Epidermal filaggrin deficiency mediates increased systemic T-helper 17 immune response.

BACKGROUND: Cellular T-helper (Th)17 infiltrates dominate skin inflammation in filaggrin-deficient flaky tail (ft/ft) mice, and Th17 cells are found in both the skin and blood of patients with acute atopic dermatitis. However, the potential role of loss-of-function mutations in the filaggrin gene (FLG) for increased peripheral Th17 cells is unclear. OBJECTIVES: To study whether mutations in FLG influence the frequency of peripheral Th17 cells. METHODS: We studied blood samples from six adults with mutations in FLG and five controls without mutations for frequencies of cytokine-producing CD4(+) T cells. We evaluated ft/ft mice and wild-type (WT) control mice for interleukin (IL)-17-producing CD4(+) T cells in naive mice and following 2,4-dinitrofluorobenzene (DNFB) challenge. In addition, the T-cell receptor (TCR) Vß-chain repertoire was analysed by flow cytometry. RESULTS: Human studies showed increased frequency of peripheral Th17 cells in FLG mutation carriers when compared with WT individuals. Mouse studies showed increased frequency of peripheral Th17 cells in adult ft/ft mice but not in 2-week-old ft/ft mice. Moreover, altered TCR Vß-chain repertoire was found in ft/ft mice when compared with WT mice. An increased frequency of CD4(+) Vß10(+) T cells producing IL-17 was found in the spleen of adult ft/ft mice when compared with WT mice. Finally, DNFB challenge induced an increased number of Th17 cells in ft/ft mice compared with WT mice. CONCLUSIONS: Deficiency of filaggrin appeared to be a driver of increased peripheral levels of Th17 cells. This increase must be acquired as peripheral Th17 cells were found in adult ft/ft mice but not in 2-week-old ft/ft mice indicating involvement of exogenous factors.

The role of glutathione S-transferase and claudin-1 gene polymorphisms in contact sensitization: a cross-sectional study.

BACKGROUND: Contact sensitization is frequent in the general population and arises from excessive or repeated skin exposure to chemicals and metals. However, little is known about its genetic susceptibility. OBJECTIVES: To determine the role of polymorphisms of glutathione S-transferase (GST) genes and the claudin-1 gene (CLDN1) on the risk of contact sensitization, taking common filaggrin gene (FLG) mutations into account. METHODS: In total, 3471 adult Danes from the general population were standard patch tested and filled out a questionnaire on their general health. They were genotyped for the following polymorphisms: GSTM1 and GSTT1 deletion, GSTP1 single nucleotide polymorphism (SNP) rs1695, four CLDN1 SNPs (rs893051, rs9290927, rs9290929 and rs17501010) and the FLG null mutations R501X and 2282del4. RESULTS: In individuals without ear piercings, a higher prevalence of nickel sensitization was found in those with the minor allele of CLDN1 SNP rs9290927 (P(trend)=0·013). For CLDN1 rs17501010, contact sensitization to organic compounds was associated with the major allele (P(trend)=0·031). The risk pattern was also identified for self-reported nickel dermatitis (P(trend)=0·011). The fragrance sensitization prevalence differed in a pairwise comparison of the CLDN1 rs893051 SNP genotypes (P=0·022), with the minor allele being associated with a higher prevalence. The associations were confirmed in logistic regression analyses. CONCLUSIONS: The CLDN1 polymorphisms rs9290927, rs893051 and rs17501010 were associated, respectively, with nickel contact sensitization in individuals without ear piercings, contact sensitization to fragrances, and with both organic compounds and nickel contact dermatitis. We could not find associations between GST gene polymorphisms and contact sensitization. FLG mutations did not affect the observed associations.

Filaggrin loss-of-function mutation R501X and 2282del4 carrier status is associated with fissured skin on the hands: results from a cross-sectional population study.

BACKGROUND: Filaggrin metabolites act as osmolytes and are important for skin hydration. Carriers of filaggrin loss-of-function mutations have a higher prevalence of atopic dermatitis and dry skin. There is also evidence to suggest that filaggrin mutations increase the risk of hand eczema in atopic individuals. In our clinic, we have observed a distinct phenotype of hand eczema in patients with filaggrin mutation carrier status, characterized by fissured dermatitis on the dorsal aspect of the hands and with only sparse involvement of the palms including fine scaling. OBJECTIVES: To investigate whether filaggrin loss-of-function mutations are associated with skin fissures on the hands and/or fingers in the general population. METHODS: Participants in a population-based study were questioned about skin symptoms, genotyped for filaggrin mutation, patch tested for nickel allergy and skin prick tested. RESULTS: In an adjusted logistic regression analysis, filaggrin mutation status was significantly associated with fissured skin on the hands and/or fingers in adults (odds ratio 1·93, 95% confidence interval 1·05-3·55) and showed a nearly significant negative interaction with atopic dermatitis (P=0·055), suggesting that the effect was predominantly in subjects without atopic dermatitis. CONCLUSIONS: Filaggrin loss-of-function mutations seem not only to increase the risk of atopic dermatitis and dry skin but also the risk of fissures on the hands and/or fingers in subjects without atopic dermatitis. Prophylactic emollient therapy should be particularly encouraged in filaggrin loss-of-function mutation carriers.

[Did the distribution of trauma treatment by general practitioners and emergency departments in the county of Ringkøbing change after the introduction of the on-call coverage for general practitioners?]. / Aendres fordelingen af skadebehandlingen i Ringkøbing Amt mellem almen praksis og skadestue ved etablering af storvagtkredse for alment praktiserende laeger?

The aim of the study was to investigate the changes in minor trauma treatment structure after a reduction in the number of general practitioners on call in a county, where minor trauma treatment is supposed to be carried out by general practitioners and only major trauma is supposed to be treated at the hospital Accident and Emergency Department. The design was a cross-sectional analysis of trauma treatment in Ringkøbing County before and after the reduction in the number of general practitioners on call. Over a four week period before and after the reduction in the number of general practitioners on call all trauma treatment at the Accident and Emergency Departments was registered together with trauma treatment by general practitioners. Furthermore a questionnaire was given before and after the reduction to a sample of the population regarding the population's behaviour and attitude towards minor trauma. Analysis showed that there was a minor reduction in the total number of trauma treatments after the reduction in the number of general practitioners on call was made. The percentage of patients that were treated at the Accident and Emergency Departments at hospital directly without being referred from general practitioners was reduced from 30% to 21%. The population's behaviour and attitude towards minor trauma was unchanged.