Abstract
T cells mediate the inflammatory responses observed in asthma among genetically susceptible individuals and have been suspected to be prone to epigenetic regulation. However, these relationships are not well established from past clinical studies that have had limited capacity to control for the effects of variable genetic predisposition and early environmental exposures. Relying on a cohort of monozygotic twins discordant for asthma we sought to determine if epigenetic modifications in T cells were associated with current asthma and explored whether such modifications were associated with second hand smoke exposures. Our study was conducted in a monozygotic twin cohort of adult twin pairs (n = 21) all discordant for asthma. Regulatory T cell (Treg) and effector T cell (Teff) subsets were assessed for levels of cellular function, protein expression, gene expression and CpG methylation within Forkhead box P3 (FOXP3) and interferon gamma-γ (IFNγ) loci. Comparisons by asthma and current report of exposure to second hand smoke were made. Treg from asthmatic discordant twins demonstrated decreased FOXP3 protein expression and impaired Treg function that was associated with increased levels of CpG methylation within the FOXP3 locus when compared to their non-asthmatic twin partner. In parallel, Teff from discordant asthmatic twins demonstrated increased methylation of the IFNγ locus, decreased IFNγ expression and reduced Teff function when compared to Teff from the non-asthmatic twin. Finally, report of current exposure to second hand smoke was associated with modifications in both Treg and Teff at the transcriptional level among asthmatics. The results of the current study provide evidence for differential function of T cell subsets in monozygotic twins discordant for asthma that are regulated by changes in DNA methylation. Our preliminary data suggest exposure to second hand smoke may augment the modified T cell responses associated with asthma.
Highlights
Despite the rising rates of asthma prevalence and recent advancements in the use of genome-wide association studies, the mechanisms underlying the immunopathogenesis of asthma have yet to be elucidated
Reduced T Cell Function in Asthmatic Twins To address the hypothesis that functional impairment of Treg and Teff cells are due to molecular modifications in Forkhead box P3 (FOXP3) and interferon gamma-c (IFNc) that are linked mechanistically to outcomes of asthma, we first determined the extent to which Treg and Teff cell function was impaired in the monozygotic twins (MZT) with asthma vs. the paired MZT without asthma
We tested the suppressive activities of Treg against autologous responder Teff and found that function of peripheral blood (PB) Treg from asthmatic twins was significantly lower when compared to non-asthmatic twins (Figure 1A, p,.05)
Summary
Despite the rising rates of asthma prevalence and recent advancements in the use of genome-wide association studies, the mechanisms underlying the immunopathogenesis of asthma have yet to be elucidated. Studies among twins, monozygotic twins (MZT) in particular, have great potential to provide critical information on the role of genetic predisposition given the expected high concordance rate for asthma in twin pairs [2]. In addition to their identical genetic background, MZTs have similar childhood environmental exposures (i.e. diet, residential environment, maternal smoking, sibling order). Previous studies have identified childhood second hand smoke (SHS) as one of the environmental triggers associated with asthma [4,5,6,7]. There is a strong link between SHS and asthma in adults and children [7,8,9,10], the mechanisms are not well established; previous studies were not able to control for genetic makeup as we were able to do in the MZT cohort used in the current study
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
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 callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
