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1.
Zhongguo Zhong Yao Za Zhi ; 46(4): 762-766, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33645108

RESUMO

Based on the clinical characteristics of atopic dermatitis( AD) in traditional Chinese medicine( TCM) and Western medicine,the existing animal models were analyzed,and the coincidence degree,advantages and disadvantages between the models and the clinical manifestations of AD were evaluated,so as to provide reference for establishing a rational animal model. After consulting relevant literatures in recent years and summarizing the existing modeling methods,it is found that spontaneous,transgenic/gene knockout models were highly consistent,but with high breeding conditions and expensive prices. The hapten-induced model was low in cost and fast in modeling. It revealed the corresponding mechanism of AD to a certain extent,but did not fully reflect the state of the entire process of AD. The modeling method was guided by Western medicine,but with a lack of pathogenic factors of traditional Chinese medicine,and so has certain limitations in TCM research. Therefore,it is necessary to combine the etiology,pathogenesis and clinical mani-festations of AD with traditional Chinese and Western medicine,so as to improve the coincidence degree between the model and the characteristics of clinical symptoms and lay the foundation for in-depth studies on AD.


Assuntos
Dermatite Atópica , Medicamentos de Ervas Chinesas , Eczema , Medicina , Animais , China , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/genética , Medicina Tradicional Chinesa
2.
Mol Genet Genomics ; 296(2): 341-353, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33438050

RESUMO

Atopic dermatitis (AD) is a condition driven by T cell-mediated immune response. Targeted therapy of AD is challenging due to its complex pathogenesis. In the current study, by analyzing multiple expression and network datasets, we aimed at: (1) identifying important transcriptomic signatures/profiles for AD to seek potential therapeutic targets and (2) discovering key regulators in the pathogenesis of AD. Our differentially expressed gene (DEG) analysis revealed multiple genes involved in immune response and dermal structural integrity. Functional enrichment analyses suggested that signaling pathways involved in epidermal barrier and inflammation and immunity are overrepresented in lesional AD. Protein-protein interaction (PPI) network and causal interactions analyses highlighted the roles of regulators of epidermal integrity and immune response in the pathogenesis of AD. Prominently, a negative regulator of the B-cell receptor-mediated immune response, PKCß, has been suggested in the predicted pathogenesis model for AD, implying B cell-mediated immune response may play an equally important role as that of the T cell-mediated immune response in AD. A further search in a perturbagen database has identified small molecular drugs that may alter expression profiles of key regulators in the pathogenesis of AD. In this study, we propose a systemic multi-omics strategy incorporating multiple analyses on various datasets of transcriptomes, diseases, and pharmacology. Such integrative analyses will effectively advance our understanding on the pathogenesis and treatment of AD.


Assuntos
Biologia Computacional/métodos , Dermatite Atópica/genética , Dinitrofluorbenzeno/análogos & derivados , Perfilação da Expressão Gênica/métodos , Redes Reguladoras de Genes , Animais , Bases de Dados Genéticas , Dermatite Atópica/induzido quimicamente , Dinitrofluorbenzeno/efeitos adversos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Mapas de Interação de Proteínas , Transdução de Sinais
3.
J Allergy Clin Immunol ; 147(3): 857-869.e7, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33485957

RESUMO

BACKGROUND: Coronavirus disease 2019 (COVID-19) is commonly associated with skin manifestations, and may also exacerbate existing skin diseases, yet the relationship between COVID-19 and skin diseases remains unclear. OBJECTIVE: By investigating this relationship through a multiomics approach, we sought to ascertain whether patients with skin conditions are more susceptible to COVID-19. METHODS: We conducted an epidemiological study and then compared gene expression across 9 different inflammatory skin conditions and severe acute respiratory syndrome coronavirus 2-infected bronchial epithelial cell lines, and then performed a genome-wide association study transdisease meta-analysis between COVID-19 susceptibility and 2 skin diseases (psoriasis and atopic dermatitis). RESULTS: Skin conditions, including psoriasis and atopic dermatitis, increase the risk of COVID-19 (odds ratio, 1.55; P = 1.4 × 10-9) but decrease the risk of mechanical ventilation (odds ratio, 0.22; P = 8.5 × 10-5). We observed significant overlap in gene expression between the infected normal bronchial epithelial cells and inflammatory skin diseases, such as psoriasis and atopic dermatitis. For genes that are commonly induced in both the severe acute respiratory syndrome coronavirus 2 infection and skin diseases, there are 4 S100 family members located in the epidermal differentiation complex, and we also identified the "IL-17 signaling pathway" (P = 4.9 × 10-77) as one of the most significantly enriched pathways. Furthermore, a shared genome-wide significant locus in the epidermal differentiation complex was identified between psoriasis and severe acute respiratory syndrome coronavirus 2 infection, with the lead marker being a significant expression quantitative trait locus for S100A12 (P = 3.3 × 10-7). CONCLUSIONS: Together our findings suggest association between inflammatory skin conditions and higher risk of COVID-19, but with less severe course, and highlight shared components involved in anti-COVID-19 immune response.


Assuntos
Dermatite Atópica , Regulação da Expressão Gênica , Predisposição Genética para Doença , Psoríase , Locos de Características Quantitativas , Proteína S100A12 , /metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , /genética , Linhagem Celular , Dermatite Atópica/epidemiologia , Dermatite Atópica/genética , Dermatite Atópica/metabolismo , Feminino , Estudo de Associação Genômica Ampla , Genômica , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/epidemiologia , Psoríase/genética , Psoríase/metabolismo , Fatores de Risco , Proteína S100A12/biossíntese , Proteína S100A12/genética , Pele/metabolismo , Pele/virologia
4.
Cells ; 9(12)2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33321931

RESUMO

MicroRNAs (miRNAs) are endogenous small non-coding RNA molecules that regulate the gene expression at a post-transcriptional level and participate in maintaining the correct cell homeostasis and functioning. Different specific profiles have been identified in lesional skin from autoimmune cutaneous diseases, and their deregulation cause aberrant control of biological pathways, contributing to pathogenic conditions. Detailed knowledge of microRNA-affected pathways is of crucial importance for understating their role in skin autoimmune diseases. They may be promising therapeutic targets with novel clinical implications. They are not only present in skin tissue, but they have also been found in other biological fluids, such as serum, plasma and urine from patients, and therefore, they are potential biomarkers for the diagnosis, prognosis and response to treatment. In this review, we discuss the current understanding of the role of described miRNAs in several cutaneous autoimmune diseases: psoriasis (Ps, 33 miRNAs), cutaneous lupus erythematosus (CLE, 2 miRNAs) and atopic dermatitis (AD, 8 miRNAs). We highlight their role as crucial elements implicated in disease pathogenesis and their applicability as biomarkers and as a novel therapeutic approach in the management of skin inflammatory diseases.


Assuntos
Dermatite Atópica/genética , Lúpus Eritematoso Cutâneo/genética , MicroRNAs/genética , Psoríase/genética , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Marcadores Genéticos , Predisposição Genética para Doença , Humanos
5.
Nat Commun ; 11(1): 4092, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796837

RESUMO

Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder. We find that KIF3A SNP rs11740584 and rs2299007 risk alleles create cytosine-phosphate-guanine sites, which are highly methylated and result in lower KIF3A expression, and this methylation is associated with increased transepidermal water loss (TEWL) in risk allele carriers. Kif3aK14∆/∆ mice have increased TEWL, disrupted junctional proteins, and increased susceptibility to develop AD. Thus, KIF3A is required for skin barrier homeostasis whereby decreased KIF3A skin expression causes disrupted skin barrier function and promotes development of AD.


Assuntos
Dermatite Atópica/metabolismo , Cinesina/metabolismo , Pele/metabolismo , Adolescente , Adulto , Alelos , Animais , Criança , Dermatite Atópica/genética , Dermatite Atópica/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cinesina/genética , Masculino , Metilação , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Pele/patologia , Adulto Jovem
6.
PLoS One ; 15(7): e0235295, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32687504

RESUMO

Spontaneous mutations in the SHANK-associated RH domain interacting protein (Sharpin) resulted in a severe autoinflammatory type of chronic proliferative dermatitis, inflammation in other organs, and lymphoid organ defects. To determine whether cell-type restricted loss of Sharpin causes similar lesions, a conditional null mutant was created. Ubiquitously expressing cre-recombinase recapitulated the phenotype seen in spontaneous mutant mice. Limiting expression to keratinocytes (using a Krt14-cre) induced a chronic eosinophilic dermatitis, but no inflammation in other organs or lymphoid organ defects. The dermatitis was associated with a markedly increased concentration of serum IgE and IL18. Crosses with S100a4-cre resulted in milder skin lesions and moderate to severe arthritis. This conditional null mutant will enable more detailed studies on the role of SHARPIN in regulating NFkB and inflammation, while the Krt14-Sharpin-/- provides a new model to study atopic dermatitis.


Assuntos
Dermatite Atópica/genética , Inflamação/genética , Queratina-14/genética , Proteínas do Tecido Nervoso/genética , Proteína A4 de Ligação a Cálcio da Família S100/genética , Animais , Apoptose/genética , Artrite/genética , Artrite/patologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Humanos , Imunoglobulina E/genética , Inflamação/patologia , Integrases/genética , Interleucina-18/genética , Queratinócitos/metabolismo , Queratinócitos/patologia , Camundongos , NF-kappa B/genética , Fenótipo , Transdução de Sinais
7.
Medicine (Baltimore) ; 99(28): e21256, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664181

RESUMO

BACKGROUND: This study aimed to investigate the role of serine protease inhibitor Kazal-type 5 (SPINK5) polymorphisms (Asn368Ser, Asp386Asn and Glu420Lys) and the risk of atopic dermatitis (AD). METHODS: Studies associated with SPINK5 mutations and AD risk were searched from three databases, including PubMed, Embase, and Cochrane library, with a retrieval deadline of April 22, 2019. An odds ratio (OR) with a 95% confidence interval (95% CI) was chosen as the effect size. Egger's linear regression test was enrolled to assess the level of publication bias. RESULTS: Overall, 6 studies met the inclusion criteria for meta-analysis. Significantly statistical differences were calculated between patients with AD and healthy individuals on Asn368Ser polymorphism in the allele model (G vs A: OR = 1.2643, 95% CI = 1.0666-1.4987, P = .0069), co-dominant model (GG vs AA: OR = 1.6609, 95% CI = 1.1736-2.3505, P = .0042; GA vs AA: OR = 1.5448, 95% CI = 1.1263-2.1189, P = .0070), and dominant model (GG+GA vs AA: OR = 1.5700, 95% CI = 1.1656-2.1146, P = .0030). However, no statistically significant difference was found in the recessive model for Asn368Ser and other genetic models for Asp386Asn and Glu420Lys (all P > .05). No significant publication bias was found. CONCLUSION: The SPINK5 Asn368Ser polymorphism may be a risk factor for AD.


Assuntos
Dermatite Atópica/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
8.
PLoS One ; 15(7): e0235500, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614886

RESUMO

INTRODUCTION: Clinical trials often suffer from significant recruitment barriers, poor adherence, and dropouts, which increase costs and negatively affect trial outcomes. The aim of this study was to examine whether making it virtual and reward-based would enable nationwide recruitment, identify patients with variable disease severity, achieve high adherence, and reduce dropouts. METHODS: In a siteless, virtual feasibility study, individuals with atopic dermatitis (AD) were recruited online. During the 8-week study, subjects used their smartphones weekly to photograph target AD lesions, and completed patient-oriented eczema measure (POEM) and treatment use questionnaires. In return, subjects were rewarded every week with personalized lifestyle reports based on their DNA. RESULTS: Over the course of the 11 day recruitment period, 164 (82% women and 18% men) filled in the form to participate, of which 65 fulfilled the inclusion criteria and signed the informed consent. Ten were excluded as they did not complete the mandatory study task of returning the DNA sample. 55 (91% women, 9% men) subjects returned the DNA sample and were enrolled throughout Denmark, the majority outside the Copenhagen capital region in rural areas with relatively low physician coverage. The mean age was 28.5 (SD ±9.5 years, range 18-52 years). The baseline POEM score was 14.5±5.6 (range 6-28). Based on the POEM, 7 individuals had mild, 28 had moderate, 17 had severe, and 3 had very severe eczema. The retention rate was 96% as 53 out of 55 enrolled completed the study. The adherence was very high, and more than 90% of all study tasks were completed. Follow up of 41 subjects showed that 90% would take part again or continue if the study had been longer. CONCLUSION: A virtual trial design enables recruitment with broad geographic reach and throughout the full spectrum of disease severity. Providing personalized genetic reports as a reward seems to contribute to high adherence and retention.


Assuntos
Dermatite Atópica/psicologia , Eczema/patologia , Recompensa , Cooperação e Adesão ao Tratamento , Adolescente , Adulto , DNA/análise , Dermatite Atópica/genética , Dermatite Atópica/patologia , Dermatite Atópica/terapia , Fármacos Dermatológicos/uso terapêutico , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Fototerapia , Índice de Gravidade de Doença , Smartphone , Inquéritos e Questionários , Adulto Jovem
9.
Immunogenetics ; 72(5): 315-323, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32556497

RESUMO

Canine atopic dermatitis (CAD) is an inflammatory and pruritic allergic skin disease with both genetic and environmental risk factors described. We performed mRNA sequencing of non-lesional axillary skin biopsies from nine German shepherd dogs. Obtained RNA sequences were mapped to the dog genome (CanFam3.1) and a high-quality skin transcriptome was generated with 23,510 expressed gene transcripts. Differentially expressed genes (DEGs) were defined by comparing three controls to five treated CAD cases. Using a leave-one-out analysis, we identified seven DEGs: five known to encode proteins with functions related to an activated immune system (CD209, CLEC4G, LOC102156842 (lipopolysaccharide-binding protein-like), LOC480601 (regakine-1-like), LOC479668 (haptoglobin-like)), one (OBP) encoding an odorant-binding protein potentially connected to rhinitis, and the last (LOC607095) encoding a novel long non-coding RNA. Furthermore, high mRNA expression of inflammatory genes was found in axillary skin from an untreated mild CAD case compared with healthy skin. In conclusion, we define genes with different expression patterns in CAD case skin helping us understand post-treatment atopic skin. Further studies in larger sample sets are warranted to confirm and to transfer these results into clinical practice.


Assuntos
Dermatite Atópica/veterinária , Doenças do Cão/genética , Regulação da Expressão Gênica/imunologia , Pele/imunologia , Animais , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Doenças do Cão/imunologia , Cães , Inflamação/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma
10.
Adv Exp Med Biol ; 1253: 107-140, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32445093

RESUMO

Atopic Dermatitis (AD) is a common inflammatory disease with a genetic background. The prevalence of AD has been increasing in many countries. AD patients often have manifestations of pruritus, generalized skin dryness, and eczematous lesions. The pathogenesis of AD is complicated. The impaired skin barrier and immune imbalance play significant roles in the development of AD. Environmental factors such as allergens and pollutants are associated with the increasing prevalence. Many genetic and environmental factors induce a skin barrier deficiency, and this can lead to immune imbalance, which exacerbates the impaired skin barrier to form a vicious cycle (outside-inside-outside view). Genetic studies find many gene mutations and genetic variants, such as filaggrin mutations, which may directly induce the deficiency of the skin barrier and immune system. Epigenetic studies provide a connection between the relationship of an impaired skin barrier and immune and environmental factors, such as tobacco exposure, pollutants, microbes, and diet and nutrients. AD is a multigene disease, and thus there are many targets for regulation of expression of these genes which may contribute to the pathogenesis of AD. However, the epigenetic regulation of environmental factors in AD pathogenesis still needs to be further researched.


Assuntos
Dermatite Atópica/genética , Epigênese Genética , Interação Gene-Ambiente , Dermatite Atópica/patologia , Eczema/genética , Humanos , Sistema Imunitário , Pele/patologia
11.
Exp Mol Pathol ; 115: 104467, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32445749

RESUMO

Asthma is a complex disease, with various genetic and environmental factors implicated in its development. Sensitization to the house dust mite (HDM) is closely linked with the development of respiratory allergies, including asthma. However, some children sensitized to HDM do not complain of any symptoms of respiratory allergies, even though HDM is correlated with an increased risk for developing asthma, suggesting the involvement of other factors. Tumor necrosis factor (TNF)-α is associated with the pathophysiologies of asthma in combination with its genetic polymorphism. The aim of the present study was to elucidate the associations between sensitization to HDM, polymorphism of TNF-α rs1800629, and asthma/bronchial hyperresponsiveness (BHR). Our results revealed that sensitization to HDM is associated with asthma diagnosis in lifetime, current asthma, and BHR in Korean children. Furthermore, the genetic polymorphism of TNF-a rs1800629 was found to modify and interact with these associations. This study suggests that prevention strategies for childhood asthma need to be targeted according to genetic susceptibility.


Assuntos
Asma/genética , Asma/fisiopatologia , Hiper-Reatividade Brônquica/genética , Polimorfismo de Nucleotídeo Único/genética , Pyroglyphidae/fisiologia , Fator de Necrose Tumoral alfa/genética , Animais , Asma/parasitologia , Criança , Dermatite Atópica/genética , Humanos , Rinite Alérgica/genética
12.
Ann Allergy Asthma Immunol ; 125(3): 287-293, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32371243

RESUMO

BACKGROUND: Although previous studies had reported an important role of interleukin 13 (IL13) and its genetic polymorphisms in atopic dermatitis (AD), many of these previous reports focused on the missense variant rs20541 (Gln144Arg) without fine mapping of the gene region. OBJECTIVE: To analyze the potential associations of other IL13 variants and their haplotypes with AD and assess total serum immunoglobulin E (IgE) levels. METHODS: We performed fine mapping of single-nucleotide polymorphisms (SNPs) within the IL13 gene in a pilot study of 495 children with AD and 444 healthy controls. Then, we conducted a replication study of 757 children with AD and 1620 healthy controls to evaluate the association between the rs20541 variant of IL13 and AD. RESULTS: In the pilot study, the rs20541 and rs1295685 SNPs in the 3'-untranslated region of IL13 had significant associations with AD (P < .001 and .01, respectively). In addition, 2 haplotypes (BL2_ht1 and BL2_ht2), which harbored the significant rs20541 and rs1295685 SNPs, had an association with AD (minimum P = .006). BL2_ht1 and BL2_ht2 had nominal signals associated with the total serum IgE levels (P < .05) but not with the severity of AD (P > .05). In the replication study, rs20541 was associated with the total serum IgE levels but not with the severity of AD. CONCLUSION: An additional IL13 gene SNP, rs1295685, has a strong linkage disequilibrium with rs20541, and its haplotypes are associated with AD and the total serum IgE levels.


Assuntos
Dermatite Atópica/genética , Predisposição Genética para Doença/genética , Haplótipos/genética , Interleucina-13/genética , Polimorfismo de Nucleotídeo Único/genética , Estudos de Casos e Controles , Criança , Dermatite Atópica/sangue , Feminino , Humanos , Imunoglobulina E/sangue , Masculino , Projetos Piloto
13.
Immunogenetics ; 72(4): 241-250, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32219493

RESUMO

Canine atopic dermatitis (AD) is a very common inflammatory skin disease, but limited data are available on the genetic characterization (somatic mutations, microarrays, and genome-wide association study (GWAS)) of skin lesions in affected dogs. microRNAs are good biomarkers in inflammatory and neoplastic diseases in people. The aim of this study was to evaluate microRNA expression in the skin of atopic beagles, before and after exposure to Dermatophagoides farinae. Four atopic and four unrelated age-matched healthy beagle dogs were enrolled. Total RNA was extracted from flash-frozen skin biopsies of healthy and atopic dogs. For the atopic dogs, skin biopsies were taken from non-lesional (day 0) and lesional skin (day 28 of weekly environmental challenge with Dermatophagoides farinae). Small RNA libraries were constructed and sequenced. The microRNA sequences were aligned to CanFam3.1 genome. Differential expressed microRNAs were selected on the basis of fold-change and statistical significance (fold-change ≥ 1.5 and p ≤ 0.05 as thresholds. A total of 277 microRNAs were sequenced. One hundred and twenty-one differentially regulated microRNAs were identified between non-lesional and healthy skin. Among these, two were increased amount and 119 were decreased amount. A total of 45 differentially regulated microRNAs between lesional and healthy skin were identified, 44 were decreased amount and one was increased amount. Finally, only two increased amount microRNAs were present in lesional skin when compared with that of non-lesional skin. This is the first study in which dysregulation of microRNAs has been associated with lesional and non-lesional canine AD. Larger studies are needed to understand the role of microRNA in canine AD.


Assuntos
Dermatite Atópica/genética , Doenças do Cão/genética , MicroRNAs/genética , Animais , Estudos de Casos e Controles , Dermatite Atópica/patologia , Dermatophagoides farinae/patogenicidade , Cães , Expressão Gênica , Sequenciamento de Nucleotídeos em Larga Escala , Reprodutibilidade dos Testes , Pele/patologia
14.
An Bras Dermatol ; 95(2): 173-179, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32151410

RESUMO

BACKGROUND: Polymorphisms of the filaggrin 2 gene (rs 12568784 and rs 16899374) are associated with persistent atopic dermatitis in African American patients. Filaggrin 2 is a protein with a function similar to filaggrin and also encoded in the epidermal differentiation complex on chromosome 1q21. OBJECTIVE: To evaluate the polymorphisms in the filaggrin 2 gene (rs 12568784 and rs 16899374) in children and adults with atopic dermatitis and to verify the association of these with the severity of the clinical picture, presence of other allergic diseases, and socio-demographic factors. METHOD: The study was carried out with patients and control group. Questionnaires were used to evaluate ethnicity, sex, age, family history, scoring, atopic dermatitis (SCORAD), among other parameters. Genotyping of the filaggrin 2 gene was performed by real-time polymerase chain reaction. RESULTS: Forty-eight patients and 83 controls were evaluated. No correlation was found between the variables studied in patients with atopic dermatitis and polymorphisms, no significant difference between the prevalence of polymorphisms in the patients and in the control group p>0.05. STUDY LIMITS: The exclusive use of self-reported ethnicity information and the sample size. RESULTS: The results of this work can be an incentive for the study of the polymorphisms in atopic dermaititis, considering the characteristic of the Brazilian multi ethnic population. CONCLUSION: This is an unpublished work in Brazil and the first study in the world to have a control group to evaluate alterations in the gene of filaggrin 2.


Assuntos
Dermatite Atópica/genética , Polimorfismo Genético/genética , Proteínas S100/genética , Adolescente , Adulto , Brasil , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Dermatite Atópica/etnologia , Dermatite Atópica/patologia , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase em Tempo Real , Índice de Gravidade de Doença , Fatores Sexuais , Fatores Socioeconômicos , Inquéritos e Questionários , Adulto Jovem
15.
Sci Rep ; 10(1): 2721, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066784

RESUMO

The genetic background of Atopic Dermatitis (AD) with chronic pruritus is complex. Filaggrin (FLG) is an essential gene in the epidermal barrier formation s. Loss-of-function (LOF) variants in FLG associated with skin barrier dysfunction constitute the most well-known genetic risk factor for AD. In this study, we focused on the frequency and effect of FLG loss-of-function variants in association with self-reported age-of-onset of AD. The dataset consisted of 386 whole-genome sequencing (WGS) samples. We observe a significant association between FLG LOF status and age-of-onset, with earlier age of onset of AD observed in the FLG LOF carrier group (p-value 0.0003, Wilcoxon two-sample test). We first tested this on the two most prevalent FLG variants. Interestingly, the effect is even stronger when considering all detected FLG LOF variants. Having two or more FLG LOF variants associates with the onset of AD at 2 years of age. In this study, we have shown enrichment of rare variants in the EDC region in cases compared with controls. Age-of-onset analysis shows not only the effect of the FLG and likely EDC variants in terms of the heightened risk of AD, but foremost enables to predict early-onset, lending further credence to the penetrance and causative effect of the identified variants. Understanding the genetic background and risk of early-onset is suggestive of skin barrier dysfunction etiology of AD with chronic pruritus.


Assuntos
Dermatite Atópica/genética , Predisposição Genética para Doença , Mutação com Perda de Função , Prurido/genética , Proteínas S100/genética , Pele/metabolismo , Adulto , Idade de Início , Pré-Escolar , Doença Crônica , Dermatite Atópica/metabolismo , Dermatite Atópica/patologia , Feminino , Expressão Gênica , Humanos , Masculino , Permeabilidade , Prurido/metabolismo , Prurido/patologia , Proteínas S100/metabolismo , Índice de Gravidade de Doença , Pele/patologia , Sequenciamento Completo do Genoma
16.
Ann Allergy Asthma Immunol ; 124(5): 500-504, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32035937

RESUMO

BACKGROUND: Carriers of loss-of-function mutations in the filaggrin gene (LoF FLG) have less natural moisturizing factor (NMF) in their stratum corneum (SC) and an increased risk of atopic dermatitis (AD). Natural moisturizing factor can be measured noninvasively by Raman spectroscopy. The use of Raman-derived NMF at birth to screen for FLG genotype could inform targeted AD prevention, but values in neonatal populations are largely unexplored. OBJECTIVE: To examine the associations between Raman-derived neonatal NMF measurements and FLG genotype. METHODS: Natural moisturizing factor was measured by Raman spectroscopy in the SC of the thenar eminence within 4 days of birth in 139 term neonates. Filaggrin genotyping was performed for 117 neonates (84%). RESULTS: The mean (SD) NMF was 0.37 (0.11) g/g protein, with values increasing across the first 3 days (day 1 vs 3: 0.29 [0.09] vs 0.43 [0.08, P < .001]). Twelve infants (10.3%) were carriers of LoF FLG, all heterozygous. Natural moisturizing factor was lower in LoF FLG carriers compared with wild-type (0.27 [0.08] vs 0.38 [0.11] g/g protein, P ≤ .001). Natural moisturizing factor had good discriminatory power for FLG genotype (area under the receiver operating curve [AUROC]: 0.79; 95% CI: 0.66, 0.91; P ≤ .001). This improved after correcting day 1 and 2 measurements to day 3 (AUROC: 0.83; 95% CI: 0.75, 0.92; P < .001). CONCLUSION: This study suggests that Raman-derived NMF measured in the early postnatal period may have the potential to classify by FLG genotype. The full translational value of this needs to be determined.


Assuntos
Dermatite Atópica/genética , Genótipo , Mutação/genética , Proteínas S100/genética , Pele/patologia , Análise Espectral Raman/métodos , Eczema , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Higroscópicos/metabolismo , Lactente , Recém-Nascido , Masculino , Pele/metabolismo
17.
Int J Mol Sci ; 21(3)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973112

RESUMO

During the last decades, high-throughput assessment of gene expression in patient tissues using microarray technology or RNA-Seq took center stage in clinical research. Insights into the diversity and frequency of transcripts in healthy and diseased conditions provide valuable information on the cellular status in the respective tissues. Growing with the technique, the bioinformatic analysis toolkit reveals biologically relevant pathways which assist in understanding basic pathophysiological mechanisms. Conventional classification systems of inflammatory skin diseases rely on descriptive assessments by pathologists. In contrast to this, molecular profiling may uncover previously unknown disease classifying features. Thereby, treatments and prognostics of patients may be improved. Furthermore, disease models in basic research in comparison to the human disease can be directly validated. The aim of this article is not only to provide the reader with information on the opportunities of these techniques, but to outline potential pitfalls and technical limitations as well. Major published findings are briefly discussed to provide a broad overview on the current findings in transcriptomics in inflammatory skin diseases.


Assuntos
Dermatite Atópica/metabolismo , Psoríase/metabolismo , Dermatopatias/metabolismo , Transcriptoma , Biologia Computacional , Bases de Dados Factuais , Dermatite Atópica/genética , Perfilação da Expressão Gênica/métodos , Humanos , Prognóstico , Psoríase/genética , RNA-Seq/métodos , Pele/metabolismo , Dermatopatias/classificação , Dermatopatias/genética
18.
Lab Invest ; 100(5): 751-761, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31925326

RESUMO

The skin plays a critical role in maintenance of water homeostasis. Dysfunction of the skin barrier causes not only delayed wound healing and hypertrophic scarring, but it also contributes to the development of various skin diseases. Dermatitis is a chronic inflammatory skin disorder that has several different subtypes. Skin of contact dermatitis and atopic dermatitis (AD) show epidermal barrier dysfunction. Nax is a sodium channel that regulates inflammatory gene expression in response to perturbation of barrier function of the skin. We found that in vivo knockdown of Nax using RNAi reduced hyperkeratosis and keratinocyte hyperproliferation in rabbit ear dermatitic skin. Increased infiltration of inflammatory cells (mast cells, eosinophils, T cells, and macrophages), a characteristic of dermatitis, was reduced by Nax knockdown. Upregulation of PAR-2 and thymic stromal lymphopoietin (TSLP), which induce Th2-mediated allergic responses, was inhibited by Nax knockdown. In addition, expression of COX-2, IL-1ß, IL-8, and S100A9, which are downstream genes of Nax and are involved in dermatitis pathogenesis, were also decreased by Nax knockdown. Our data show that knockdown of Nax relieved dermatitis symptoms in vivo and indicate that Nax is a novel therapeutic target for dermatitis, which currently has limited therapeutic options.


Assuntos
Dermatite Atópica , Pele , Canais de Sódio Disparados por Voltagem , Animais , Proliferação de Células/genética , Dermatite Atópica/genética , Dermatite Atópica/patologia , Dermatite Atópica/fisiopatologia , Regulação para Baixo/genética , Eosinófilos/metabolismo , Feminino , Técnicas de Silenciamento de Genes , Inflamação/genética , Inflamação/patologia , Inflamação/fisiopatologia , Queratinócitos/metabolismo , Ceratose/genética , Ceratose/patologia , Ceratose/fisiopatologia , Mastócitos/metabolismo , Coelhos , Pele/citologia , Pele/patologia , Pele/fisiopatologia , Canais de Sódio Disparados por Voltagem/genética , Canais de Sódio Disparados por Voltagem/metabolismo
19.
J Dermatol ; 47(1): 58-60, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31773767

RESUMO

A case of atopic dermatitis (AD) with X-linked agammaglobulinemia (XLA), which is one of the primary immunodeficiency diseases, is reported. A 12-year-old boy had suffered from dry skin and recurrent itchy eruptions since he was 2 years old, and he was diagnosed as having XLA at the age of 4 years. His total immunoglobulin (Ig)E level was 7 IU/mL, even with regular Ig replacement therapy. Furthermore, filaggrin (FLG) mutations known in the Japanese population were not found. His skin lesions were well controlled by the application of a mild-class topical steroid and a moisturizer, though he developed folliculitis due to Staphylococcus aureus infection during treatment with a strong-class topical steroid. This case suggests that the FLG mutation and IgE-mediated sensitization are not necessary to induce AD skin manifestation.


Assuntos
Agamaglobulinemia/genética , Agamaglobulinemia/imunologia , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Imunoglobulina E/imunologia , Proteínas S100/genética , Agamaglobulinemia/sangue , Agamaglobulinemia/complicações , Criança , Dermatite Atópica/sangue , Doenças Genéticas Ligadas ao Cromossomo X/sangue , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Humanos , Imunoglobulina E/sangue , Mutação com Perda de Função , Masculino
20.
J Am Acad Dermatol ; 82(3): 690-699, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31669080

RESUMO

BACKGROUND: Moderate-to-severe atopic dermatitis (AD) is increasingly recognized as a systemic disease, largely due to proteomic blood studies. There are growing efforts to develop AD biomarkers using minimal tissues. OBJECTIVE: To characterize the AD skin proteomic signature and its relationship with the blood proteome and genomic skin profile in the same individuals. METHODS: We evaluated lesional and nonlesional biopsy samples and blood from 20 individuals with moderate-to-severe AD and 28 healthy individuals using Olink Proteomics (Uppsala, Sweden), using 10 µg/10 µL for skin and blood and RNA sequencing of the skin. RESULTS: The AD skin proteome demonstrated significant upregulation in lesional and even in nonlesional skin compared with controls in inflammatory markers (matrix metalloproteinase 12; T-helper cell [Th]2/interleukin [IL]-1 receptor-like 1[IL1RL1]/IL-33R, IL-13, chemokine [C-C motif] ligand [CCL] 17; Th1/C-X-C motif chemokine 10; Th17/Th22/PI3, CCL20, S100A12), and in cardiovascular-associated proteins (E-selectin, matrix metalloproteinases, platelet growth factor, myeloperoxidase, fatty acid binding protein 4, and vascular endothelial growth factor A; false discovery rate, <0.05). Skin proteins demonstrated much higher and significant upregulations (vs controls) compared with blood, suggesting a skin source for the inflammatory/cardiovascular profile. Gene and protein expressions were correlated (r = 0.410, P < .001), with commonly upregulated inflammatory and cardiovascular risk-associated products, suggesting protein translation in skin. LIMITATIONS: Our analysis was limited to 354 proteins. CONCLUSIONS: The AD skin proteome shows an inflammatory and cardiovascular signature even in nonlesional skin, emphasizing the need for proactive treatment. Skin proteomics presents a sensitive option for biomarker monitoring.


Assuntos
Dermatite Atópica/genética , Proteômica , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Dermatite Atópica/sangue , Dermatite Atópica/patologia , Feminino , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Pele/patologia , Adulto Jovem
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