Large-scale DNA microarray analysis of atopic skin lesions shows overexpression of an epidermal differentiation gene cluster in the alternative pathway and lack of protective gene expression in the cornified envelope

Sugiura, Hisashi; Ebise, H.; Tazawa, Takahiro; Tanaka, Keiko; Sugiura, Yasuo; Uehara, Masami; Kikuchi, Keiji; Kimura, Tsutomu

doi:10.1111/j.1365-2133.2005.06352.x

Cited by 158 publications

(157 citation statements)

References 15 publications

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“…This is contradictory to previous studies by Sugiara et al [28] and Jensen et al [29]. Using gene microarrays, Sugiara et al [28] observed increased IVL and decreased LOR gene expression in lesional AD skin. Jensen et al [29] observed increased LOR and decreased IVL expression using immunohistochemistry and western blotting.…”

Section: Discussioncontrasting

confidence: 55%

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Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6

Kim

Leung

Boguniewicz

et al. 2008

Clinical Immunology

446

206

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Atopic dermatitis (AD) is characterized by a defective skin barrier which allows increased allergen and pathogen penetration. Loricrin (LOR) and involucrin (IVL) are proteins important for skin barrier formation and integrity. In this study, we demonstrate that the gene and protein expression of LOR and IVL is significantly decreased in acute (LOR: p<0.001; IVL: p<0.001) and non-lesional (LOR: p<0.001; IVL: p<0.001) skin of AD subjects, as compared to skin from healthy subjects. Using primary keratinocytes, we further demonstrate the down-regulatory effect of IL-4 and IL-13 -which are over-expressed in the skin of AD patients -on LOR and IVL expression in keratinocytes. Additionally, skin biopsies from signal transducer and activator of transcription (STAT)-6 transgenic mice were deficient in the expression and production of LOR and IVL. This study suggests that Th2 cytokines inhibit expression of LOR and IVL through a STAT-6 dependent mechanism.

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Section: Discussioncontrasting

confidence: 55%

“…This factor is not clearly defined in either of the previous studies [28,29]. AD lesions are bi-phasic with acute lesions having more of a Th2 cytokine milieu and chronic lesions having more of a Th1 cytokine milieu [19].…”

Section: Discussionmentioning

confidence: 69%

Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6

Kim

Leung

Boguniewicz

et al. 2008

Clinical Immunology

446

206

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“…Recent data suggest that cutaneous expression of antimicrobial peptides/proteins may influence disease, and indeed altered defensin expression in lesional AD skin has been documented (30,31). Furthermore, AD has been linked to a region of chromosome 1 that contains numerous genes thought to encode antimicrobial proteins (32). At any point, the vast majority of skin-homing T cells are believed to be resident in the skin (33) and thus are likely to represent a diverse pool of cells with the potential TCR capacity to bind to SEB.…”

Section: Discussionmentioning

confidence: 99%

Bacterial superantigen facilitates epithelial presentation of allergen to T helper 2 cells

Ardern‐Jones

Black

Bateman

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Although clinical and laboratory evidence support roles for both staphylococcal infection and environmental allergens in the pathogenesis of atopic dermatitis, human studies have largely considered these variables independently. We sought to test the hypothesis that staphylococcal superantigen influences the allergen-specific T cell response. We first mapped a Der p 1 epitope and used HLA DRB1*1501 class II tetramer-based cell sorted populations to show that specific CD4 ؉ T cells were able to recognize the peptide presented by HLA DR-matched keratinocytes. We observed that staphylococcal enterotoxin B (SEB) enhanced the IL-4 Der p 1-specific T cell response. This response was mediated by two synergistic mechanisms: first, SEB-induced IFN-␥ promoted class II and intercellular adhesion molecule-1 expression by presenting keratinocytes; and second, SEB-induced IL-4 directly amplified allergen-specific CD4 ؉ T cell production of many cytokines. We propose that handling of staphylococcal infection is a critical step in the amplification of the allergen-specific T cell response, linking two common disease associations and with implications for the prevention and treatment of atopic disease.T here is convincing evidence that allergic reactivity to environmental challenge has a role in the pathogenesis of atopic dermatitis (AD). For example, the histology of AD shares many features with classic allergic contact delayed-type hypersensitivity, including spongiosis and a dominant T cell inflammatory infiltrate that is distributed predominantly in a dermal, and to a lesser extent epidermal pattern. Approximately 80% of individuals with AD have circulating specific IgE recognizing one or more of house dust mite, cat, dog, grass, and other ubiquitous environmental allergens (1). In many studies, allergen-specific CD4 ϩ and CD8 ϩ T cells have been documented to be present in the peripheral blood and lesional skin of affected individuals and to produce diverse cytokines but with a frequent T helper 2 (Th2) dominance (2, 3). House dust mite extract application to the skin of individuals with AD can reproduce eczematous changes (4, 5), and allergen avoidance has been shown by some to be partially effective (6, 7). Keratinocytes have been shown to up-regulate HLA class II and intercellular adhesion molecule-1 (ICAM-1) in AD and other inflammatory dermatoses (8, 9) and also in response to injection of IFN-␥ into normal skin (10). However, in isolation, allergic reactivity to an environmental challenge does not explain all of the features of AD. Twenty percent of affected individuals do not generate IgE responses to such ubiquitous proteins, and it is unclear why disease incidence changes during age and between different geographical regions. The risk of disease is clearly influenced by genetic susceptibility factors, some of which affect the immune response, e.g., polymorphisms of the Fc R1 and IL-4R genes (11-13). However, it is becoming increasingly clear from the genetic studies that skin-specific genes, determining variables s...

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“…Impairment of epidermal-barrier function is a clinical hallmark of AD. Microarray analysis revealed decreased expression of FLG messenger ribonucleic acid (mRNA) in active atopic skin (Sugiura et al 2005). These findings suggest that dysfunction of FLG is an important factor in AD development.…”

Section: Discussionmentioning

confidence: 99%

Filaggrin null mutations are associated with atopic dermatitis and elevated levels of IgE in the Japanese population: a family and case–control study

et al. 2008

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Filaggrin (FLG) plays an important role in the barrier function of the skin. Several loss-of-function mutations in the FLG gene have been identified in patients with ichthyosis vulgaris, and these null mutations are associated with atopic dermatitis (AD) development. In this study, we examined tag single nucleotide polymorphisms (tSNPs) and null mutations in FLG for possible associations with AD and atopic phenotypes in a Japanese population. Transmission disequilibrium test of 105 AD families showed that the null allele of the S2554X variant of FLG tended to be overtransmitted to AD-affected offspring; however, the P value did not reach statistical significance. In a casecontrol comparison of 376 AD cases and 923 nonallergic controls, the null allele of S2554X was significantly associated with AD (P = 0.0012), and the association was strengthened in subjects with AD alone (P = 0.000024). We found that 3321delA and S2554X were also associated with elevated levels of immunoglobulin E (IgE). Combined null mutation carriers were observed more in AD patients and in subjects with high IgE than in control subjects. The combined P value for the family and case-control data was significant for the S2554X and combined null mutations. Our data further support the importance of FLG in AD development.

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Large-scale DNA microarray analysis of atopic skin lesions shows overexpression of an epidermal differentiation gene cluster in the alternative pathway and lack of protective gene expression in the cornified envelope

Abstract: Our results, showing downregulation of the cornified envelope genes and upregulation of the alternative keratinization pathway, are the first to suggest abnormal epidermal differentiation and defective defences as key abnormalities in AD.

Cited by 158 publications

References 15 publications

Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6

Loricrin and involucrin expression is down-regulated by Th2 cytokines through STAT-6

Bacterial superantigen facilitates epithelial presentation of allergen to T helper 2 cells

Filaggrin null mutations are associated with atopic dermatitis and elevated levels of IgE in the Japanese population: a family and case–control study

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