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1.
Exp Dermatol ; 33(4): e15072, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38576105

RESUMO

Autosomal recessive congenital ichthyoses (ARCI) is a genetically heterogeneous condition that can be caused by pathogenic variants in at least 12 genes, including ABCA12. ARCI mainly consists of congenital ichthyosiform erythroderma (CIE), lamellar ichthyosis (LI) and harlequin ichthyosis (HI). The objective was to determine previously unreported pathogenic variants in ABCA12 and to update genotype-phenotype correlations for patients with pathogenic ABCA12 variants. Pathogenic variants in ABCA12 were detected using Sanger sequencing or a combination of Sanger sequencing and whole-exome sequencing. To verify the pathogenicity of a previously unreported large deletion and intron variant, cDNA analysis was performed using total RNA extracted from hair roots. Genetic analyses were performed on the patients with CIE, LI, HI and non-congenital ichthyosis with unusual phenotypes (NIUP), and 11 previously unreported ABCA12 variants were identified. Sequencing of cDNA confirmed the aberrant splicing of the variant ABCA12 in the patients with the previously unreported large deletion and intron variant. Our findings expand the phenotype spectrum of ichthyosis patients with ABCA12 pathogenic variants. The present missense variants in ABCA12 are considered to be heterogenous in pathogenicity, and they lead to varying disease severities in patients with ARCI and non-congenital ichthyosis with unusual phenotypes (NIUP).


Assuntos
Eritrodermia Ictiosiforme Congênita , Ictiose Lamelar , Ictiose , Humanos , Ictiose Lamelar/genética , Ictiose Lamelar/patologia , DNA Complementar , Genes Recessivos , Mutação , Ictiose/genética , Eritrodermia Ictiosiforme Congênita/genética , Estudos de Associação Genética , Transportadores de Cassetes de Ligação de ATP/genética
2.
Acta Derm Venereol ; 104: adv39950, 2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38751178

RESUMO

Pruritus in the elderly, particularly those cases without skin dryness or other identifiable causes, makes treatment challenging due to the lack of evidence regarding the therapeutic effects of antipruritics. This study proposes an age-related alloknesis mouse model for an evaluation system for such cases, and aimed to investigate the effectiveness and mechanisms of action of several drugs commonly used as antipruritics in Japan, utilizing this model. Mice 69-80 weeks old were used as aged mice, and the level of mechanical alloknesis was counted as the number of scratching behaviours in response to innocuous stimuli. Bepotastine, neurotropin, pregabalin, baricitinib, and abrocitinib were used as antipruritics, and yohimbine and methysergide as inhibitors of the descending inhibitory pathway. The findings suggest that mechanical alloknesis in aged mice is a suitable animal model for assessing pruritus in the elderly without xerosis, and pregabalin, neurotropin, baricitinib, and abrocitinib may be effective antipruritics in the elderly through activating both the noradrenergic and serotonergic descending inhibitory pathways. These findings may be useful for the selection of antipruritics for pruritus in the elderly without skin lesions or dryness.


Assuntos
Antipruriginosos , Modelos Animais de Doenças , Prurido , Animais , Prurido/tratamento farmacológico , Antipruriginosos/farmacologia , Antipruriginosos/uso terapêutico , Doença Crônica , Comportamento Animal/efeitos dos fármacos , Camundongos , Fatores Etários , Masculino , Sulfonamidas/farmacologia , Pregabalina/farmacologia , Pregabalina/uso terapêutico , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Purinas/farmacologia , Purinas/uso terapêutico , Envelhecimento/efeitos dos fármacos , Azetidinas/farmacologia , Azetidinas/uso terapêutico
3.
J Immunol ; 205(4): 907-914, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32690656

RESUMO

Atopic dermatitis is a chronic form of allergic contact dermatitis that is closely associated with a compromised epidermal barrier. Immunogenicity of a given electrophilic hapten after penetration of this barrier depends directly on biochemical reactions in the thiol-rich layer in the stratum granulosum. In response to electrophilic hapten, NF-erythroid 2-related factor 2 (NRF2) in keratinocytes efficiently induces the production of antioxidants. In this study, we show that the immunogenicity of a given hapten depends directly on the extent to which it induces antioxidant host defenses within the epidermal tissue. We found that allergic contact dermatitis did not develop in NRF2-deficient mice because of compromise of the epidermal innate immune responses that upregulate IL-1α. We also analyzed epidermal NRF2 in association with congenital disorders with features similar to atopic dermatitis in humans. Epidermal samples from patients with Netherton syndrome and peeling skin syndrome exhibited elevated levels of NRF2 and also elevated levels of its downstream target, small proline-rich protein 2. Taken together, these results suggest that the thiol-mediated biochemical responses in the stratum granulosum provide a critical link between defective epidermal barrier function and the development of atopy. Likewise, our results suggested that NRF2 may have a profound impact on the generation of cutaneous immunological memory.


Assuntos
Antioxidantes/metabolismo , Dermatite Atópica/metabolismo , Epiderme/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Pele/metabolismo , Animais , Células Cultivadas , Dermatite Atópica/imunologia , Dermatite Esfoliativa/imunologia , Dermatite Esfoliativa/metabolismo , Epiderme/imunologia , Humanos , Imunidade Inata/imunologia , Interleucina-1alfa/imunologia , Interleucina-1alfa/metabolismo , Queratinócitos/imunologia , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator 2 Relacionado a NF-E2/imunologia , Síndrome de Netherton/imunologia , Síndrome de Netherton/metabolismo , Pele/imunologia , Dermatopatias Genéticas/imunologia , Dermatopatias Genéticas/metabolismo , Regulação para Cima/imunologia
4.
Int J Mol Sci ; 23(14)2022 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-35887135

RESUMO

Superficial epidermolytic ichthyosis (SEI) is an autosomal dominant inherited ichthyosis. SEI is caused by mutations in KRT2 and frequently shows erythroderma and widespread blistering at birth. We report the clinical manifestations of two patients from a Japanese family with SEI caused by a hotspot mutation, p.Glu487Lys, in KRT2. In addition, we summarize previous reports on SEI patients with the identical mutation. One of the two patients had disease onset at the age of 7 months. The other patient's age of onset is unknown, but it was in childhood. Neither of the two patients showed erythroderma. To perform deep phenotyping, we studied the age of onset and the frequency of erythroderma in 34 reported SEI cases with the p.Glu487Lys mutation, including the present cases. Among the cases with sufficient clinical information, 44.4% of the cases that were due to p.Glu487Lys in KRT2 occurred at birth. Erythroderma was observed in 11.1% of the cases with p.Glu487Lys in KRT2.


Assuntos
Dermatite Esfoliativa , Hiperceratose Epidermolítica , Queratina-2 , Dermatite Esfoliativa/genética , Humanos , Hiperceratose Epidermolítica/genética , Lactente , Recém-Nascido , Queratina-2/genética , Mutação
5.
Int J Mol Sci ; 22(19)2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34638865

RESUMO

Neuronal morphological changes in the epidermis are considered to be one of causes of abnormal skin sensations in dry skin-based skin diseases. The present study aimed to develop an in vitro model optimised for human skin to test the external factors that lead to its exacerbation. Human-induced pluripotent stem cell-derived sensory neurons (hiPSC-SNs) were used as a model of human sensory neurons. The effects of chemical substances on these neurons were evaluated by observing the elongation of nerve fibers, incidence of blebs (bead-like swellings), and the expression of nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2). The nerve fiber length increased upon exposure to two common cosmetic preservatives-methylparaben and phenoxyethanol-but not to benzo[a]pyrene, an air pollutant at the estimated concentrations in the epidermis. Furthermore, the incidence of blebs increased upon exposure to benzo[a]pyrene. However, there was a decrease in the expression of NMNAT2 in nerve fibers, suggesting degenerative changes. No such degeneration was found after methylparaben or phenoxyethanol at the estimated concentrations in the epidermis. These findings suggest that methylparaben and phenoxyethanol promote nerve elongation in hiPSC-SNs, whereas benzo[a]pyrene induces nerve degeneration. Such alterations may be at least partly involved in the onset and progression of sensitive skin.


Assuntos
Bioensaio , Forma Celular/efeitos dos fármacos , Etilenoglicóis/farmacocinética , Células-Tronco Pluripotentes Induzidas , Parabenos/farmacologia , Células Receptoras Sensoriais , Benzo(a)pireno/toxicidade , Avaliação Pré-Clínica de Medicamentos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Fibras Nervosas/metabolismo , Fibras Nervosas/patologia , Nicotinamida-Nucleotídeo Adenililtransferase/biossíntese , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia
6.
Biochem Biophys Res Commun ; 529(4): 1073-1079, 2020 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-32819567

RESUMO

DNA methylation is an epigenetic modification that regulates gene transcription. DNA methyltransferase 1 (DNMT1) plays an important role in DNA methylation. However, the involvement of DNMT1 and DNA methylation in the pathogenesis of atopic dermatitis (AD) remains unclear. In this study, microarray analysis revealed that peripheral blood mononuclear cells of AD patients with low DNMT1 expression (DNMT1-low) highly expressed dendritic cell (DC) activation-related genes. Also, DNMT1-low AD patients exhibited a higher itch score compared to AD patients with high DNMT1 expression (DNMT1-high). By using an AD-like mouse model induced by the application of Dermatophagoides farinae body ointment, we found that Dnmt1 expression was decreased, while the expression of C-C chemokine receptor type 7 (Ccr7) was upregulated in mouse skin DCs. Furthermore, mice exposed to social defeat stress exhibited Dnmt1 downregulation and Ccr7 upregulation in skin DCs. Additionally, dermatitis and itch-related scratching behavior were exacerbated in AD mice exposed to stress. The relationship between low DNMT1 and itch induction was found in both human AD patients and AD mice. In mouse bone marrow-derived DCs, Ccr7 expression was inhibited by 5-aza-2-deoxycytidine, a methylation inhibitor. Furthermore, in mouse skin DCs, methylation of CpG sites in Ccr7 was modified by either AD induction or social defeat stress. Collectively, these findings suggest that social defeat stress exacerbates AD pathology through Dnmt1 downregulation and Ccr7 upregulation in mouse skin DCs. The data also suggest a role of DNMT1 downregulation in the exacerbation of AD pathology.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Células Dendríticas/metabolismo , Dermatite Atópica/enzimologia , Regulação para Baixo , Receptores CCR7/genética , Derrota Social , Estresse Psicológico/enzimologia , Regulação para Cima , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Metilação de DNA , Dermatite Atópica/sangue , Dermatite Atópica/genética , Feminino , Humanos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Prurido/sangue , Prurido/patologia , Receptores CCR7/metabolismo , Pele/patologia , Estresse Psicológico/sangue
7.
Am J Med Genet A ; 182(8): 1933-1938, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32449269

RESUMO

Pathogenic germline variants in the gap junction protein alpha 1 (GJA1) gene have been identified in several congenital disorders affecting cutaneous, skeletal, and cardiac tissues. Here, we describe a 12-year-old patient with a GJA1 c.113G>A, p.(Gly38Glu) variant, who presented with fulminant myocarditis following recurrent generalized erythrokeratoderma. His mother and younger sister had the same clinical manifestations with the same GJA1 variant, but did not have cardiac dysfunction. GJA1 variants have been reported in patients with congenital cardiac malformations, while acute myocarditis in GJA1-related disorders has not been reported so far.


Assuntos
Conexina 43/genética , Eritroceratodermia Variável/genética , Cardiopatias Congênitas/genética , Miocardite/genética , Adulto , Criança , Eritroceratodermia Variável/complicações , Eritroceratodermia Variável/patologia , Feminino , Mutação em Linhagem Germinativa/genética , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/patologia , Heterozigoto , Humanos , Masculino , Miocardite/complicações , Miocardite/patologia , Irmãos
8.
J Am Acad Dermatol ; 83(3): 847-853, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32029302

RESUMO

BACKGROUND: Trichorrhexis invaginata, the main diagnostic feature of Netherton syndrome, is often difficult to detect, especially in adult patients. OBJECTIVE: We sought to describe a characteristic feature of hairs in Netherton syndrome using a polarized light microscope and the underlying histopathologic changes. METHODS: Hairs obtained from 8 patients with Netherton syndrome were observed under polarized light, and we evaluated the correlation between number of band-like patterns and disease severity. RESULTS: Under polarized microscopy, the hair shafts of 8 patients showed a characteristic band-like pattern under polarized light that was not observed in healthy control individuals or patients with atopic dermatitis. This discontinuity of polarized light shows a band-like pattern in which the bands mostly ranged from 0.1 to 1.0 mm in width. The observed ratio of this finding was significantly higher than that of trichorrhexis invaginata observed under light microscopy, and patients with severe dermatitis tended to have a higher ratio than those with less severe dermatitis. LIMITATIONS: Comparative examination among other congenital ichthyoses was not performed. CONCLUSIONS: A band-like pattern in hairs with polarized light microscopy can be seen in Netherton syndrome and may have potential utility as a diagnostic marker.


Assuntos
Cabelo/anormalidades , Cabelo/patologia , Síndrome de Netherton/diagnóstico , Adolescente , Adulto , Pré-Escolar , Análise Mutacional de DNA , Diagnóstico Diferencial , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Microscopia de Polarização , Pessoa de Meia-Idade , Mutação , Síndrome de Netherton/genética , Síndrome de Netherton/patologia , Inibidor de Serinopeptidase do Tipo Kazal 5/genética , Índice de Gravidade de Doença , Síndromes de Tricotiodistrofia/diagnóstico
9.
Photodermatol Photoimmunol Photomed ; 36(3): 185-191, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31880842

RESUMO

BACKGROUND: The skin microbiome has been implicated in the pathophysiology of atopic dermatitis (AD). Although 308 nm excimer light treatment is an effective phototherapy for AD, its effects on the skin microbiome currently remain unclear. Therefore, we investigated the effects of the excimer light treatment on the skin bacterial and fungal microbiome of lesional skin of AD. METHODS: Swab samples were collected from 11 healthy controls, non-lesional and lesional skin of 11 AD patients. The excimer light treatment was administered to the lesional skin. The composition of the skin microbiome, the clinical score and skin barrier function of the lesional skin were examined before and after the treatment. The composition of the skin microbiome was determined by sequencing bacterial 16S and fungal internal transcribed spacer regions. RESULTS: The excimer light treatment significantly changed the composition of the bacterial microbiome in the lesional skin of AD, as well as improved the clinical score and skin barrier function. The treatment increased the relative abundance of the phylum Cyanobacteria and decreased that of the phylum Bacteroidetes in lesional skin. At the species level, the treatment significantly decreased the relative abundance of Staphylococcus aureus (S aureus) in lesional skin. There was also a significant correlation between the reduction of S aureus and improvement of the clinical outcomes. CONCLUSION: Our findings suggest that alterations of the skin microbiome with excimer light treatment, specifically the decrease in the abundance of S aureus, are partly involved in the improvement of AD lesions.


Assuntos
Dermatite Atópica/microbiologia , Dermatite Atópica/radioterapia , Lasers de Excimer/uso terapêutico , Microbiota/efeitos da radiação , Pele/microbiologia , Adulto , Bacteroidetes/isolamento & purificação , Cianobactérias/isolamento & purificação , Feminino , Humanos , Malassezia/isolamento & purificação , Masculino , Fenômenos Fisiológicos da Pele/efeitos da radiação , Staphylococcus aureus/isolamento & purificação , Resultado do Tratamento , Perda Insensível de Água/efeitos da radiação , Adulto Jovem
10.
Mycopathologia ; 185(6): 947-958, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32449054

RESUMO

In this report, we describe the first isolation of two highly terbinafine (TRF)-resistant Trichophyton interdigitale-like strains from a Nepali patient and an Indian patient with tinea corporis in Japan. These strains (designated NUBS19006 and NUBS19007) exhibited a TRF minimal inhibitory concentration (MIC) of > 32 mg/L and contained a missense mutation (Phe397Leu) in squalene epoxidase (SQLE) gene. The internal transcribed spacer (ITS) region sequences amplified from the isolates (NUBS19006 and NUBS19007) were 99.5% identical to Japanese isolates of T. interdigitale and T. interdigitale strain CBS 428.63. The homology of region sequences were also 97.6% identical to T. mentagrophytes strain CBS 318.56. Moreover, the ITS sequences amplified from the isolates were 100% identical to highly TRF-resistant strains of T. interdigitale, which were isolated in Delhi, India, and harbored mutations in SQLE. The urease test on Christensen's urease agar was positive for T. mentagrophytes and T. interdigitale after 7 days of incubation. On the other hand, the type strain of T. rubrum CBS 100081 T and highly TRF-resistant strains (NUBS19006 and NUBS19007) were negative on Christensen urease agar after 7 and 14 days of incubation. Moreover, NUBS19006 and NUBS19007 were also negative reaction on the hair perforation test. To avoid confusion in the taxonomy of the T. mentagrophytes/T. interdigitale complex, we suggest that the highly TRF-resistant Indian strains be considered a new species independent of T. interdigitale, according to clinical and mycological features.


Assuntos
Antifúngicos/farmacologia , Arthrodermataceae , Terbinafina/farmacologia , Tinha/microbiologia , Arthrodermataceae/classificação , Arthrodermataceae/efeitos dos fármacos , Arthrodermataceae/isolamento & purificação , Genes Fúngicos , Humanos , Índia , Japão , Mutação de Sentido Incorreto , Nepal , Esqualeno Mono-Oxigenase/genética
11.
Int J Mol Sci ; 21(21)2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33182442

RESUMO

Itch (or pruritus) was not previously recognized as a serious symptom of psoriasis. However, approximately 60-90% of psoriatic patients with pruritus have stated that it deteriorates their quality of life. Since conventional antipruritic therapies, such as antihistamines, only exert limited effects, the establishment of a treatment option for itch in psoriasis is urgently needed. Although a definitive drug is not currently available, various itch mediators are known to be involved in pruritus in psoriasis. In this review, we describe the clinical features of pruritus in psoriasis, classify a wide range of itch mediators into categories, such as the nervous, immune, endocrine, and vascular systems, and discuss the mechanisms by which these mediators induce or aggravate itch in the pathophysiology of psoriasis.


Assuntos
Prurido/patologia , Psoríase/patologia , Animais , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Prurido/tratamento farmacológico , Psoríase/tratamento farmacológico , Qualidade de Vida , Índice de Gravidade de Doença
14.
Mediators Inflamm ; 2015: 120748, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26609196

RESUMO

Glycosphingolipids (GSLs) are composed of hydrophobic ceramide and hydrophilic sugar chains. GSLs cluster to form membrane microdomains (lipid rafts) on plasma membranes, along with several kinds of transducer molecules, including Src family kinases and small G proteins. However, GSL-mediated biological functions remain unclear. Lactosylceramide (LacCer, CDw17) is highly expressed on the plasma membranes of human phagocytes and mediates several immunological and inflammatory reactions, including phagocytosis, chemotaxis, and superoxide generation. LacCer forms membrane microdomains with the Src family tyrosine kinase Lyn and the Gαi subunit of heterotrimeric G proteins. The very long fatty acids C24:0 and C24:1 are the main ceramide components of LacCer in neutrophil plasma membranes and are directly connected with the fatty acids of Lyn and Gαi. These observations suggest that the very long fatty acid chains of ceramide are critical for GSL-mediated outside-in signaling. Sphingosine is another component of ceramide, with the hydrolysis of ceramide by ceramidase producing sphingosine and fatty acids. Sphingosine is phosphorylated by sphingosine kinase to sphingosine-1-phosphate, which is involved in a wide range of cellular functions, including growth, differentiation, survival, chemotaxis, angiogenesis, and embryogenesis, in various types of cells. This review describes the role of ceramide moiety of GSLs and its metabolites in immunological and inflammatory reactions in human.


Assuntos
Ceramidas/fisiologia , Glicoesfingolipídeos/fisiologia , Inflamação/etiologia , Humanos , Queratinócitos/imunologia , Lisofosfolipídeos/fisiologia , Microdomínios da Membrana/química , Transdução de Sinais , Esfingosina/análogos & derivados , Esfingosina/fisiologia
15.
J Dermatol ; 51(1): 95-97, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37698040

RESUMO

To date, 10 types of human papillomavirus have been identified that cause flat warts, including human papillomavirus type 3, which belongs to species group 2 of the genus alpha papillomavirus. Among these 10 types, human papillomavirus type 94 is most closely related to human papillomavirus type 10, sharing 86% homology. In this study, we conducted polymerase chain reaction analysis with sequencing on samples obtained from cutaneous lesions located on the face and lower legs of an individual, revealing the presence of human papillomavirus type 94. Dermatoscopic findings revealed numerous dotted vessels within one group of macular brown lesions located on the lower leg, which contributed to the diagnosis of flat warts. An online search revealed that human papillomavirus type 94 has previously been detected in various skin diseases, and we provide a review of prior reports.


Assuntos
Infecções por Papillomavirus , Verrugas , Humanos , Infecções por Papillomavirus/diagnóstico , Papillomavirus Humano , DNA Viral/genética , Verrugas/patologia , Papillomaviridae/genética
16.
JID Innov ; 4(3): 100271, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38585194

RESUMO

Hand-foot skin reaction is the most common adverse event of multikinase inhibitors, such as sorafenib. Although hand-foot skin reaction is not life threatening, severe cases impair quality of life because of pain and reduced activities of daily living. However, the pathological mechanisms of hand-foot skin reaction have not yet been elucidated in detail, and there is currently no effective treatment. We aimed to identify keratinocyte cytoprotectants against sorafenib toxicity. The screening of cytoprotectants against sorafenib toxicity was performed using cultured normal human epidermal keratinocytes or a reconstructed human epidermis model and off-patent approved drugs in the Prestwick Chemical library. Among 1273 drugs in the chemical library, 8 dose-dependently increased cell viability by >200% in the presence of sorafenib. In the presence of sorafenib, the number of proliferating cell nuclear antigen-positive cells was significantly higher in clofazimine-, cyclosporin A-, and itraconazole-treated reconstructed human epidermis models than in sorafenib-treated models, and candidate drugs suppressed sorafenib-induced apoptosis in normal human epidermal keratinocytes. In addition, clofazimine, itraconazole, and pyrvinium pamoate significantly recovered the phosphorylation of extracellular signal-regulated kinase 1/2 in the presence of sorafenib. Collectively, hit drugs promoted cell viability and normalized keratinocyte proliferation in the presence of sorafenib. These candidate drugs have potential as treatments for multikinase inhibitor-induced hand-foot skin reaction.

17.
J Am Acad Dermatol ; 68(4): 609-617, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-23332516

RESUMO

BACKGROUND: Generalized pustular psoriasis (GPP) is a chronic autoimmune disease characterized by fever, erythema, and neutrophilic pustules over large areas of the skin. GPP does not respond well to pharmacologic intervention. OBJECTIVE: We sought to assess efficacy of selectively depleting the myeloid lineage leukocytes in patients with GPP. METHODS: Fifteen patients with persistent moderate to severe GPP despite conventional therapy were included. Eligible patients had more than 10% of their skin area covered by pustules. Treatment with oral etretinate, cyclosporine, methotrexate, prednisolone, and topical prednisolone/vitamin D3 was continued if had been initiated well in advance of study entry. Five sessions of adsorptive granulocyte and monocyte apheresis (GMA) with the Adacolumn (JIMRO Co Ltd, Takasaki, Japan) were administered (1 session/wk over 5 weeks) to selectively deplete Fcγ receptor and complement receptor bearing leukocytes. Efficacy was assessed by measuring the skin areas covered by pustules at baseline and 2 weeks after the last GMA session. RESULTS: One patient did not complete the first GMA session. Based on the GPP severity scores relative to entry, the overall scores improved (n = 14, P = .0027), and the area of erythroderma (P = .0042), pustules (P = .0031), and edema (P = .0014) decreased. Likewise, Dermatology Life Quality Index improved (P = .0016), reflecting better daily function and quality of life. Twelve patients were judged as responders (85.7%), and 10 patients maintained the clinical response for 10 weeks after the last GMA session without any change in medication. LIMITATIONS: This study was unblinded and without a placebo arm. CONCLUSION: GMA in this clinical setting was safe and effective, suggested a major role for granulocytes/monocytes in the immunopathogenesis of GPP.


Assuntos
Procedimentos de Redução de Leucócitos , Psoríase/imunologia , Psoríase/terapia , Adulto , Idoso , Feminino , Humanos , Leucócitos/imunologia , Masculino , Pessoa de Meia-Idade , Psoríase/patologia
18.
Cells ; 12(2)2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36672173

RESUMO

Dupilumab attenuates itch and skin inflammation in patients with atopic dermatitis (AD). However, itch-related events that are improved by dupilumab remain unclear. Therefore, the present study investigated changes in clinical scores, serum biomarkers, and the number of intraepidermal nerve fibers (IENFs) using skin biopsies and blood samples from 12 patients with moderate to severe AD before and after treatment with dupilumab. Clinical manifestations were assessed using eczema area and severity index (EASI) and visual analogue scale (VAS) scores at baseline and after 8 and 16 weeks of treatment. Serum levels of total immunoglobulin E (IgE), thymus and activation-regulated chemokine (TARC), interleukin (IL)-4, IL-13, IL-22, and IL-31 were examined by electrochemiluminescence, chemiluminescent enzyme immunoassays, ProQuantum immunoassays, and enzyme-linked immunosorbent assays (ELISA) at baseline and after 8 and 16 weeks of treatment. In skin biopsies from AD patients at baseline and after 16 weeks of treatment, IENFs were examined immunohistochemically with the anti-protein gene product (PGP) 9.5 antibody. The dupilumab treatment significantly improved EASI and VAS scores and decreased serum levels of TARC, IgE, and IL-22, whereas those of IL-13 and IL-31, and the number of IENFs remained unchanged and those of IL-4 increased. VAS scores were positively correlated with serum TARC, IL-22, and IgE levels and the degree of epidermal thickening. Serum IL-31 levels were positively correlated with the number of IENFs. These results suggest that serum TARC, IL-22, and IgE levels and epidermal thickness are itch-related events associated with dupilumab treatment and that serum IL-31 levels may reflect the degree of IENF density in AD patients. Therefore, dynamic changes may be used to assess the efficacy of dupilumab treatment to treat itching and inflammation in patients with AD.


Assuntos
Dermatite Atópica , Humanos , Dermatite Atópica/complicações , Dermatite Atópica/tratamento farmacológico , Interleucina-13 , Prurido/tratamento farmacológico , Resultado do Tratamento , Imunoglobulina E , Inflamação
19.
J Dermatol Sci ; 110(1): 2-9, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37003921

RESUMO

BACKGROUND: Bleomycin hydrolase (BH), which is expressed in the stratum granulosum and lower stratum corneum (SC), is involved in final filaggrin degradation. Furthermore, BH plays an essential role in producing free amino acids, which constitute the majority of natural moisturizing factors (NMF). However, the effects of BH expression and protease activity on human skin aging remain unclear. OBJECTIVE: This study was designed to evaluate the activity and expression patterns of BH in SC extracts from healthy young and elderly individuals. METHODS: SC samples were collected by tape stripping. BH activity was assessed by measuring the citrulline aminopeptidase activity. BH expression was determined by Western blotting, and NMF was quantified by liquid chromatography/mass spectrometry. Skin barrier function was determined by measuring SC hydration, transepidermal water loss (TEWL), and skin pH. RESULTS: The activity and expression of BH were higher in the elderly skin than in young skin, and BH activity was correlated with BH expression levels. Evaluation of the NMF showed that the levels of total amino acids, such as glycine, serine, aspartic acid, citrulline, pyrrolidone carboxylic acid (a metabolite of glutamic acid), and trans-urocanic acid (a metabolite of histidine), were significantly higher in elderly skin than in young skin. Moreover, SC hydration and TEWL were significantly lower in elderly, indicating dry skin, and pH was significantly higher in elderly, indicating greater skin alkalinization. CONCLUSION: These results suggest that BH activity and expression, as well as NMF amino acids, increase in elderly people as compensatory mechanisms against dry skin.


Assuntos
Citrulina , Pele , Humanos , Idoso , Citrulina/análise , Citrulina/metabolismo , Citrulina/farmacologia , Pele/metabolismo , Cisteína Endopeptidases/análise , Epiderme/metabolismo , Água/análise
20.
Pflugers Arch ; 463(5): 715-25, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22374181

RESUMO

The state of the skin changes drastically depending on the ambient temperature. Skin epidermal keratinocytes express thermosensitive transient receptor potential vanilloid (TRPV) cation channels, TRPV3 and TRPV4. These multimodal receptors are activated by various kinds of chemical and physical stimuli, including warm temperatures (>30°C). It has been suggested that TRPV4 is involved in cell-cell junction maturation; however, the effect of temperature fluctuations on TRPV4-dependent barrier homeostasis is unclear. In the present study, we demonstrated that activation of TRPV4 was crucial for barrier formation and recovery, both of which were critical for the prevention of excess dehydration of human skin keratinocytes. TRPV4 activation by physiological skin temperature (33°C), GSK1016790A or 4α-PDD allowed influx of Ca(2+) from extracellular spaces which promoted cell-cell junction development. These changes resulted in augmentation of intercellular barrier integrity in vitro and ex vivo. TRPV4 disruption reduced the increase in trans-epidermal resistance and increased intercellular permeation after a Ca(2+) switch. Furthermore, barrier recovery after the disruption of the stratum corneum was accelerated by the activation of TRPV4 either by warm temperature or a chemical activator. Our results suggest that physiological skin temperatures play important roles in cell-cell junction and skin barrier homeostasis through TRPV4 activation.


Assuntos
Epiderme/fisiologia , Queratinócitos/fisiologia , Fenômenos Fisiológicos da Pele , Canais de Cátion TRPV/metabolismo , Cálcio/metabolismo , Células Cultivadas , Desidratação/metabolismo , Epiderme/metabolismo , Homeostase/fisiologia , Humanos , Junções Intercelulares/metabolismo , Junções Intercelulares/fisiologia , Queratinócitos/metabolismo , Pele/metabolismo , Temperatura , beta Catenina/metabolismo
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