Background Mutations in the filaggrin gene (FLG) affect epidermal barrier function and increase the risk of atopic dermatitis (AD). We hypothesized that FLG mutations affect immune cell composition... Show moreBackground Mutations in the filaggrin gene (FLG) affect epidermal barrier function and increase the risk of atopic dermatitis (AD). We hypothesized that FLG mutations affect immune cell composition in a general pediatric population. Therefore, we investigated whether school-aged children with and without FLG mutations have differences in T- and B-cell subsets.Methods This study was embedded in a population-based prospective cohort study, the Generation R Study, and included 523 children of European genetic ancestry aged 10 years. The most common FLG mutations in the European population (R501X, S1085CfsX36, R2447X, and S3247X) were genotyped. Additionally, 11-color flow cytometry was performed on peripheral blood samples to determine helper T (Th), regulatory T (Treg), and CD27(+) and CD27(-) memory B cells. Subset analysis was performed in 358 non-AD and 102 AD cases, assessed by parental questionnaires.Results FLG mutations were observed in 8.4% of the total population and in 15.7% of the AD cases. Children with any FLG mutation had higher Th22 cell numbers compared to FLG wild-type children in the general and non-AD population. Children with and without FLG mutations had no difference in Th1, Th2, Th17, Treg, or memory B-cell numbers. Furthermore, in children with AD, FLG mutation carriership was not associated with differences in T- and B-cell subsets.Conclusions School-aged children of a general population with FLG mutations have higher Th22 cell numbers, which reflects the immunological response to the skin barrier dysfunction. FLG mutations did not otherwise affect the composition of the adaptive immunity in this general pediatric population. Show less
Drongelen, V. van; Danso, M.O.; Out, J.J.; Mulder, A.; Lavrijsen, A.P.M.; Bouwstra, J.A.; Ghalbzouri, A. el 2015
Atopic Dermatitis (AD) is a frequent occurring inflammatory skin disease causing physical discomfort, social embarrassment and stress. This skin disease is characterized by decreased skin barrier... Show moreAtopic Dermatitis (AD) is a frequent occurring inflammatory skin disease causing physical discomfort, social embarrassment and stress. This skin disease is characterized by decreased skin barrier function and various other epidermal changes, as well as immunological changes. A decreased skin barrier function allows environmental factors such as allergens and pathogens to penetrate through the skin and evoke an immunological response, which in turn may negatively affect the skin barrier function. The skin barrier is composed of cornified keratinocytes, extracellular lipids and multiple proteins, including filaggrin. The discovery of mutations in the filaggrin gene as a major risk factor for development of AD has intensified research on this protein and its role in AD development, but its exact role in AD is still not clarified. This thesis describes the development of several reconstructed human skin equivalents (HSEs) which recapitulate various characteristics of AD. They display for example reduced filaggrin expression or alterations in epidermal characteristics due to the presence of AD-related inflammatory cytokines. These HSEs are a powerful tool that in the future might be used for screening purposes and/or development of new therapies for this life disabling skin disease. Show less
Janssens, M.; Mulder, A.A.; Smeden, J. van; Pilgram, G.S.K.; Wolterbeek, R.; Lavrijsen, A.P.M.; ... ; Bouwstra, J.A. 2013
Formation of the epidermal barrier is a complex process involving the tight regulation of the expression of structural proteins, enzymes and cytokines, implementing different signaling pathways... Show moreFormation of the epidermal barrier is a complex process involving the tight regulation of the expression of structural proteins, enzymes and cytokines, implementing different signaling pathways depending on the differentiation stage of KC. Alterations of skin barrier formation occur as consequence of many skin diseases but can also be the primary event leading to skin diseases. Organotypic skin models have greatly contributed to delineate molecular mechanisms underlying the epidermal differentiation process. In this thesis we have adapted a human organotypic skin model to knock-down individual genes and study their impact on the differentiation of epidermal KC in vitro. Using this model we have provided new insights in the formation of the skin barrier of human skin. Show less
Kazem, S.; Meijden, E. van der; Struijk, L.; Gruijl, F.R. de; Feltkamp, M.C.W. 2012
