Fallon PG, Sasaki T, Sandilands A et al.A homozygous frameshift mutation in the mouse Flg gene facilitates enhanced percutaneous allergen priming. Nat Genet 41:602-608

Institute of Molecular Medicine, Trinity College Dublin, Ireland.
Nature Genetics (Impact Factor: 29.35). 05/2009; 41(5):602-8. DOI: 10.1038/ng.358
Source: PubMed


Loss-of-function mutations in the FLG (filaggrin) gene cause the semidominant keratinizing disorder ichthyosis vulgaris and convey major genetic risk for atopic dermatitis (eczema), eczema-associated asthma and other allergic phenotypes. Several low-frequency FLG null alleles occur in Europeans and Asians, with a cumulative frequency of approximately 9% in Europe. Here we report a 1-bp deletion mutation, 5303delA, analogous to common human FLG mutations, within the murine Flg gene in the spontaneous mouse mutant flaky tail (ft). We demonstrate that topical application of allergen to mice homozygous for this mutation results in cutaneous inflammatory infiltrates and enhanced cutaneous allergen priming with development of allergen-specific antibody responses. These data validate flaky tail as a useful model of filaggrin deficiency and provide experimental evidence for the hypothesis that antigen transfer through a defective epidermal barrier is a key mechanism underlying elevated IgE sensitization and initiation of cutaneous inflammation in humans with filaggrin-related atopic disease.

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Available from: Padraic Fallon
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    • "Dalsze badania powinny oceniać możliwość zmniejszenia uczulenia związanego z obecnością przeciwciał IgE przez działania ochronne na barierę skórną. Badania przeprowadzone u ludzi i myszy sugerują, że bariera skórna może być miejscem powstawania uczulenia w mechanizmie związanym z IgE [30] [31] [32]. Jeśli rzeczywiście tak jest, zaproponowana metoda może stać się nowa strategią zapobiegania astmie alergicznej i alergii pokarmowej. "
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    ABSTRACT: Atopowe zapalenie skóry (wyprysk atopowy) jest przewlekłą zapalną chorobą skóry, która na całym świecie przybiera rozmiar epidemii wśród dzieci, z ciągle zwiększającą się zachorowalnością. Z uwagi na istotny wpływ atopowego zapalenia skóry społeczno-ekonomiczny i na jakość życia chorych dzieci oraz ich rodzin, przez całe dekady prowadzono badania kliniczne skoncentrowane na zapobieganiu chorobie, z ograniczonym skutkiem. Ostatnie postępy wiedzy na temat biologii skóry sugerują, że zaburzenia bariery skórnej mogą być kluczowymi czynnikami inicjującymi atopowe zapalenie skóry i być może uczulenie na alergeny.
    Full-text · Article · Nov 2014
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    • "The data provided in this publication draw attention to the complexity of the issue of allergic diseases. Transdermal permeation of allergens to the organism, including food allergens, may cause a state of over-sensitiveness and a fixed food allergy [53]. Therefore, further research aimed at learning the pathomechanisms of atopic diseases in the context of epidermal barrier function and the role of filaggrin are indispensable. "
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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.
    Full-text · Article · Sep 2014 · Przegląd Gastroenterologiczny
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    • "In European studies, the prevalence of FLG mutations in AD subjects is 3% in Italy, 15.2%-22.9% in Germany, 40.2%-42% in the UK and 45.2%-55.8% in Ireland, and this pattern suggests a higher tendency for FLG mutation prevalence in AD patients who reside in countries of higher latitudes than in those of lower latitudes.16 Patients with FLG mutations can develop ichthyosis vulgaris without manifestations of AD, and approximately 50%-90% of AD patients have no FLG defects.16,17 In fact, mice with the FLG null mutation exhibited no spontaneous AD-like skin lesions.18 "
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    ABSTRACT: Atopic dermatitis (AD) is a multifactorial inflammatory skin disease perpetuated by gene-environmental interactions and which is characterized by genetic barrier defects and allergic inflammation. Recent studies demonstrate an important role for the epidermal permeability barrier in AD that is closely related to chronic immune activation in the skin during systemic allergic reactions. Moreover, acquired stressors (e.g., Staphylococcus aureus infection) to the skin barrier may also initiate inflammation in AD. Many studies involving patients with AD revealed that defective skin barriers combined with abnormal immune responses might contribute to the pathophysiology of AD, supporting the outside-inside hypothesis. In this review, we discuss the recent advances in human and animal models, focusing on the defects of the epidermal permeability barrier, its immunologic role and barrier repair therapy in AD.
    Full-text · Article · Jul 2014 · Allergy, asthma & immunology research
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