally we have characterized PBMC samples to determine frequency, activation state and function of the immune cell subpopulations and are currently in the process of data analysis.
Plain language summary: Many humans suffer from allergic disease, which often develops in early life years, can be severe and impose a significant burden over the course of their lives. Why some people develop disease and others do not is still not well understood. We are studying immune cells from identical twins of which one suffers and one does not suffer from allergic disease to identify specific mechanisms that may play important roles in disease development.
Funder: National Health and Medical Research Council of Australia.