Kato A, Fukai K, Oiso N, Hosomi N, Murakami T, Ishii MAssociation of SPINK5 gene polymorphisms with atopic dermatitis in the Japanese population. Br J Dermatol 148:665-669

Department of Dermatology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi Abenoku, Osaka 545-8585, Japan.
British Journal of Dermatology (Impact Factor: 4.28). 05/2003; 148(4):665-9. DOI: 10.1046/j.1365-2133.2003.05243.x
Source: PubMed


Netherton's syndrome (NS) is an autosomal recessive disorder characterized by trichorrhexis invaginata ('bamboo hair'), congenital ichthyosiform erythroderma and an atopic diathesis. NS has recently been shown to be due to a defect in the SPINK5 gene, encoding LEKTI, a 15-domain serine protease inhibitor. SPINK5 maps to chromosome 5q31-q32, and has been suggested to be a locus predisposing to atopy in general. Recently, coding polymorphisms in SPINK5 exons 13 and 14 have been reported to be associated with atopy, asthma and atopic dermatitis (AD).
To examine whether these polymorphisms are also associated with AD in Japan.
We characterized eight polymorphisms in SPINK5 exons 13 and 14 in 124 Japanese patients with AD and 110 healthy controls. The polymorphisms we examined were IVS12-26C-->T, IVS12-10A-->G, 1103A-->G (Asn368Ser, in exon 13), 1156G-->A (Asp386Asn, in exon 13), 1188T-->C (His396His, in exon 13), IVS13-50G-->A, 1258G-->A (Glu420Lys, in exon 14) and IVS14+19G-->A.
We found significant associations between seven of these polymorphisms and AD in Japanese patients.
This study confirms the previous suggestion of an association between SPINK5 and AD.

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    • "These data suggest that LEKTI is a key regulator of KLK5 and KLK7 activity, and defective SC adhesion caused by epidermal protease hyperactivity is the primary pathogenic event in NS.13 In addition, several studies reported that the polymorphisms in the SPINK5 gene are associated with AD.37,38 Moreover, cystatin A, a cysteine protease inhibitor, inhibits the endogenous cathepsins B, -H, and -L and the exogenous proteases from house dust mites of dermatophagoides pteronyssinus (Der p) 1 and dermatophagoides farinae (Der f) 1.13,39 "
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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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    • "Thus, perturbation of the SC barrier not only allows allergen penetration throughout this barrier but also triggers LC activation and facilitates subsequent uptake of antigens by LCs across the epidermal TJ barrier. After antigen acquisition, LC migrate to draining lymph nodes and activate antigen-specific T cells.4,13 Further allergens and microbial factors that have penetrated defective skin barriers induce inflammation while inflammation itself can alter skin barrier integrity. "
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    ABSTRACT: Atopic diseases such as atopic dermatitis (AD) are very common in industrialized countries. Up to 15%-30% of all children and 2%-10% of all adults suffer from AD. Already in early disease stages, a defective epidermal barrier is known to contribute to the pathogenesis of AD. Central elements in the epidermal barrier are antimicrobial peptides (AMPs), which are secreted by keratinocytes, sweat gland cells but also infiltrating immune cells. AMPs function as endogenous antibiotics and are able to kill bacteria, viruses, and fungi. Furthermore AMPs act as immune modulators with effects on the innate and adaptive immune system. The probably best studied AMPs in human skin are the defensins and cathelicidin. In atopic diseases the functions of AMPs such as cathelicidin might be impaired and microbial superinfections could serve as cofactors for allergic sensitization. Hence, induction of AMPs could be beneficial in these patients. Cathelicidin which is often referred to its peptide form hCAP18 or LL-37 can be induced by ultraviolet light B (UVB) irradiation and is upregulated in infected and injured skin. The cathelicidin gene carries a vitamin D response element and the vitamin D pathway could therefore be targeted for cathelicidin regulation. As the development and course of atopic diseases might be influenced by vitamin D signaling these pathomechanisms could explain the growing evidence connecting vitamin D to allergic diseases, including AD, allergic rhinitis, food allergies and asthma. In this review the role of vitamin D and the AMP cathelicidin in the pathogenesis of atopic diseases with impaired barrier function will be discussed.
    Full-text · Article · May 2013 · Allergy, asthma & immunology research
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    • "SPINK5, which plays a role in the terminal differentiation of keratinocytes and epithelial formation, is colocalized with KLK proteases in the SC where it inhibits KLK5 and KLK7 [23]. Mutations in the SPINK5 gene have been associated with AD in studies of Japanese [24, 25] and Caucasian populations [26]. Evidence of an association between KLK7 gain-of-function polymorphism and AD also has been reported [27]. "
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    ABSTRACT: Atopic dermatitis is a common inflammatory skin disorder that afflicts a growing number of young children. Genetic, immune, and environmental factors interact in a complex fashion to contribute to disease expression. The compromised stratum corneum found in atopic dermatitis leads to skin barrier dysfunction, which results in aggravation of symptoms by aeroallergens, microbes, and other insults. Infants-whose immune system and epidermal barrier are still developing-display a higher frequency of atopic dermatitis. Management of patients with atopic dermatitis includes maintaining optimal skin care, avoiding allergic triggers, and routinely using emollients to maintain a hydrated stratum corneum and to improve barrier function. Flares of atopic dermatitis are often managed with courses of topical corticosteroids or calcineurin inhibitors. This paper discusses the role of emollients in the management of atopic dermatitis, with particular emphasis on infants and young children.
    Full-text · Article · Sep 2012 · Dermatology Research and Practice
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