Loss-of-Function Mutations in the Filaggrin Gene and Allergic Contact Sensitization to Nickel

Department of Dermatology and Allergy, University of Bonn, Bonn, Germany.
Journal of Investigative Dermatology (Impact Factor: 6.37). 07/2008; 128(6):1430-5. DOI: 10.1038/sj.jid.5701190
Source: PubMed

ABSTRACT Allergic contact dermatitis is one of the most frequent dermatological problems affecting 7% of the general population. Impaired skin barrier function facilitates the penetration of contact allergens and irritants into the epidermal layer and is regarded as an important cofactor promoting the process of allergic contact sensitization. Filaggrin is crucial for the maintenance of the skin barrier function. Loss-of-function mutations within the filaggrin (FLG) gene are associated with skin barrier diseases such as ichthyosis vulgaris and atopic eczema (AE). To assess the impact of FLG on allergic contact sensitization and plausible intermediate traits, the two prevalent FLG mutations R501X and 2282del4 were typed in 1,502 individuals of the KORA C population-based cohort with extensive dermatologic phenotyping. Associations of FLG mutations with AE could be replicated. Strong associations were seen with dry skin, palmar hyperlinearity, and keratosis pilaris. In addition, an association with contact sensitization to nickel and contact sensitization to nickel combined with intolerance to fashion jewelry, but not with other contact allergens, was observed. From these data, we conclude that a genetically determined FLG deficiency manifests as dry skin and features of ichthyosis vulgaris. In addition, FLG deficiency may also represent a risk factor for contact sensitization to allergens.

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Available from: Joachim Heinrich, Mar 19, 2014
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    • "Besides the intrinsic hazard of a chemical to induce skin sensitization, the risk of becoming sensitized is infl uenced by factors that increase susceptibility to acquire ACD. These include a compromised skin barrier through mutations in fi laggrin (de Jongh et al. 2008, Novak et al. 2008, Thyssen et al. 2008), and altered metabolism of the enzymes N -acetyltransferase 1 and 2 ( NAT1 and NAT2 ). These enzymes have an important role in the detoxifi cation and bioactivation of chemicals through N -acetylation and N-O -acetylation (Najim et al. 2005, Schnuch et al. 1998, Nacak et al. 2006). "
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    ABSTRACT: Allergic contact dermatitis (ACD) is a hypersensitivity immune response induced by small protein-reactive chemicals. Currently, the murine local lymph node assay (LLNA) provides hazard identification and quantitative estimation of sensitizing potency. Given the complexity of ACD, a single alternative method cannot replace the LLNA, but it is necessary to combine methods through an integrated testing strategy (ITS). In the development of an ITS, information regarding mechanisms and molecular processes involved in skin sensitization is crucial. The recently published adverse outcome pathway (AOP) for skin sensitization captures mechanistic knowledge into key events that lead to ACD. To understand the molecular processes in ACD, a systematic review of murine in vivo studies was performed and an ACD molecular map was constructed. In addition, comparing the molecular map to the limited human in vivo toxicogenomic data available suggests that certain processes are similarly triggered in mice and humans, but additional human data will be needed to confirm these findings and identify differences. To gain insight in the molecular mechanisms represented by various human in vitro systems, the map was compared to in vitro toxicogenomic data. This analysis allows for comparison of emerging in vitro methods on a molecular basis, in addition to mathematical predictive value. Finally, a survey of the current in silico, in chemico, and in vitro methods was used to indicate which AOP key event is modeled by each method. By anchoring emerging classification methods to the AOP and the ACD molecular map, complementing methods can be identified, which provides a cornerstone for the development of a testing strategy that accurately reflects the key events in skin sensitization.
    Critical Reviews in Toxicology 07/2014; 44(7):1-10. DOI:10.3109/10408444.2014.925425 · 6.41 Impact Factor
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    • "Nickel is considered to be the most frequent contact allergen for patients with AD [12]. A recently published study of a German population showed a positive association between filaggrin mutations, which have been shown to be strongly associated with AD, and contact sensitization to nickel [13]. Another study also reported a positive association between nickel sensitization and AD, in a subanalysis of nonpierced women [14]. "
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    ABSTRACT: Contact dermatitis is produced by external skin exposure to an allergen, but sometimes a systemically administered allergen may reach the skin and remain concentrated there with the aid of the circulatory system, leading to the production of systemic contact dermatitis (SCD). Metals such as nickel, cobalt, chromium, and zinc are ubiquitous in our environment. Metal allergy may result in allergic contact dermatitis and also SCD. Systemic reactions, such as hand dermatitis or generalized eczematous reactions, can occur due to dietary nickel or cobalt ingestion. Zinc-containing dental fillings can induce oral lichen planus, palmoplantar pustulosis, and maculopapular rash. A diagnosis of sensitivity to metal is established by epicutaneous patch testing and oral metal challenge with metals such as nickel, cobalt, chromium, and zinc. In vitro tests, such as the lymphocyte stimulating test (LST), have some advantages over patch testing to diagnose allergic contact dermatitis. Additionally, the determination of the production of several cytokines by primary peripheral blood mononuclear cell cultures is a potentially promising in vitro method for the discrimination of metal allergies, including SCD, as compared with the LST.
    Dermatology Research and Practice 05/2012; 2012:749561. DOI:10.1155/2012/749561
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    • "When the site of hapten exposure was not the same as the CpG administration site, no effect on skin sensitization was observed, illustrating that co-existing inflammatory signaling in the same skin area is needed to enhance the response (Akiba et al., 2004). There is evidence that a reduced skin barrier function, caused by mutations in the filaggrin gene, increases the sensitization rates to nickel (Novak et al., 2008; Metz & Maurer, 2009). Possibly, the impaired barrier function leads to more pathogen exposure and increased TLR activation. "
    Contact Dermatitis, 12/2011; , ISBN: 978-953-307-577-8
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