RESUMO
The mechanism of action of pimecrolimus (PIM) on atopic lesions is still under consideration. Thus far, we have evidence of its anti-inflammatory and immunomodulatory activity, and recent papers focus on its effect on epidermal barrier function. This study analysed changes in the expression of genes associated with skin barrier dysfunction in atopic dermatitis (AD) skin lesions after 2 weeks of exposure to PIM 1% cream. A real-time quantitative PCR analysis of selected epidermal differentiation complex genes and three alternative pathway keratins was performed in skin biopsies from 11 individuals with AD before and after PIM exposure. The real-time quantitative PCR analysis was compared to non-lesional skin in the same patients. Involucrin, a small proline-rich region (SPRR) 2C gene, and alternative pathway keratin 16 showed significant over-expression in lesional skin followed by significant decrease after PIM therapy. The SPRR1A gene, S100A9, and keratin 6A were also increased; however, the decrease after PIM treatment was not significant. The changes in S100 A2, A7 and A8 followed a similar course with borderline significance. SPRR4 had a significant decrease in expression in lesional versus non-lesional skin, which persisted after PIM treatment. No significant changes were detected in mRNA expression levels of filaggrin and loricrin. Our results suggest that PIM can be effective in restoring the epidermal barrier in patients with AD at least in part by its impact on expression of genes, which are important for the normal barrier function of skin.
Assuntos
Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Perfilação da Expressão Gênica , Pele/efeitos dos fármacos , Tacrolimo/análogos & derivados , Adulto , Proteínas Ricas em Prolina do Estrato Córneo/genética , Proteínas Ricas em Prolina do Estrato Córneo/metabolismo , Dermatite Atópica/genética , Dermatite Atópica/fisiopatologia , Fármacos Dermatológicos/farmacologia , Feminino , Proteínas Filagrinas , Expressão Gênica/efeitos dos fármacos , Humanos , Queratina-16/genética , Queratina-16/metabolismo , Queratina-6/genética , Queratina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Pomadas , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Pele/metabolismo , Tacrolimo/farmacologia , Tacrolimo/uso terapêutico , Resultado do Tratamento , Adulto JovemRESUMO
UNLABELLED: Chronic spontaneous urticaria (CSU) is the most common form of chronic urticaria. A considerable amount of data supports an immunological basis for CSU. Some research has focused on the association between chronic urticaria and specific human leukocyte antigen (HLA) alleles. The aim of this study was to investigate the HLA status of Polish patients diagnosed with CSU. METHODS: The standard complement-dependent microlymphocytotoxicity assay and PCR amplification with sequence-specific primers were used to analyze HLA alleles in 115 patients diagnosed with CSU, and the results were compared to those from 162 healthy, genetically unrelated individuals. RESULTS: Among the HLA-A alleles, A-33 occurred significantly more often in the control group (p < 0.01). Analysis of the HLA-B allele frequencies revealed the prevalence of the B44 antigen in the study group (p < 0.0001). Frequencies of HLA-C alleles and HLA-DQ did not differ significantly between the groups. Among the HLA class II alleles, DRB1*04 was observed significantly more often in the study population (p < 0.001), mainly in the autoimmunological subtype of urticaria. CONCLUSION: HLA alleles may be involved in CSU development or play a protective role in CSU.
Assuntos
Antígenos HLA-A/metabolismo , Antígenos HLA-B/metabolismo , Antígenos HLA-DR/metabolismo , Urticária/genética , Urticária/imunologia , Adolescente , Adulto , Idoso , Doença Crônica , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Antígenos HLA-A/genética , Antígenos HLA-A/imunologia , Antígenos HLA-B/genética , Antígenos HLA-B/imunologia , Antígeno HLA-B44 , Antígenos HLA-DR/genética , Antígenos HLA-DR/imunologia , Cadeias HLA-DRB1 , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Polônia , Polimorfismo GenéticoRESUMO
BACKGROUND: Discovery of the significant impact of filaggrin (FLG) mutations on the genetic predisposition to atopic dermatitis (AD) focused attention on the 1q21 locus, where not only FLG but also other epidermal genes are located. In the present study, we compared 1q21 gene expression in lesional versus nonlesional AD skin. METHODS: A real-time quantitative PCR analysis of 10 1q21 genes, selected on the basis of a previous microarray study, was performed in skin biopsies from 33 individuals with AD. Three alternative pathway keratins were also evaluated. RESULTS: In chronic AD skin lesions, we observed an increase in RNA encoding involucrin, S100 calcium-binding proteins A2 and A7-A9 and small proline-rich region (SPRR) proteins 1A and 2C, with fold changes ranging from 2.0 for S100A2 to 15.4 for S100A8 (p < 0.001, Bonferroni corrected), in parallel to the overexpression of the alternative pathway keratins 6A, 6B and 16. The loricrin (LOR) expression level was significantly decreased in lesional AD skin (fold change 0.5; p < 0.01). The expression of the majority of 1q21 genes and alternative keratins was closely correlated; however, for SPRR1A (and SPRR2C) in lesional skin, the correlation with other genes was lost. CONCLUSIONS: We hypothesize that the deregulated increase in SPRR1A expression in chronic atopic skin lesions reflects an insufficient rise in SPRR transcripts, unable to compensate for the lack of LOR and thus contributing to the persistence of chronic AD skin lesions. Turning off the stress response in the skin may be regarded as a goal in the treatment of AD skin lesions, and SPRR genes might be targets for such an approach.
