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Skin Barrier Function and mRNA Expression Profiles in Patients with Atopic Dermatitis, Ichthyosis Vulgaris, and X-linked Recessive Ichthyosis: Aetiopathogenic Differences and the Impact of Moisturizing Treatment
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Atopic dermatitis (AD), ichthyosis vulgaris (IV), and X-linked recessive ichthyosis (XLRI) are characterized by dry skin and impaired skin barrier. AD and IV are related to loss-of-function mutations in FLG (encoding filaggrin), whereas XLRI is caused by deletions or inactivating mutations in the steroid sulphatase gene (STS). Patients regularly use moisturizing creams, but little is known about the creams’ effects on the skin barrier.

The present work combines objective scorings, non-invasive techniques, and molecular analyses of skin biopsies to characterize the skin in 57 patients with AD, IV, or XLRI, and in 14 healthy controls. Patients were classified according to their FLG and STS mutation status: AD with FLG+/+ (n = 14), AD with FLG+/– (n = 14), AD/IV with FLG–/– (n = 15), and XLRI with STS– (n = 14), as well as one man with a novel point mutation. Assessments were conducted at baseline and after four weeks of treatment with three different moisturizers applied to volar forearm skin.

At baseline, dryness scoring and non-invasive assessments verified impaired skin barrier function in all patients. In patients with AD/IV, microarray analysis identified 300–3000 up- or downregulated mRNA transcripts involved in signalling pathways important for inflammation and barrier repair. The skin phenotype and number of altered transcripts were correlated with the FLG mutation status, with FLG–/– patients displaying the highest transepidermal water loss (TEWL) and the most altered transcript levels. In contrast, despite an equally dysfunctional skin barrier, only limited changes in mRNA transcripts occurred in XLRI patients. Treatment with moisturizers improved skin dryness similarly in all groups, but TEWL behaved differently: it decreased slightly in the AD/IV group and increased in the XLRI group, especially after urea treatment. Only minute effects on skin pH and mRNA expression were observed.

In conclusion, FLG mutations elicit pro-inflammatory mechanisms probably aimed at restoring barrier competence. This does not occur in patients with XLRI, presumably because STS deficiency automatically increases the barrier thickness. Moisturizing treatment improves skin dryness in patients with AD, IV, or XLRI, but does not seem to normalize the altered epidermal gene expression profile in AD/IV patients.

 

 

 

 

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 49 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 859
Keyword [en]
atopic dermatitis, ichthyosis vulgaris, X-linked recessive ichthyosis, skin barrier function, moisturizers, transepidermal water loss, gene expression
National Category
Dermatology and Venereal Diseases
Research subject
Dermatology and Venerology
Identifiers
URN: urn:nbn:se:uu:diva-192396ISBN: 978-91-554-8583-2 (print)OAI: oai:DiVA.org:uu-192396DiVA: diva2:589839
Public defence
2013-03-08, Rosénsalen, Ingång 95/96, Akademiska Sjukhuset, Uppsala, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2013-02-15 Created: 2013-01-20 Last updated: 2013-04-02
List of papers
1. Filaggrin genotype determines functional and molecular alterations in skin of patients with atopic dermatitis and ichthyosis vulgaris
Open this publication in new window or tab >>Filaggrin genotype determines functional and molecular alterations in skin of patients with atopic dermatitis and ichthyosis vulgaris
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2011 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 12, e28254Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

Several common genetic and environmental disease mechanisms are important for the pathophysiology behind atopic dermatitis (AD). Filaggrin (FLG) loss-of-function is of great significance for barrier impairment in AD and ichthyosis vulgaris (IV), which is commonly associated with AD. The molecular background is, however, complex and various clusters of genes are altered, including inflammatory and epidermal-differentiation genes.

OBJECTIVE:

The objective was to study whether the functional and molecular alterations in AD and IV skin depend directly on FLG loss-of-function, and whether FLG genotype determines the type of downstream molecular pathway affected.

METHODS AND FINDINGS:

Patients with AD/IV (n = 43) and controls (n = 15) were recruited from two Swedish outpatient clinics and a Swedish AD family material with known FLG genotype. They were clinically examined and their medical history recorded using a standardized questionnaire. Blood samples and punch biopsies were taken and trans-epidermal water loss (TEWL) and skin pH was assessed with standard techniques. In addition to FLG genotyping, the STS gene was analyzed to exclude X-linked recessive ichthyosis (XLI). Microarrays and quantitative real-time PCR were used to compare differences in gene expression depending on FLG genotype. Several different signalling pathways were altered depending on FLG genotype in patients suffering from AD or AD/IV. Disease severity, TEWL and pH follow FLG deficiency in the skin; and the number of altered genes and pathways are correlated to FLG mRNA expression.

CONCLUSIONS:

We emphasize further the role of FLG in skin-barrier integrity and the complex compensatory activation of signalling pathways. This involves inflammation, epidermal differentiation, lipid metabolism, cell signalling and adhesion in response to FLG-dependent skin-barrier dysfunction.

National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:uu:diva-164269 (URN)10.1371/journal.pone.0028254 (DOI)000298171400054 ()22164253 (PubMedID)
Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-12-08Bibliographically approved
2. Novel point mutation in the STS gene in a patient with X-linked recessive ichthyosis
Open this publication in new window or tab >>Novel point mutation in the STS gene in a patient with X-linked recessive ichthyosis
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2011 (English)In: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 63, no 1, 62-64 p.Article in journal, Letter (Refereed) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-155356 (URN)10.1016/j.jdermsci.2011.03.011 (DOI)000291846500009 ()21530180 (PubMedID)
Available from: 2011-06-21 Created: 2011-06-21 Last updated: 2017-12-11Bibliographically approved
3. Moisturizing treatment of patients with atopic dermatitis and ichthyosis vulgaris improves dry skin, but has a modest effect on gene expression regardless of FLG genotype
Open this publication in new window or tab >>Moisturizing treatment of patients with atopic dermatitis and ichthyosis vulgaris improves dry skin, but has a modest effect on gene expression regardless of FLG genotype
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2015 (English)In: Journal of the European Academy of Dermatology and Venereology, ISSN 0926-9959, E-ISSN 1468-3083, Vol. 29, no 1, 174-177 p.Article in journal (Refereed) Published
Abstract [en]

Background

Loss-of-function mutations in FLG (encoding filaggrin) are a predisposing factor for atopic dermatitis (AD) and cause ichthyosis vulgaris (IV). Patients with AD and IV display impaired skin barrier and dry skin, and altered epidermal expression of genes in pro-inflammatory and lipid metabolic pathways are often evident.

Objectives

To evaluate the effect of three different moisturizers on skin barrier function and epidermal gene expression in patients with AD/IV in relation to FLG mutation status.

Methods

Patients (n = 43) were classified according to their FLG status: AD with FLG+/+ (n = 14), AD with FLG+/− (n = 14), and AD/IV with FLG−/− (n = 15). Dryness score and transepidermal water loss (TEWL) were monitored on volar forearms, and punch biopsies were taken for analysis of gene expression. Measurements were repeated after 4 weeks of treatment with either of two moisturizers on each forearm.

Results

Treatment with any of the three moisturizers significantly reduced dryness score and TEWL in the group as a whole. FLG−/− patients displayed the largest reduction in dryness score. Only minute changes occurred in the mRNA expression of 15 selected epidermal genes.

Conclusions

Moisturizing treatment improves dry skin and certain aspects of abnormal skin barrier function, especially in patients with AD/IV and dual FLG mutations, but does not normalize the epidermal gene expression profile.

National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:uu:diva-191808 (URN)10.1111/jdv.12333 (DOI)000346733800028 ()24330146 (PubMedID)
Available from: 2013-01-14 Created: 2013-01-14 Last updated: 2017-12-06Bibliographically approved
4. X-linked recessive ichthyosis: an impaired barrier function evokes limited gene responses before and after moisturizing treatments
Open this publication in new window or tab >>X-linked recessive ichthyosis: an impaired barrier function evokes limited gene responses before and after moisturizing treatments
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2012 (English)In: British Journal of Dermatology, ISSN 0007-0963, E-ISSN 1365-2133, Vol. 167, no 3, 514-522 p.Article in journal (Refereed) Published
Abstract [en]

Background

X-linked recessive ichthyosis (XLRI) is due to deletions or inactivating mutations in the steroid sulfatase (STS) gene. This results in an accumulation of cholesterol sulphate affecting the packing of intercorneocyte lipids. XLRI is characterized by dry, scaly skin and increased skin barrier permeability; patients are often dependent on daily use of moisturizers.

Objectives

To examine the biophysical and molecular changes in the skin of patients with XLRI compared with healthy volunteers, and to analyse the effects of moisturizers on the patients' barrier function.

Methods 

Patients with XLRI (= 14) and healthy controls (= 14) were included in the study. Skin dryness score, transepidermal water loss (TEWL) and skin surface pH were monitored at baseline, and punch biopsies were obtained for mRNA expression profiles determined by oligonucleotide arrays. Measurements were repeated in the patients with XLRI after a 4-week treatment with three different moisturizers on the volar forearms. Results  Patients with XLRI showed, compared with healthy controls, increased dryness and TEWL, equal skin pH and altered expression of 27 genes. There were no signs of activation of inflammation or repair pathways. Five selected genes were significantly altered also on quantitative polymerase chain reaction analysis. Treatment with the moisturizers showed similar effects: they improved skin dryness but had no effect on TEWL, pH or expression of selected genes.

Conclusions 

Despite a dysfunctional skin barrier, the limited number of genes altered in XLRI skin suggests that no inflammatory or repair mechanisms are triggered. Treatment with moisturizers does not have any major impact on the skin barrier properties of patients with XLRI.

National Category
Dermatology and Venereal Diseases
Identifiers
urn:nbn:se:uu:diva-180402 (URN)10.1111/j.1365-2133.2012.10979.x (DOI)000308130900011 ()22486194 (PubMedID)
Available from: 2012-09-06 Created: 2012-09-06 Last updated: 2017-12-07Bibliographically approved

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