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2.
Am J Hum Genet ; 107(3): 527-538, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758447

RESUMO

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%-41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E-08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E-09); this effect was stronger when including IL36RN mutations (1.48E-13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP's pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.


Assuntos
Inflamação/genética , Interleucinas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Adulto , Animais , Citocinas/genética , Armadilhas Extracelulares/genética , Feminino , Humanos , Inflamação/patologia , Interleucina-1/genética , Interleucinas/metabolismo , Masculino , Camundongos , Mutação/genética , Neutrófilos/metabolismo , Psoríase/patologia , Doenças Raras/enzimologia , Doenças Raras/genética , Doenças Raras/patologia , Pele/enzimologia , Pele/patologia , Dermatopatias/patologia
3.
Am J Hum Genet ; 107(3): 539-543, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32758448

RESUMO

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10-6 and p = 3.6 × 10-5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10-10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.


Assuntos
Doenças Neurodegenerativas/genética , Peroxidase/genética , Psoríase/genética , Dermatopatias/genética , Ácido 4-Aminobenzoico/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular/efeitos dos fármacos , Feminino , Genótipo , Humanos , Mutação com Perda de Função/genética , Doenças Neurodegenerativas/tratamento farmacológico , Doenças Neurodegenerativas/patologia , Neutrófilos/efeitos dos fármacos , Peroxidase/antagonistas & inibidores , Fenótipo , Psoríase/tratamento farmacológico , Psoríase/patologia , Pele/efeitos dos fármacos , Pele/patologia , Dermatopatias/tratamento farmacológico , Dermatopatias/patologia
4.
Am J Hum Genet ; 107(1): 158-163, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32516568

RESUMO

The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.


Assuntos
Ácido Aspártico Endopeptidases/genética , Hereditariedade/genética , Ictiose Lamelar/genética , Mutação de Sentido Incorreto/genética , Dermatopatias/genética , Heterozigoto , Humanos , Proteínas de Filamentos Intermediários/genética , Fenótipo , Sequenciamento Completo do Exoma/métodos
5.
Vet Clin North Am Equine Pract ; 36(2): 323-339, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32534850

RESUMO

Equine skin diseases are common, causing increased costs and reduced welfare of affected horses.Genetic testing, if available, can complement early detection, disease diagnosis, and clinical treatment and offers horse breeders the possibility to rule out carrier status. The mechanisms of complex disease can be investigated by using the latest state-of-the-art genomic technologies. Genome-based strategies may also serve as an efficient and cost-effective strategy for the management of the disease severity levels, with particular interest in complex traits such as insect bite hypersensitivity, chronic progressive lymphedema, and melanoma.


Assuntos
Doenças dos Cavalos/genética , Dermatopatias/veterinária , Animais , Cavalos , Dermatopatias/genética
6.
Virchows Arch ; 477(5): 749-753, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32372223

RESUMO

Langerhans cell histiocytosis (LCH) is characterized by mutations of the RAS-RAF-MAPK signaling pathway. We analyzed MAP2K1, NRAS and KIT mutation incidence in skin lesions of BRAF wild-type (wt) LCH patients. We evaluated the occurrence of MAP2K1, NRAS and KIT mutations in seven LCH and one indeterminate cell histiocytosis (ICH) patients. MAP2K1 mutation frequency was found to be 3/7 (42.9%) in LCH and also found in ICH. Similarly, the KIT mutation frequency was found to be equally prevalent (4/7, 57.1%) in LCH and also occurred in ICH. Involvement of KIT exons in LCH-ICH indicated that exon 9/11/18 were equally prevalent followed by exon 13. This exploratory analysis on BRAF-wt LCH revealed a KIT mutation rate comparable to MAP2K1. Although the detected KIT mutations are different from activating mutations found in other KIT-dependent neoplasms, our data suggest that KIT-inhibitors might have a role in treating BRAF-wt LCH patients.


Assuntos
Histiocitose de Células de Langerhans/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-kit/genética , Dermatopatias/genética , Adolescente , Adulto , Idoso , Feminino , GTP Fosfo-Hidrolases/genética , Predisposição Genética para Doença , Histiocitose de Células de Langerhans/patologia , Histiocitose de Células de Langerhans/terapia , Humanos , Lactente , MAP Quinase Quinase 1/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Taxa de Mutação , Fenótipo , Prognóstico , Dermatopatias/patologia , Dermatopatias/terapia , Adulto Jovem
7.
Am J Physiol Cell Physiol ; 319(1): C105-C115, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32374674

RESUMO

Transforming growth factor-ß (TGF-ß)-induced fibroblast activation is a key pathological event during tissue fibrosis. Long noncoding RNA (lncRNA) is a class of versatile gene regulators participating in various cellular and molecular processes. However, the function of lncRNA in fibroblast activation is still poorly understood. In this study, we identified growth arrest-specific transcript 5 (GAS5) as a novel regulator for TGF-ß-induced fibroblast activation. GAS5 expression was downregulated in cultured fibroblasts by TGF-ß and in resident fibroblasts from bleomycin-treated skin tissues. Overexpression of GAS5 suppressed TGF-ß-induced fibroblast to myofibroblast differentiation. Mechanistically, GAS5 directly bound mothers against decapentaplegic homolog 3 (Smad3) and promoted Smad3 binding to Protein phosphatase 1A (PPM1A), a Smad3 dephosphatase, and thus accelerated Smad3 dephosphorylation in TGF-ß-treated fibroblasts. In addition, GAS5 inhibited fibroblast proliferation. Importantly, local delivery of GAS5 via adenoviral vector suppressed bleomycin-induced skin fibrosis in mice. Collectively, our data revealed that GAS5 suppresses fibroblast activation and fibrogenesis through inhibiting TGF-ß/Smad3 signaling, which provides a rationale for an lncRNA-based therapy to treat fibrotic diseases.


Assuntos
Fibroblastos/metabolismo , RNA Longo não Codificante/biossíntese , Transdução de Sinais/fisiologia , Proteína Smad3/antagonistas & inibidores , Proteína Smad3/metabolismo , Animais , Fibroblastos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , RNA Longo não Codificante/genética , Dermatopatias/genética , Dermatopatias/patologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator de Crescimento Transformador beta/metabolismo
8.
PLoS One ; 15(4): e0230587, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32271766

RESUMO

As high-throughput sequencing is increasingly applied to the molecular diagnosis of rare Mendelian disorders, a large number of patients with diverse phenotypes have their genetic and phenotypic data pooled together to uncover new gene-phenotype relations. We introduce Phenogenon, a statistical tool that combines, Human Phenotype Ontology (HPO) annotated patient phenotypes, gnomAD allele population frequency, and Combined Annotation Dependent Depletion (CADD) score for variant pathogenicity, in order to jointly predict the mode of inheritance and gene-phenotype associations. We ran Phenogenon on our cohort of 3,290 patients who had undergone whole exome sequencing. Among the top associations, we recapitulated previously known, such as "SRD5A3-Abnormal full-field electroretinogram-recessive" and "GRHL2 -Nail dystrophy-recessive", and discovered one potentially novel, "RRAGA-Abnormality of the skin-dominant". We also developed an interactive web interface available at https://phenogenon.phenopolis.org to visualise and explore the results.


Assuntos
Biologia Computacional/métodos , Estudos de Associação Genética , Doenças Genéticas Inatas , Sequenciamento de Nucleotídeos em Larga Escala , Doenças Raras , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Estudos de Coortes , Proteínas de Ligação a DNA/genética , Bases de Dados Genéticas , Frequência do Gene , Estudos de Associação Genética/métodos , Estudos de Associação Genética/estatística & dados numéricos , Doenças Genéticas Inatas/epidemiologia , Doenças Genéticas Inatas/genética , Predisposição Genética para Doença , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Sequenciamento de Nucleotídeos em Larga Escala/estatística & dados numéricos , Humanos , Proteínas de Membrana/genética , Proteínas Monoméricas de Ligação ao GTP/genética , Doenças da Unha/epidemiologia , Doenças da Unha/genética , Fenótipo , Doenças Raras/epidemiologia , Doenças Raras/genética , Distrofias Retinianas/epidemiologia , Distrofias Retinianas/genética , Dermatopatias/epidemiologia , Dermatopatias/genética , Fatores de Transcrição/genética , Sequenciamento Completo do Exoma
9.
Nature ; 580(7803): 391-395, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32296175

RESUMO

The biological function of Z-DNA and Z-RNA, nucleic acid structures with a left-handed double helix, is poorly understood1-3. Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) is a nucleic acid sensor that contains two Zα domains that bind Z-DNA4,5 and Z-RNA6-8. ZBP1 mediates host defence against some viruses6,7,9-14 by sensing viral nucleic acids6,7,10. RIPK1 deficiency, or mutation of its RIP homotypic interaction motif (RHIM), triggers ZBP1-dependent necroptosis and inflammation in mice15,16. However, the mechanisms that induce ZBP1 activation in the absence of viral infection remain unknown. Here we show that Zα-dependent sensing of endogenous ligands induces ZBP1-mediated perinatal lethality in mice expressing RIPK1 with mutated RHIM (Ripk1mR/mR), skin inflammation in mice with epidermis-specific RIPK1 deficiency (RIPK1E-KO) and colitis in mice with intestinal epithelial-specific FADD deficiency (FADDIEC-KO). Consistently, functional Zα domains were required for ZBP1-induced necroptosis in fibroblasts that were treated with caspase inhibitors or express RIPK1 with mutated RHIM. Inhibition of nuclear export triggered the Zα-dependent activation of RIPK3 in the nucleus resulting in cell death, which suggests that ZBP1 may recognize nuclear Z-form nucleic acids. We found that ZBP1 constitutively bound cellular double-stranded RNA in a Zα-dependent manner. Complementary reads derived from endogenous retroelements were detected in epidermal RNA, which suggests that double-stranded RNA derived from these retroelements may act as a Zα-domain ligand that triggers the activation of ZBP1. Collectively, our results provide evidence that the sensing of endogenous Z-form nucleic acids by ZBP1 triggers RIPK3-dependent necroptosis and inflammation, which could underlie the development of chronic inflammatory conditions-particularly in individuals with mutations in RIPK1 and CASP817-20.


Assuntos
Inflamação/metabolismo , Necroptose , Proteínas de Ligação a RNA/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Caspase 8/metabolismo , Feminino , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Nucleicos/metabolismo , RNA de Cadeia Dupla/metabolismo , Proteínas de Ligação a RNA/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Dermatopatias/genética , Dermatopatias/metabolismo , Dermatopatias/patologia
10.
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
11.
Eur J Endocrinol ; 182(3): C9-C12, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31972544

RESUMO

Primary adrenal insufficiency (PAI) in children is mostly due to genetic defects. The understanding of the molecular genetics of the causes of adrenal insufficiency in the pediatric population has made significant progress during the last years. It has been shown that inherited PAI can lead to certain clinical manifestations and health problems in children beyond the adrenals. Organ dysfunctions associated with different forms of PAI in children include a wide range of organs such as gonads, brain, heart, bone, growth, bone marrow, kidney, skin, parathyroid, and thyroid. Diagnosing the correct genetic cause of PAI in children is therefore crucial to adequately control long-term treatment and follow-up in such patients.


Assuntos
Doença de Addison/genética , Hiperplasia Suprarrenal Congênita/genética , Doença de Addison/complicações , Doença de Addison/diagnóstico , Doença de Addison/fisiopatologia , Hiperplasia Suprarrenal Congênita/complicações , Hiperplasia Suprarrenal Congênita/diagnóstico , Hiperplasia Suprarrenal Congênita/fisiopatologia , Doenças do Desenvolvimento Ósseo/etiologia , Doenças do Desenvolvimento Ósseo/genética , Doenças do Desenvolvimento Ósseo/fisiopatologia , Encefalopatias/etiologia , Encefalopatias/genética , Encefalopatias/fisiopatologia , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Cardiomiopatias/fisiopatologia , Transtornos do Desenvolvimento Sexual/etiologia , Transtornos do Desenvolvimento Sexual/genética , Transtornos do Desenvolvimento Sexual/fisiopatologia , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/genética , Transtornos do Crescimento/fisiopatologia , Humanos , Hipoadrenocorticismo Familiar/complicações , Hipoadrenocorticismo Familiar/diagnóstico , Hipoadrenocorticismo Familiar/genética , Hipoadrenocorticismo Familiar/fisiopatologia , Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/fisiopatologia , Técnicas de Diagnóstico Molecular , Síndrome Nefrótica/etiologia , Síndrome Nefrótica/genética , Síndrome Nefrótica/fisiopatologia , Dermatopatias/etiologia , Dermatopatias/genética , Dermatopatias/fisiopatologia
12.
Biomed Pharmacother ; 123: 109755, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31926375

RESUMO

Skin toxicities induced by epidermal growth factor receptor inhibitors such as Erlotinib plagues clinical challenges. Chinese formulas have a unique advantage in reducing side effects. Here, we aim to investigate the skin protecting function of XiaoZhenFang (XZF), a clinical adjuvant prescription made up of Lonicerae Japonicae Flos, Lithospermum Erythrorhizon, Smilacis Glabrae Rhizoma, Forsythiae Fructus, Spirodelae Herba, Cortex Moutan and Prunellae Spica. Our data showed that XZF aqueous extract effectively reduced skin toxicities induced by Erlotinib in vivo using established mice model. Next, we used a systems pharmacology approach to investigate the pharmacological mechanism of XZF with the goal of understanding its effects at the system, organ, and molecular levels. 44 candidate compounds and 103 potential targets were identified by network pharmacology. Inflammation, cell stress and the EGFR-related signal pathways, which may participate in the skin protection afforded by XZF, were analyzed by gene enrichment. Importantly, our in vivo experimental results largely validated XZF's mechanism of action, as predicted by the system pharmacology analysis. Our study uncovered the effect and mechanism of XZF in attenuating skin toxicities induced by EGFRI, providing a basis for the development of in-hospital preparations and new drugs for the prevention of skin toxicities.


Assuntos
Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Dermatopatias/metabolismo , Animais , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais/efeitos dos fármacos , Pele/efeitos dos fármacos , Pele/patologia , Dermatopatias/induzido quimicamente , Dermatopatias/genética , Dermatopatias/patologia
13.
Int J Mol Sci ; 21(2)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952341

RESUMO

Deimination, also known as citrullination, corresponds to the conversion of the amino acid arginine, within a peptide sequence, into the non-standard amino acid citrulline. This post-translational modification is catalyzed by a family of calcium-dependent enzymes called peptidylarginine deiminases (PADs). Deimination is implicated in a growing number of physiological processes (innate and adaptive immunity, gene regulation, embryonic development, etc.) and concerns several human diseases (rheumatoid arthritis, neurodegenerative diseases, female infertility, cancer, etc.). Here, we update the involvement of PADs in both the homeostasis of skin and skin diseases. We particularly focus on keratinocyte differentiation and the epidermal barrier function, and on hair follicles. Indeed, alteration of PAD activity in the hair shaft is responsible for two hair disorders, the uncombable hair syndrome and a particular form of inflammatory scarring alopecia, mainly affecting women of African ancestry.


Assuntos
Regulação da Expressão Gênica , Processamento de Proteína Pós-Traducional , Desiminases de Arginina em Proteínas/genética , Dermatopatias/genética , Fenômenos Fisiológicos da Pele/genética , Citrulinação , Homeostase/genética , Humanos , Isoenzimas/genética , Isoenzimas/metabolismo , Queratinócitos/metabolismo , Desiminases de Arginina em Proteínas/metabolismo , Pele/metabolismo , Pele/patologia , Dermatopatias/metabolismo
14.
J Dermatolog Treat ; 31(7): 716-722, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30998081

RESUMO

Dry skin is a common condition that is attributed to a lack of water in the stratum corneum. With the availability of new technologies, light has been shed on the pathophysiology of dry skin at the molecular level. With the aim to discuss implications of this latest research for the optimal formulation of emollients designed to treat dry skin, five specialists met in November 2017. Research on three topics thereby provided particularly detailed new insights on how to manage dry skin: research on the lipid composition and organization of the stratum corneum, research on natural moisturizing factors, and research on the peripheral nervous system. There was consensus that latest research expands the rationale to include physiological lipids in an emollient used for dry skin, as they were found to be essential for an adequate composition and organization in the stratum corneum but are reduced in dry skin. Latest findings also confirmed the incorporation of carefully selected humectants into a topical emollient for dry skin, given the reduced activity of enzymes involved in the synthesis of moisturizing factors when skin is dry. Overall, the group of specialists concluded that the previous concept of the five components for an ideal emollient for dry skin is well in accordance with latest research.


Assuntos
Emolientes/administração & dosagem , Fenômenos Fisiológicos da Pele , Administração Cutânea , Epiderme/fisiologia , Humanos , Lipídeos/fisiologia , Higiene da Pele , Dermatopatias/genética , Água/fisiologia
15.
Clin Immunol ; 212: 108273, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31626957

RESUMO

Stimulator of interferon genes associated vasculopathy with onset in infancy (SAVI), caused by heterozygote gain-of-function mutations in TMEM173, is characterized by fever attacks with ulcerating cutaneous manifestations on cold-sensitive areas and interstitial lung disease. A six-month-old boy was admitted to our hospital with fever, cough, and rash on the external surface of both upper and lower extremities. Respiratory symptoms consistent with ILD developed and skin lesions evolved to eschar formation particularly on acral regions. Ultimately, diagnosis of SAVI was confirmed at the age of 10 months due to the high level of interferon-score and a heterozygous N154S mutation in TMEM173. Since systemic corticosteroid and ruxolitinib were not effective, baricitinib was initiated at the age of 15 months, resulting in alleviation of fever attacks, cutaneous manifestations and respiratory symptoms within 2 months. In conclusion, we reported an infant diagnosed with SAVI at the age of 10 months and treated with baricitinib.


Assuntos
Anti-Inflamatórios/uso terapêutico , Azetidinas/uso terapêutico , Febre/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Metilprednisolona/uso terapêutico , Úlcera Cutânea/tratamento farmacológico , Sulfonamidas/uso terapêutico , Doenças Vasculares/tratamento farmacológico , Proteína C-Reativa/imunologia , Febre/genética , Febre/imunologia , Mutação com Ganho de Função , Humanos , Lactente , Doenças Pulmonares Intersticiais/genética , Doenças Pulmonares Intersticiais/imunologia , Masculino , Proteínas de Membrana/genética , Mutação , Pirazóis/uso terapêutico , Dermatopatias/tratamento farmacológico , Dermatopatias/genética , Dermatopatias/imunologia , Úlcera Cutânea/genética , Úlcera Cutânea/imunologia , Síndrome , Falha de Tratamento , Turquia , Doenças Vasculares/genética , Doenças Vasculares/imunologia
16.
Yakugaku Zasshi ; 139(12): 1495-1500, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31787635

RESUMO

The roles of chondroitin sulfate (CS) and dermatan sulfate (DS) have been demonstrated in various biological events such as the construction of the extracellular matrix, tissue development, and cell signaling through interactions with extracellular matrix components, morphogens, and growth factors. Human genetic diseases, including skeletal abnormalities, connective tissue diseases, and heart defects, were reported to be caused by mutations in the genes encoding glycosyltransferases, epimerases, and sulfotransferases that are responsible for the biosynthesis of CS and DS. Glycobiological approaches revealed that mutations in CS- and DS-biosynthetic enzymes led to reductions in their enzymatic activities and in the levels of CS and DS. Furthermore, CS at the surface of tumor cells plays a key role in pulmonary metastasis. A receptor for advanced glycation end-products (RAGE) was predominantly expressed in the lung, and was identified as a functional receptor for CS chains. CS and anti-RAGE antibodies inhibited the pulmonary metastasis of not only Lewis lung carcinoma but also B16 melanoma cells. Hence, RAGE and CS are potential targets of drug discovery for pulmonary metastasis and a number of other pathological conditions involving RAGE in the pathogenetic mechanism. This review provides an overview of glycobiological studies on characterized genetic disorders caused by the impaired biosynthesis of CS, as well as DS, and on the pulmonary metastasis of Lewis lung carcinoma cells involving CS and RAGE.


Assuntos
Doenças Ósseas/etiologia , Doenças Ósseas/genética , Carcinoma Pulmonar de Lewis/etiologia , Carcinoma Pulmonar de Lewis/secundário , Condroitina/biossíntese , Dermatan Sulfato/biossíntese , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/secundário , Receptor para Produtos Finais de Glicação Avançada , Dermatopatias/etiologia , Dermatopatias/genética , Animais , Carcinoma Pulmonar de Lewis/genética , Humanos , Neoplasias Pulmonares/genética , Camundongos , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo
17.
Int J Mol Sci ; 20(24)2019 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-31817921

RESUMO

Gap junctional channels are specialized components of the cellular membrane that allow the intercellular passage of small metabolites, ions, and second messengers to maintain homeostasis. They are comprised of members of the connexin gene family that encode a wide array of proteins that are expressed in nearly every tissue type. Cx43 is perceived to be the most broadly expressed connexin in humans, with several genetic skin diseases being linked to Cx43 mutations specifically. These mutations, in large, produce a gain of functional hemichannels that contribute to the phenotypes of Erythrokeratoderma Variabilis et Progressiva (EKVP), Palmoplantar Keratodemra Congenital Alopecia-1 (PPKCA1), and others that produce large conductance and increased permselectivity in otherwise quiescent structures. Gaining functional hemichannels can have adverse effects in the skin, inducing apoptosis via Ca2+ overload or increased ATP permeability. Here, we review the link between Cx43 and skin disease. We aim to provide insight into the mechanisms regulating the normal and pathophysiological gating of these essential proteins, as well as address current therapeutic strategies. We also demonstrate that transient transfection of neuro-2a (N2a) cells with mutant Cx43 cDNA resulted in increased hemichannel activity compared to wild-type Cx43 and untransfected cells, which is consistent with other studies in the current literature.


Assuntos
Conexina 43/genética , Canais Iônicos/fisiologia , Mutação , Dermatopatias/patologia , Animais , Conexina 43/metabolismo , Humanos , Dermatopatias/genética , Dermatopatias/metabolismo
18.
J Dtsch Dermatol Ges ; 17(12): 1227-1238, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31846220

RESUMO

Loricrin downregulation has been associated with age-related changes as well as inherited and inflammatory skin diseases. We hypothesize that changes in loricrin could be more related to altered barrier function and consequently disorders that affect epithelial cells, such as psoriasis, atopic dermatitis (AD), erythrokeratoderma, loricrin keratoderma (LK) and periodontitis. The aim of this review is to summarize what is known about the association between loricrin downregulation and epithelial-related disorders (ERDs). A search was performed on the following databases: Medline, Cochrane Library, PubMed, EMBASE, Lilacs, Scopus and Google Scholar, resulting in 16 included articles. Loricrin keratoderma was the ERD most frequently associated with loricrin mutations (730insG, 709insC and 578insG; 5/7 cases - 71.44 %). Atopic dermatitis was the ERD most frequently associated with loricrin downregulation (2/7 cases - 28.6 %). Mutilating palmoplantar keratoderma, progressive symmetrical erythrokeratoderma and a new type of erythrokeratoderma were not associated with any mutations. At the gene level, periodontitis patients showed the highest decrease (-6.89x), followed by AD (-6.5x) and psoriasis patients (-0.5x). In summary, loricrin mutation and downregulation were associated with several ERDs. The diversity in disease presentation is likely related to whether there is a total loss of loricrin, mislocalization and/or if the mutant form of loricrin causes dysfunction of other proteins and/or changes in cornification.


Assuntos
Proteínas de Membrana/metabolismo , Mutação , Dermatopatias/metabolismo , Análise Mutacional de DNA , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Ceratose/genética , Ceratose/metabolismo , Masculino , Proteínas de Membrana/genética , Membrana Mucosa/metabolismo , Psoríase/genética , Psoríase/metabolismo , RNA Mensageiro/metabolismo , Dermatopatias/genética
19.
Int J Mol Sci ; 20(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694170

RESUMO

In higher organisms, epithelia separate compartments in order to guarantee their proper function. Such structures are able to seal but also to allow substances to pass. Within the paracellular pathway, a supramolecular structure, the tight junction transport is largely controlled by the temporospatial regulation of its major protein family called claudins. Besides the fact that the expression of claudins has been identified in different forms of human diseases like cancer, clearly defined mutations in the corresponding claudin genes have been shown to cause distinct human disorders. Such disorders comprise the skin and its adjacent structures, liver, kidney, the inner ear, and the eye. From the phenotype analysis, it has also become clear that different claudins can cause a complex phenotype when expressed in different organs. To gain deeper insights into the physiology and pathophysiology of claudin-associated disorders, several mouse models have been generated. In order to model human disorders in detail, they have been designed either as full knockouts, knock-downs or knock-ins by a variety of techniques. Here, we review human disorders caused by CLDN mutations and their corresponding mouse models that have been generated thus far and assess their usefulness as a model for the corresponding human disorder.


Assuntos
Claudinas/genética , Mutação , Sequência de Aminoácidos , Animais , Claudinas/química , Modelos Animais de Doenças , Oftalmopatias/genética , Humanos , Nefropatias/genética , Hepatopatias/genética , Camundongos , Neoplasias/genética , Dermatopatias/genética
20.
Blood ; 134(23): 2092-2106, 2019 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-31578204

RESUMO

Graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloSCT) is characterized by interleukin-6 (IL-6) dysregulation. IL-6 can mediate effects via various pathways, including classical, trans, and cluster signaling. Given the recent availability of agents that differentially inhibit these discrete signaling cascades, understanding the source and signaling and cellular targets of this cytokine is paramount to inform the design of clinical studies. Here we demonstrate that IL-6 secretion from recipient dendritic cells (DCs) initiates the systemic dysregulation of this cytokine. Inhibition of DC-driven classical signaling after targeted IL-6 receptor (IL-6R) deletion in T cells eliminated pathogenic donor Th17/Th22 cell differentiation and resulted in long-term survival. After engraftment, donor DCs assume the same role, maintaining classical IL-6 signaling-dependent GVHD responses. Surprisingly, cluster signaling was not active after transplantation, whereas inhibition of trans signaling with soluble gp130Fc promoted severe, chronic cutaneous GVHD. The latter was a result of exaggerated polyfunctional Th22-cell expansion that was reversed by IL-22 deletion or IL-6R inhibition. Importantly, inhibition of IL-6 classical signaling did not impair the graft-versus-leukemia effect. Together, these data highlight IL-6 classical signaling and downstream Th17/Th22 differentiation as important therapeutic targets after alloSCT.


Assuntos
Células Dendríticas/imunologia , Doença Enxerto-Hospedeiro/imunologia , Interleucina-6/imunologia , Transdução de Sinais/imunologia , Dermatopatias/imunologia , Transplante de Células-Tronco , Aloenxertos , Animais , Diferenciação Celular/imunologia , Células Dendríticas/patologia , Deleção de Genes , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Efeito Enxerto vs Leucemia/genética , Efeito Enxerto vs Leucemia/imunologia , Interleucina-6/genética , Interleucinas/genética , Interleucinas/imunologia , Camundongos , Camundongos Transgênicos , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/imunologia , Transdução de Sinais/genética , Dermatopatias/genética , Dermatopatias/patologia , Células Th17/imunologia , Células Th17/patologia
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