Abstract
Altered DNA methylation patterns in CD4+ T-cells indicate the importance of epigenetic mechanisms in inflammatory diseases. However, the identification of these alterations is complicated by the heterogeneity of most inflammatory diseases. Seasonal allergic rhinitis (SAR) is an optimal disease model for the study of DNA methylation because of its well-defined phenotype and etiology. We generated genome-wide DNA methylation (Npatients = 8, Ncontrols = 8) and gene expression (Npatients = 9, Ncontrols = 10) profiles of CD4+ T-cells from SAR patients and healthy controls using Illumina's HumanMethylation450 and HT-12 microarrays, respectively. DNA methylation profiles clearly and robustly distinguished SAR patients from controls, during and outside the pollen season. In agreement with previously published studies, gene expression profiles of the same samples failed to separate patients and controls. Separation by methylation (Npatients = 12, Ncontrols = 12), but not by gene expression (Npatients = 21, Ncontrols = 21) was also observed in an in vitro model system in which purified PBMCs from patients and healthy controls were challenged with allergen. We observed changes in the proportions of memory T-cell populations between patients (Npatients = 35) and controls (Ncontrols = 12), which could explain the observed difference in DNA methylation. Our data highlight the potential of epigenomics in the stratification of immune disease and represents the first successful molecular classification of SAR using CD4+ T cells.
Highlights
The modest effects of genetic variants in inflammatory diseases indicate the importance of epigenetic mechanisms like DNA methylation to disease pathology
We aimed to test the ability of CD4+ T-cell DNA methylation to separate Seasonal allergic rhinitis (SAR) patients from healthy controls
Seven days post-challenge, total CD4+ T-cells were isolated by magnetic-activated cell sorting (MACS, positive-selection), and the mRNA expression profile determined by gene expression microarray (GEO: GSE50223)
Summary
The modest effects of genetic variants in inflammatory diseases indicate the importance of epigenetic mechanisms like DNA methylation to disease pathology. Studies of inflammatory diseases have shown conflicting results. In monozygotic twins discordant for multiple sclerosis (MS), no significant differences in DNA methylation profile were found [1]. A more recent study of monozygotic twins discordant for psoriasis identified widespread differences between siblings [2]. Other studies of autoimmune diseases have reported varying findings [3]. Discordant monozygotic twin studies benefit from a constant genetic background on which to identify disease-associated epigenetic changes. Intrinsically, such studies tend to involve small samples sizes, and may lack the power to detect small, rare, disease-associated changes in DNA methylation. The variation between studies may be due to disease heterogeneity, variations in disease course and the confounding effects of treatment, and as the disease causing agent is unknown, it is difficult to experimentally model disease pathogenesis
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call