title: Asthma discordance in twins is linked to epigenetic modifications of T cells.
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.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Runyon
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Cachola
authors.forename: Nitya
authors.initials: N
authors.lastname: Rajeshuni
authors.forename: Tessa
authors.initials: T
authors.lastname: Hunter
authors.forename: Marco
authors.initials: M
authors.lastname: Garcia
authors.forename: Regina
authors.initials: R
authors.lastname: Ahn
authors.forename: Fred
authors.initials: F
authors.lastname: Lurmann
authors.forename: Ruth
authors.initials: R
authors.lastname: Krasnow
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Jack
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Miller
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
authors.forename: Arunima
authors.initials: A
authors.lastname: Kohli
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Jacobson
authors.forename: Kari C
authors.initials: KC
authors.lastname: Nadeau
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001249:Asthma / Q000209:etiology* / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002648:Child; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D059647:Gene-Environment Interaction; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D014028:Tobacco Smoke Pollution / Q000009:adverse effects*; D014158:Transcription, Genetic; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D014028:Tobacco Smoke Pollution; D007371:Interferon-gamma