RESUMO
BACKGROUND: Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2-driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. OBJECTIVE: This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). METHODS: Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. RESULTS: Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4-16). Mean improvements in a meta-analysis-derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and -10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P < .001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13, IL31, CCL17, CCL18, and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS, CD11c, and CTLA4), and TH17/TH22 activity (IL17A, IL-22, and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG], loricrin [LOR], claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P = .001; week 16, P = .0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. CONCLUSION: Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Dermatite Atópica , Regulação da Expressão Gênica/efeitos dos fármacos , Pele , Transcriptoma/efeitos dos fármacos , Adulto , Anticorpos Monoclonais Humanizados , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Método Duplo-Cego , Feminino , Proteínas Filagrinas , Humanos , Masculino , Pessoa de Meia-Idade , Pele/imunologia , Pele/metabolismo , Pele/patologiaRESUMO
BACKGROUND: B cells undergo maturation and class-switching in response to antigen exposure and T-cell help. Early B-cell differentiation has not been defined in patients with early-onset atopic dermatitis (AD). OBJECTIVE: We sought to define the frequency of B-cell subsets associated with progressive B-cell maturation and IgE class-switching. METHODS: We studied 27 children and 34 adults with moderate-to-severe AD (mean SCORAD score, 55 and 65, respectively) and age-matched control subjects (15 children and 27 adults). IgD/CD27 and CD24/CD38 core gating systems and an 11-color flow cytometric panel were used to determine the frequencies of circulating B-cell subsets. Serum total and allergen-specific IgE (sIgE) levels were measured by using ImmunoCAP. RESULTS: Compared with adults, children showed T-cell predominance in the skin. Circulating CD19+CD20+ B-cell counts were lower in patients with pediatric AD than in control subjects (24% vs 33%, P = .04), whereas CD3+ T-cell counts were higher (62% vs 52%, P = .05). A decreased B-cell/T-cell lymphocyte ratio with age was observed only in pediatric control subjects (r = -0.48, P = .07). In pediatric patients with AD, a positive correlation was observed between B-cell/T-cell ratio and nonswitched memory B-cell counts (r = 0.42, P = .03). Higher frequencies of positive sIgE levels were seen in pediatric patients with AD (P < .0001). Diverse sIgE levels correlated with SCORAD scores and age of pediatric patients with AD (P < .01). Positive correlations were observed between activated B-cell and memory T-cell counts (P < .02). In patients with AD, IgE sensitization to most allergens clustered with age, TH1, TH2, total IgE levels, and B-cell memory subsets. CONCLUSIONS: Peripheral B and T cells are altered in pediatric patients with early AD, but T cells predominate in skin lesions.
Assuntos
Subpopulações de Linfócitos B/imunologia , Dermatite Atópica/imunologia , Adulto , Envelhecimento/imunologia , Alérgenos/imunologia , Pré-Escolar , Dermatite Atópica/sangue , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Lactente , Masculino , Pessoa de Meia-Idade , Pele/citologia , Pele/imunologia , Linfócitos T/imunologiaRESUMO
BACKGROUND: The ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis-based therapy is largely lacking because the underlying molecular basis is poorly understood. OBJECTIVE: We sought to characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics. METHODS: We analyzed biopsy specimens from 21 genotyped patients with ichthyosis (congenital ichthyosiform erythroderma, n = 6; lamellar ichthyosis, n = 7; epidermolytic ichthyosis, n = 5; and Netherton syndrome, n = 3) using immunohistochemistry and RT-PCR and compared them with specimens from healthy control subjects, patients with atopic dermatitis (AD), and patients with psoriasis. Clinical measures included the Ichthyosis Area Severity Index (IASI), which integrates erythema (IASI-E) and scaling (IASI-S); transepidermal water loss; and pruritus. RESULTS: Ichthyosis samples showed increased epidermal hyperplasia (increased thickness and keratin 16 expression) and T-cell and dendritic cell infiltrates. Increases of general inflammatory (IL-2), innate (IL-1ß), and some TH1/interferon (IFN-γ) markers in patients with ichthyosis were comparable with those in patients with psoriasis or AD. TNF-α levels in patients with ichthyosis were increased only in those with Netherton syndrome but were much lower than in patients with psoriasis and those with AD. Expression of TH2 cytokines (IL-13 and IL-31) was similar to that seen in control subjects. The striking induction of IL-17-related genes or markers synergistically induced by IL-17 and TNF-α (IL-17A/C, IL-19, CXCL1, PI3, CCL20, and IL36G; P < .05) in patients with ichthyosis was similar to that seen in patients with psoriasis. IASI and IASI-E scores strongly correlated with IL-17A (r = 0.74, P < .001) and IL-17/TNF-synergistic/additive gene expression. These markers also significantly correlated with transepidermal water loss, suggesting a link between the barrier defect and inflammation in patients with ichthyosis. CONCLUSION: Our data associate a shared TH17/IL-23 immune fingerprint with the major orphan forms of ichthyosis and raise the possibility of IL-17-targeting strategies.
Assuntos
Ictiose/imunologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Adolescente , Adulto , Idoso , Criança , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Feminino , Expressão Gênica , Humanos , Ictiose/genética , Interleucina-17/genética , Interleucina-23/genética , Masculino , Pessoa de Meia-Idade , Psoríase/genética , Psoríase/imunologia , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Pele/imunologia , Adulto JovemRESUMO
BACKGROUND: Atopic dermatitis (AD) and psoriasis pathogeneses involve skin barrier impairment and immune dysregulation; however, the contribution of B-cell imbalances to these diseases has not yet been determined. OBJECTIVE: We sought to quantify B-cell populations and antibody-secreting cells in the blood of patients with AD, patients with psoriasis, and control subjects. METHODS: We studied 34 adults with moderate-to-severe AD (mean SCORAD score, 65), 24 patients with psoriasis (mean Psoriasis Area and Severity Index score, 16), and 27 healthy subjects using an 11-color flow cytometric antibody panel. IgD/CD27 and CD24/CD38 core gating systems were used to determine frequencies of plasmablasts and naive, memory, transitional, and activated B cells. RESULTS: We measured increased CD19(+)CD20(+) B-cell counts in the skin and blood of patients with AD (P < .01). Significantly higher frequencies of chronically activated CD27(+) memory and nonswitched memory B cells were observed in patients with AD (P < .05), with lower values of double-negative populations (4% for patients with AD vs. 7% for patients with psoriasis [P = .001] and 6% for control subjects [P = .02]). CD23 expression was highest in patients with AD and correlated with IgE levels (P < .01) and disease severity (r = 0.6, P = .0002). Plasmablast frequencies and IgE expression were highest in all memory subsets of patients with AD (P < .01). Finally, CD19(+)CD24(++)CD38(++) transitional and CD19(+)CD24(-)CD38(-) new memory B-cell counts were higher in patients with AD versus those in patients with psoriasis (2.8% vs. 1.4% [P = .001] and 9.2% vs. 5.7% [P = .02], respectively). CONCLUSIONS: AD is accompanied by systemic expansion of transitional and chronically activated CD27(+) memory, plasmablast, and IgE-expressing memory subsets. These data create a critical basis for the future understanding of this debilitating skin disease.
Assuntos
Subpopulações de Linfócitos B/imunologia , Dermatite Atópica/imunologia , Psoríase/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/imunologia , Dermatite Atópica/sangue , Feminino , Humanos , Imunoglobulina E/sangue , Ativação Linfocitária , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Atopic dermatitis (AD) affects 15% to 25% of children and 4% to 7% of adults. Paradigm-shifting discoveries about AD have been based on adult biomarkers, reflecting decades of disease activity, although 85% of cases begin by 5 years. Blood phenotyping shows only TH2 skewing in patients with early-onset pediatric AD, but alterations in early pediatric skin lesions are unknown, limiting advancement of targeted therapies. OBJECTIVE: We sought to characterize the early pediatric AD skin phenotype and its differences from pediatric control subjects and adults with AD. METHODS: Using immunohistochemistry and quantitative real-time PCR, we assessed biopsy specimens from 19 children with AD younger than 5 years within 6 months of disease onset in comparison with adults with AD or psoriasis and pediatric and adult control subjects. RESULTS: In lesional skin children showed comparable or greater epidermal hyperplasia (thickness and keratin 16) and cellular infiltration (CD3+, CD11c+, and FcεRI+) than adults with AD. Similar to adults, strong activation of the TH2 (IL-13, IL-31, and CCL17) and TH22 (IL-22 and S100As) axes and some TH1 skewing (IFN-γ and CXCL10) were present. Children showed significantly higher induction of TH17-related cytokines and antimicrobials (IL-17A, IL-19, CCL20, LL37, and peptidase inhibitor 3/elafin), TH9/IL-9, IL-33, and innate markers (IL-8) than adults (P < .02). Despite the characteristic downregulation in adult patients with AD, filaggrin expression was similar in children with AD and healthy children. Nonlesional skin in pediatric patients with AD showed higher levels of inflammation (particularly IL-17A and the related molecules IL-19 and LL37) and epidermal proliferation (keratin 16 and S100As) markers (P < .001). CONCLUSION: The skin phenotype of new-onset pediatric AD is substantially different from that of adult AD. Although excess TH2 activation characterizes both, TH9 and TH17 are highly activated at disease initiation. Increases in IL-19 levels might link TH2 and TH17 activation.
Assuntos
Dermatite Atópica/patologia , Eczema/patologia , Hispânico ou Latino , Psoríase/patologia , Pele/patologia , Células Th17/imunologia , Células Th2/imunologia , Adulto , Fatores Etários , Idoso , Pré-Escolar , Citocinas/metabolismo , Dermatite Atópica/imunologia , Eczema/imunologia , Feminino , Proteínas Filagrinas , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Psoríase/imunologia , Estados UnidosRESUMO
BACKGROUND: Identifying differences and similarities between cutaneous lymphocyte antigen (CLA)(+) polarized T-cell subsets in children versus adults with atopic dermatitis (AD) is critical for directing new treatments toward children. OBJECTIVE: We sought to compare activation markers and frequencies of skin-homing (CLA(+)) versus systemic (CLA(-)) "polar" CD4 and CD8 T-cell subsets in patients with early pediatric AD, adults with AD, and control subjects. METHODS: Flow cytometry was used to measure CD69/inducible costimulator/HLA-DR frequency in memory cell subsets, as well as IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines, defining TH1/cytotoxic T (TC) 1, TH2/TC2, TH9/TC9, TH17/TC17, and TH22/TC22 populations in CD4 and CD8 cells, respectively. We compared peripheral blood from 19 children less than 5 years old and 42 adults with well-characterized moderate-to-severe AD, as well as age-matched control subjects (17 children and 25 adults). RESULTS: Selective inducible costimulator activation (P < .001) was seen in children. CLA(+) TH2 T cells were markedly expanded in both children and adults with AD compared with those in control subjects, but decreases in CLA(+) TH1 T-cell numbers were greater in children with AD (17% vs 7.4%, P = .007). Unlike in adults, no imbalances were detected in CLA(-) T cells from pediatric patients with AD nor were there altered frequencies of TH22 T cells within the CLA(+) or CLA(-) compartments. Adults with AD had increased frequencies of IL-22-producing CD4 and CD8 T cells within the skin-homing population, compared with controls (9.5% vs 4.5% and 8.6% vs 2.4%, respectively; P < .001), as well as increased HLA-DR activation (P < .01). CONCLUSIONS: These data suggest that TH2 activation within skin-homing T cells might drive AD in children and that reduced counterregulation by TH1 T cells might contribute to excess TH2 activation. TH22 "spreading" of AD is not seen in young children and might be influenced by immune development, disease chronicity, or recurrent skin infections.
Assuntos
Dermatite Atópica/imunologia , Interleucinas/metabolismo , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Adulto , Idoso , Antígenos de Diferenciação de Linfócitos T/metabolismo , Separação Celular , Criança , Pré-Escolar , Citometria de Fluxo , Humanos , Imunofenotipagem , Lactente , Ativação Linfocitária , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Equilíbrio Th1-Th2 , Adulto Jovem , Interleucina 22RESUMO
BACKGROUND: The molecular signature of atopic dermatitis (AD) lesions is associated with TH2 and TH22 activation and epidermal alterations. However, the epidermal and dermal AD transcriptomes and their respective contributions to abnormalities in respective immune and barrier phenotypes are unknown. OBJECTIVE: We sought to establish the genomic profile of the epidermal and dermal compartments of lesional and nonlesional AD skin compared with normal skin. METHODS: Laser capture microdissection was performed to separate the epidermis and dermis of lesional and nonlesional skin from patients with AD and normal skin from healthy volunteers, followed by gene expression (microarrays and real-time PCR) and immunostaining studies. RESULTS: Our study identified novel immune and barrier genes, including the IL-34 cytokine and claudins 4 and 8, and showed increased detection of key AD genes usually undetectable on arrays (ie, IL22, thymic stromal lymphopoietin [TSLP], CCL22, and CCL26). Overall, the combined epidermal and dermal transcriptomes enlarged the AD transcriptome, adding 674 upregulated and 405 downregulated differentially expressed genes between lesional and nonlesional skin to the AD transcriptome. We were also able to localize individual transcripts as primarily epidermal (defensin, beta 4A [DEFB4A]) or dermal (IL22, cytotoxic T-lymphocyte antigen 4 [CTLA4], and CCR7) and link their expressions to possible cellular sources. CONCLUSIONS: This is the first report that establishes robust epidermal and dermal genomic signatures of lesional and nonlesional AD skin and normal skin compared with whole tissues. These data establish the utility of laser capture microdissection to separate different compartments and cellular subsets in patients with AD, allowing localization of key barrier or immune molecules and enabling detection of gene products usually not detected on arrays.
Assuntos
Dermatite Atópica/genética , Perfilação da Expressão Gênica , Microdissecção e Captura a Laser , Pele/metabolismo , Adulto , Dermatite Atópica/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Population cohort studies are important for understanding the current status of the target disease and its relation to comorbidity, gender, age, or environmental factors. To better understand atopic dermatitis (AD) and its related diseases, we initiated in 2001 a population cohort study of nursery school children from Ishigaki Island, Okinawa, Japan. The cohort study comprised a dermatologist-based physical examination, questionnaire administration, and blood sample analysis. The mean prevalence of AD was 6.3%. Questionnaire-based bronchial asthma and egg allergy in the children and paternal and sibling AD were statistically significant risk factors for AD. Boys with AD had a high incidence of asthma that was coexistent with a high serum total immunoglobulin E level. Also a high incidence of egg allergy was associated with greater AD severity as assessed by TARC/CCL17.
Assuntos
Quimiocina CCL17/sangue , Dermatite Atópica/epidemiologia , Imunoglobulina E/sangue , Povo Asiático , Asma/epidemiologia , Pré-Escolar , Estudos de Coortes , Dermatite Atópica/sangue , Hipersensibilidade a Ovo/epidemiologia , Feminino , Predisposição Genética para Doença , Humanos , Incidência , Japão/epidemiologia , Masculino , Prevalência , Rinite Alérgica/epidemiologia , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
BACKGROUND: We sometimes encounter difficulties in assessing the severity of pediatric atopic dermatitis (AD) using currently available biomarkers such as thymus and activation-regulated chemokine (TARC) due to the higher baseline values in non-AD children. Recent case control studies have indicated the usefulness of squamous cell carcinoma antigens (SCCAs) in pediatric and adult AD. Notably, SCCAs are induced by IL-4 and IL-13, vital Th2 cytokines that play important roles in AD etiology. OBJECTIVES: Relatively low prevalence and mild disease severity of pediatric AD are observed in our Ishigaki cohort presumably due to the moisturising subtropical climate, which could conversely mean possible higher allergic potential of non-AD subjects towards AD. Thus, the purpose of this study was to further investigate the feasibility of using SCCAs together with TARC and periostin as biomarkers for pediatric AD even in the Ishigaki cohort. METHODS: We enrolled 1459 nursery school children and identified 96 as having AD through 2009-2011. As statistical analyses, we performed Student's t-test, correlation analysis, and receiver and operating characteristic (ROC) analysis. RESULTS: Serum SCCA1, SCCA2, periostin and TARC levels were all significantly increased in AD compared with those in non-AD, but only serum SCCA2 showed a significant increase in AD when assessed in each age group or in subgroup analysis. Among the biomarkers tested, serum SCCA2 also showed the best correlations with clinical AD severity and TARC and showed the best diagnosability for AD in ROC analysis. CONCLUSIONS: SCCA2 is a potent biomarker for pediatric AD in the Ishigaki cohort.
Assuntos
Antígenos de Neoplasias/sangue , Dermatite Atópica/diagnóstico , Serpinas/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Quimiocina CCL17/sangue , Criança , Pré-Escolar , Estudos de Coortes , Dermatite Atópica/sangue , Estudos de Viabilidade , Feminino , Humanos , Lactente , Recém-Nascido , Japão , Masculino , Índice de Gravidade de DoençaRESUMO
Topical corticosteroid phobia is an important problem in the treatment of atopic dermatitis as it can affect the ability to control disease severity and itch by reducing treatment adherence. Topical corticosteroid phobia often ends up even non-corticosteroid adherence. As such, non-corticosteroid adherence, disease severity and itch are likely to be associated with each other, but their relationship has yet to be thoroughly investigated. Thus, the purpose of this study is to investigate it in atopic dermatitis. Using data from 1190 participants in an Internet survey, we identified 255 non-corticosteroid users and 225 with moderate to severe itch who were defined as non-corticosteroid adherents. Corticosteroid users with the same itch categories (n = 878) served as controls. We also examined how itch severity affects the perception of itch in atopic dermatitis. Unexpectedly, non-corticosteroid adherents were less sensitive to the conditions to elicit itch such as perspiring, commuting homeward, drinking alcohol and wearing woolen clothes compared with the control. We also found that patients with severer itch were more sensitive to itch during/after bathing, when lying in bed, commuting homeward, studying/working, drinking alcohol, undressing, getting up in the morning, after a meal, ingesting piquant foods and when they were unoccupied, angry, busy, nervous, sad or enjoying themselves. In conclusion, we found that non-corticosteroid adherence and itch severity influence perception of itch in atopic dermatitis and discuss possible mechanisms underlying these results. The information obtained in this study may be useful for communication with and education of atopic dermatitis patients and their treatment in outpatient clinics.
Assuntos
Antipruriginosos/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Adesão à Medicação/psicologia , Prurido/tratamento farmacológico , Adolescente , Adulto , Assistência Ambulatorial/métodos , Criança , Dermatite Atópica/complicações , Dermatite Atópica/psicologia , Feminino , Glucocorticoides/efeitos adversos , Humanos , Masculino , Adesão à Medicação/estatística & dados numéricos , Pessoa de Meia-Idade , Educação de Pacientes como Assunto , Percepção , Transtornos Fóbicos/etiologia , Transtornos Fóbicos/psicologia , Prurido/etiologia , Prurido/psicologia , Autorrelato , Índice de Gravidade de Doença , Adulto JovemRESUMO
Atopic dermatitis (AD) is a multifactorial T-helper (Th)2-mediated skin disease frequently associated with elevated serum immunoglobulin (Ig)E and food allergy is also a Th2- and IgE-mediated adverse immunological reaction. Our previous study indicated the relation of egg allergy history and disease severity of AD. Thus, the purpose of the study was to investigate the levels of IgE specific to major food allergens (egg, milk, wheat) and Th2 chemokines (chemokine [C-C motif] ligand [CCL]17/thymus and activation regulated chemokine [TARC] and CCL22/macrophage-derived chemokine [MDC]) and the relationship between them. A total of 743 nursery school children were enrolled. Dermatologist-based physical examination and a questionnaire survey were also conducted. Significantly increased levels of disease severity markers (CCL17/TARC and CCL22/MDC) were confirmed in children with AD. The levels of CCL22/MDC in all of the children were markedly high compared with those reported in adults. IgE specific to egg white, ovomucoid, wheat and mite antigen were significantly higher in the AD group than in the non-AD group. Among them, IgE specific to egg allergens were well associated with disease severity markers, and IgE specific to ovomucoid seemed particularly well correlated with the presence of egg allergy history. In conclusion, the markedly high level of CCL22/MDC in children as compared with those reported in adults may partly explain the AD-prone nature of children and their spontaneous remission afterwards. Mild but significant correlation of IgE specific to egg allergens and Th2 chemokines may explain correlation of disease severity and comorbidity of egg allergy in our previous study.
Assuntos
Quimiocina CCL17/sangue , Quimiocina CCL22/sangue , Dermatite Atópica/epidemiologia , Hipersensibilidade Alimentar/imunologia , Imunoglobulina E/sangue , Criança , Pré-Escolar , Estudos de Coortes , Dermatite Atópica/sangue , Dermatite Atópica/imunologia , Humanos , Japão/epidemiologiaRESUMO
Opuntia ficus-indica (OFI) is a cactus species widely used as an anti-inflammatory, antilipidemic, and hypoglycemic agent. It has been shown that OFI extract (OFIE) inhibits oxidative stress in animal models of diabetes and hepatic disease; however, its antioxidant mechanism remains largely unknown. In this study, we demonstrated that OFIE exhibited potent antioxidant activity through the activation of nuclear factor erythroid 2-related factor 2 (NRF2) and the downstream antioxidant enzyme NAD(P)H: quinone oxidoreductase 1 (NQO1), which inhibited the generation of reactive oxygen species in keratinocytes challenged with tumor necrosis factor α or benzo[α]pyrene. The antioxidant capacity of OFIE was canceled in NRF2 knockdown keratinocytes. OFIE exerted this NRF2-NQO1 upregulation through activation of the aryl hydrocarbon receptor (AHR). Moreover, the ligation of AHR by OFIE upregulated the expression of epidermal barrier proteins: filaggrin and loricrin. OFIE also prevented TH2 cytokine-mediated downregulation of filaggrin and loricrin expression in an AHR-dependent manner because it was canceled in AHR knockdown keratinocytes. Antioxidant OFIE is a potent activator of AHR-NRF2-NQO1 signaling and may be beneficial in treating barrier-disrupted skin disorders.
Assuntos
Proteínas de Filamentos Intermediários/análise , Queratinócitos/efeitos dos fármacos , Proteínas de Membrana/análise , Fator 2 Relacionado a NF-E2/fisiologia , Opuntia/química , Receptores de Hidrocarboneto Arílico/metabolismo , Antioxidantes/farmacologia , Células Cultivadas , Proteínas Filagrinas , Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Queratinócitos/química , Queratinócitos/metabolismo , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/deficiência , Fator 2 Relacionado a NF-E2/genética , Extratos Vegetais/farmacologia , Receptores de Hidrocarboneto Arílico/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Dermatopatias/tratamento farmacológicoRESUMO
Atopic dermatitis (AD) is a common, chronic or chronically relapsing, severely pruritic and eczematous skin disease. AD is the second most frequently observed skin disease in dermatology clinics in Japan. Prevalence of childhood AD is 12-13% in mainland Japan; however, it is only half that (~6%) in children from Ishigaki Island, Okinawa. Here, we summarize the prevalence, incidence and spontaneous regression of AD and the relation of AD to other allergic diseases from previous reports. We also refer to our recent findings from a population cohort study on Ishigaki Island, Okinawa.
Assuntos
Dermatite Atópica/epidemiologia , Estudos de Coortes , Dermatologia/estatística & dados numéricos , Humanos , Incidência , Japão/epidemiologia , Remissão EspontâneaAssuntos
Produtos Biológicos/efeitos adversos , Fármacos Dermatológicos/efeitos adversos , Psoríase/tratamento farmacológico , Trombocitopenia/induzido quimicamente , Adalimumab/administração & dosagem , Adalimumab/efeitos adversos , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Produtos Biológicos/administração & dosagem , Fármacos Dermatológicos/administração & dosagem , Substituição de Medicamentos/efeitos adversos , Feminino , Humanos , Trombocitopenia/diagnóstico , Ustekinumab/administração & dosagem , Ustekinumab/efeitos adversosAssuntos
Quimiocina CCL20/metabolismo , Dermatite Atópica/imunologia , Prurido/imunologia , Pele/patologia , Células Th17/imunologia , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Quimiocina CCL20/imunologia , Dermatite Atópica/complicações , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Humanos , Prurido/tratamento farmacológico , Prurido/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Pele/efeitos dos fármacos , Pele/imunologia , Resultado do Tratamento , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologiaRESUMO
BACKGROUND: Serum thymus and activation-regulated chemokine (TARC) levels closely reflect the disease activity of atopic dermatitis (AD). AD is characterized by impaired epidermal barrier function and atopic dry skin. However, dry skin is also a very common problem in healthy individuals. OBJECTIVE: To investigate the relationship between serum TARC levels and epidermal barrier function in healthy subjects and patients with mild AD. METHODS: This study included 2 groups, 121 healthy subjects (healthy group) and 66 patients with mild AD (mild AD group). Barrier function was assessed by transepidermal water loss (TEWL) and stratum corneum hydration (SCH). RESULTS: Significantly elevated serum TARC levels and TEWL values and significantly decreased SCH values were detected in the mild AD group compared to those in the healthy group. In the mild AD group, serum TARC levels were significantly correlated with TEWL values and were inversely correlated with SCH values. Importantly, serum TARC levels were also inversely correlated with SCH values in the healthy controls. TEWL values in the healthy group tended to be correlated with TARC levels but did not reach statistical significance. CONCLUSION: Together with TEWL and SCH, serum TARC level is a useful biomarker, reflecting impairment of epidermal function in AD patients as well as healthy subjects.
Assuntos
Quimiocina CCL17/sangue , Dermatite Atópica/sangue , Dermatite Atópica/diagnóstico , Epiderme/metabolismo , Índice de Gravidade de Doença , Adulto , Biomarcadores/sangue , Quimiocina CCL17/imunologia , Dermatite Atópica/imunologia , Epiderme/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Permeabilidade , Perda Insensível de Água/imunologia , Adulto JovemRESUMO
Atopic dermatitis (AD) is a common inflammatory skin disease caused by multiple genetic and environmental factors. AD is characterized by the local infiltration of T helper type 2 (Th2) cells. Recent clinical studies have shown important roles of the Th2 chemokines, CCL22 and CCL17 in the pathogenesis of AD. To investigate whether polymorphisms of the CCL22 gene affect the susceptibility to AD, we conducted association studies and functional studies of the related variants. We first resequenced the CCL22 gene and found a total of 39 SNPs. We selected seven tag SNPs in the CCL22 gene, and conducted association studies using two independent Japanese populations (1(st) population, 916 cases and 1,032 controls; 2(nd) population 1,034 cases and 1,004 controls). After the association results were combined by inverse variance method, we observed a significant association at rs4359426 (meta-analysis, combined Pâ=â9.6×10â»6; OR, 0.74; 95% CI, 0.65-0.85). Functional analysis revealed that the risk allele of rs4359426 contributed to higher expression levels of CCL22 mRNA. We further examined the allelic differences in the binding of nuclear proteins by electrophoretic mobility shift assay. The signal intensity of the DNA-protein complex derived from the G allele of rs223821, which was in absolute LD with rs4359426, was higher than that from the A allele. Although further functional analyses are needed, it is likely that related variants play a role in susceptibility to AD in a gain-of-function manner. Our findings provide a new insight into the etiology and pathogenesis of AD.
Assuntos
Quimiocina CCL22/genética , Dermatite Atópica/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Povo Asiático/genética , Estudos de Casos e Controles , Quimiocina CCL22/metabolismo , Dermatite Atópica/etnologia , Dermatite Atópica/metabolismo , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Japão , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/metabolismo , Ligação Proteica , Adulto JovemRESUMO
BACKGROUND: Increased sprouting of epidermal nerve fibers of lesional skin are thought to be associated with persistent pruritus in chronic inflammatory dermatitis such as atopic dermatitis as supported by a murine study using tacrolimus (or FK506: FK) which was shown to inhibit both epidermal sprouting of nerves and scratching behavior or by immunohistochemical observations of lesional skin in the patients with atopic dermatitis or prurigo, etc. OBJECTIVES: To examine a mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) inhibitor (CX-659S: CX) for a possible anti-pruritic property in vivo since some MEK1/2 inhibitors have been reported to inhibit neurite growth in vitro. METHODS: CX, FK and corticosteroids (betamethasone valerate: BV) were topically applied on inflamed skin in a mouse model of chronic dermatitis using repetitive hapten painting to examine anti-pruritic property and anti-inflammatory effects. Scratching behaviors were assessed using MicroAct automatic measuring system, and epidermal sprouting of nerves and skin inflammation was assessed histologically. RESULTS: FK significantly decrease scratching behavior, but CX and BV failed to do so despite of their ability to significantly inhibit epidermal nerve fiber sprouting and skin inflammation, respectively. In addition, CX+BV mixture synergistically inhibited epidermal nerve fiber sprouting and skin inflammation even more potently than FK without decreasing scratching behavior. CONCLUSIONS: These findings suggest that the scratching behavior does not necessarily correlate with epidermal nerve fiber sprouting or inflammatory cell infiltration.