Genetic and epigenetic studies of atopic dermatitis

Abstract

BackgroundAtopic dermatitis (AD) is a chronic inflammatory disease caused by the complex interaction of genetic, immune and environmental factors. There have many recent discoveries involving the genetic and epigenetic studies of AD.MethodsA retrospective PubMed search was carried out from June 2009 to June 2016 using the terms “atopic dermatitis”, “association”, “eczema”, “gene”, “polymorphism”, “mutation”, “variant”, “genome wide association study”, “microarray” “gene profiling”, “RNA sequencing”, “epigenetics” and “microRNA”. A total of 132 publications in English were identified.ResultsTo elucidate the genetic factors for AD pathogenesis, candidate gene association studies, genome-wide association studies (GWAS) and transcriptomic profiling assays have been performed in this period. Epigenetic mechanisms for AD development, including genomic DNA modification and microRNA posttranscriptional regulation, have been explored. To date, candidate gene association studies indicate that filaggrin (FLG) null gene mutations are the most significant known risk factor for AD, and genes in the type 2 T helper lymphocyte (Th2) signaling pathways are the second replicated genetic risk factor for AD. GWAS studies identified 34 risk loci for AD, these loci also suggest that genes in immune responses and epidermal skin barrier functions are associated with AD. Additionally, gene profiling assays demonstrated AD is associated with decreased gene expression of epidermal differentiation complex genes and elevated Th2 and Th17 genes. Hypomethylation of TSLP and FCER1G in AD were reported; and miR-155, which target the immune suppressor CTLA-4, was found to be significantly over-expressed in infiltrating T cells in AD skin lesions.ConclusionsThe results suggest that two major biologic pathways are responsible for AD etiology: skin epithelial function and innate/adaptive immune responses. The dysfunctional epidermal barrier and immune responses reciprocally affect each other, and thereby drive development of AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13223-016-0158-5) contains supplementary material, which is available to authorized users.

Plasmacytoid dendritic cells suppress Th2 responses induced by epicutaneous sensitization

“…Recently, omalizumab (anti‐IgE Ab) treatment was shown to augment pDC IFNα responses and attenuate pDC FcεRI expression . Moreover, the promoter polymorphism of TLR9, which plays a pivotal role in IFNα production of pDCs, has been shown to have putative association with AD . Our results in this study which employed a protein‐patch murine model of EC sensitization are in agreement with these clinical data.…”

Interplay between barrier epithelial cells and dendritic cells in allergic sensitization through the lung and the skin

“…Therefore, it is not very surprising that Genome Wide Association studies revealed that epidermal barrier defects, caused by dysfunction of important TJ or scaffolding proteins, are correlated with allergen sensitization in human diseases . In fact, a recent retrospective PubMed search study disclosed that the most significant risk factor for the development of AD is null mutations in the filaggrin ( Flg ) gene, which codes for a protein with multiple roles in the maintenance of epidermal barrier function . The importance of the epidermal barrier function in sensitization to allergens was emphasized by numerous experimental models where proteins involved in barrier integrity were genetically mutated [reviewed in ].…”

Simultaneous detection of barrier- and immune-related gene variations in patients with atopic dermatitis by reverse blot hybridization assay

“…Recently, there have been many discoveries involving the genetic and epigenetic studies of AD. Two major biological pathways are responsible for AD aetiology: skin barrier function and innate/adaptive immune responses . The dysfunctional epidermal barrier and immune response reciprocally affect each other and thereby drive development of AD .…”

“…Two major biological pathways are responsible for AD aetiology: skin barrier function and innate/adaptive immune responses . The dysfunctional epidermal barrier and immune response reciprocally affect each other and thereby drive development of AD . In terms of skin barrier function, variations in the filaggrin gene ( FLG ), serine protease inhibitor Kazal‐type 5 gene ( SPINK5 ) and serine protease Kallikrein 7 gene ( KLK7 ) have been identified to play roles .…”