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: 7.22). 07/2008; 128(6):1430-5. DOI: 10.1038/sj.jid.5701190
Source: PubMed


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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    • "It was also observed in the study that the presence of an FLG gene mutation may be the cause of lowering the age at which the allergy induced by contact with nickel sulphate occurs. It has been also confirmed that the existence of a mutation in the FLG gene and body piercing at an early age may increase the risk of a more rapid allergic and inflammatory reactions induced by nickel haptens and may cause retention of those conditions in adult patients as well [48–50]. "
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    ABSTRACT: The results of long-term epidemiological studies show that the number of people suffering from allergic diseases, especially from food allergies and atopic dermatitis (AD), is still increasing. Although the research thus far has been conducted mainly in Europe, North America, and Asia, there are also data appearing from the first studies in that field among the African population. This may indicate the importance of the problem of allergic diseases. The discovery that loss-of-function mutations in the gene coding filaggrin (FLG) are the cause of ichthyosis vulgaris marked a significant breakthrough in understanding the pathogenesis of allergic diseases. The presence of mutations in the filaggrin gene is also an important factor that predisposes to such allergic diseases as: allergic rhinitis, atopic dermatitis, atopic asthma, and food allergy. So far, over 40 loss-of-function mutations and numerous silent mutations in filaggrin have been discovered.
    Przegląd Gastroenterologiczny 09/2014; 9(4):200-207. DOI:10.5114/pg.2014.45100 · 0.38 Impact Factor
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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 · 5.10 Impact Factor
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    • "Recent findings have shown that disruption of epidermal barrier systems, for example, filaggrin deficiency, is involved in the pathogenesis of atopic diseases via augmented percutaneous sensitization with allergens that penetrate the body through the abrogated barrier of the SC1234. Contact sensitization against small metal ions such as nickel has been associated with filaggrin deficiency, suggesting that filaggrin deficiency affects the barrier properties of the SC even against small metal ions567. "
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    ABSTRACT: The stratum corneum (SC), the outermost barrier of mammalian bodies, consists of layers of cornified keratinocytes with intercellular spaces sealed with lipids. The insolubility of the SC has hampered in-depth analysis, and the SC has been considered a homogeneous barrier. Here, we applied time-of-flight secondary ion mass spectrometry to demonstrate that the SC consists of three layers with distinct properties. Arginine, a major component of filaggrin-derived natural moisturizing factors, was concentrated in the middle layer, suggesting that this layer functions in skin hydration. Topical application of metal ions revealed that the outer layer allowed their passive influx and efflux, while the middle and lower layers exhibited distinct barrier properties, depending on the metal tested. Notably, filaggrin deficiency abrogated the lower layer barrier, allowing specific metal ions to permeate viable layers. These findings elucidate the multi-layered barrier function of the SC and its defects in filaggrin-deficient atopic disease patients.
    Scientific Reports 04/2013; 3:1731. DOI:10.1038/srep01731 · 5.58 Impact Factor
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