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2.
Sci Transl Med ; 12(560)2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32908007

RESUMO

Dysbiosis of the skin microbiota is increasingly implicated as a contributor to the pathogenesis of atopic dermatitis (AD). We previously reported first-in-human safety and clinical activity results from topical application of the commensal skin bacterium Roseomonas mucosa for the treatment of AD in 10 adults and 5 children older than 9 years of age. Here, we examined the potential mechanism of action of R. mucosa treatment and its impact on children with AD less than 7 years of age, the most common age group for children with AD. In 15 children with AD, R. mucosa treatment was associated with amelioration of disease severity, improvement in epithelial barrier function, reduced Staphylococcus aureus burden on the skin, and a reduction in topical steroid requirements without severe adverse events. Our observed response rates to R. mucosa treatment were greater than those seen in historical placebo control groups in prior AD studies. Skin improvements and colonization by R. mucosa persisted for up to 8 months after cessation of treatment. Analyses of cellular scratch assays and the MC903 mouse model of AD suggested that production of sphingolipids by R. mucosa, cholinergic signaling, and flagellin expression may have contributed to therapeutic impact through induction of a TNFR2-mediated epithelial-to-mesenchymal transition. These results suggest that a randomized, placebo-controlled trial of R. mucosa treatment in individuals with AD is warranted and implicate commensals in the maintenance of the skin epithelial barrier.


Assuntos
Dermatite Atópica , Eczema , Methylobacteriaceae , Adulto , Criança , Dermatite Atópica/tratamento farmacológico , Humanos , Lipídeos , Pele
3.
Front Allergy ; 12020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34308414

RESUMO

Atopic diseases, particularly atopic dermatitis (AD), asthma, and allergic rhinitis (AR) share a common pathogenesis of inflammation and barrier dysfunction. Epithelial to mesenchymal transition (EMT) is a process where epithelial cells take on a migratory mesenchymal phenotype and is essential for normal tissue repair and signal through multiple inflammatory pathways. However, while links between EMT and both asthma and AR have been demonstrated, as we outline in this mini-review, the literature investigating AD and EMT is far less well-elucidated. Furthermore, current studies on EMT and atopy are mostly animal models or ex vivo studies on cell cultures or tissue biopsies. The literature covered in this mini-review on EMT-related barrier dysfunction as a contributor to AD as well as the related (perhaps resultant) atopic diseases indicates a potential for therapeutic targeting and carry treatment implications for topical steroid use and environmental exposure assessments. Further research, particularly in vivo studies, may greatly advance the field and translate into benefit for patients and families.

4.
PLoS One ; 13(9): e0198862, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30208113

RESUMO

Keratinocytes are the most abundant cell type in the epidermis. They prevent desiccation and provide immunological and barrier defense against potential pathogens such as Staphylococcus aureus and Candida albicans. The study of this first line of immune defense may be hindered by invasive isolation methods and/or improper culture conditions to support stem cell maintenance and other potential mechanisms contributing to long-term subcultivation in vitro. Primary keratinocytes have been successfully isolated from blister roofs induced by negative pressure, which separates the epidermis from the dermis in vivo in human subjects. This method allows collection of pure epidermal cells without dermal contamination in a minimally invasive manner. However, the isolated keratinocytes differentiate and senesce when cultured in vitro beyond five passages. Here, we present evidence that the Rho kinase (ROCK) inhibitor Y-27632 can be used to effectively increase the proliferative capabilities of keratinocytes isolated using the suction blister method, similar to what has been previously reported for primary keratinocytes isolated using alternative methods. We show that the increase in passage number is directly correlated to delayed differentiation, and that cells passaged long term with the inhibitor retain their ability to stratify in organotypic raft cultures and respond to cytokine treatment; additionally, the late passage cells have a heterogeneous mix of differentiated and non-differentiated cells which may be predicted by a ratio of select differentiation markers. The described method presents a minimally invasive procedure for keratinocyte isolation and prolonged culture that allows analysis of keratinocyte function in both healthy volunteers and patients with dermatologic diseases.


Assuntos
Amidas/farmacologia , Vesícula/metabolismo , Técnicas de Cultura de Células/métodos , Epiderme/metabolismo , Queratinócitos/metabolismo , Piridinas/farmacologia , Quinases Associadas a rho/antagonistas & inibidores , Vesícula/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Epiderme/patologia , Humanos , Queratinócitos/patologia
5.
J Clin Invest ; 128(8): 3595-3604, 2018 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30035749

RESUMO

Autosomal dominant hyper IgE syndrome (AD-HIES), or Job's syndrome, is a primary immune deficiency caused by dominant-negative mutations in STAT3. Recurrent Staphylococcus aureus skin abscesses are a defining feature of this syndrome. A widely held hypothesis that defects in peripheral Th17 differentiation confer this susceptibility has never been directly evaluated. To assess the cutaneous immune response in AD-HIES, we induced suction blisters in healthy volunteers (HVs) and patients with AD-HIES and then challenged the wound with lethally irradiated bacteria. We show that cutaneous production of IL-17A and IL-17F was normal in patients with AD-HIES. Overproduction of TNF-α differentiated the responses in AD-HIES from HVs. This was associated with reduced IL-10 family signaling in blister-infiltrating cells and defective epithelial cell function. Mouse models of AD-HIES recapitulated these aberrant epithelial responses to S. aureus and involved defective epithelial-to-mesenchymal transition (EMT) rather than a failure of bacterial killing. Defective responses in mouse models of AD-HIES and primary keratinocyte cultures from patients with AD-HIES could be reversed by TNF-α blockade and by drugs with reported modulatory effects on EMT. Our results identify these as potential therapeutic approaches in patients with AD-HIES suffering S. aureus infections.


Assuntos
Células Epiteliais/imunologia , Furunculose/imunologia , Síndrome de Job/imunologia , Queratinócitos/imunologia , Staphylococcus aureus/imunologia , Fator de Necrose Tumoral alfa/imunologia , Adulto , Animais , Modelos Animais de Doenças , Células Epiteliais/patologia , Transição Epitelial-Mesenquimal/genética , Transição Epitelial-Mesenquimal/imunologia , Feminino , Furunculose/genética , Furunculose/patologia , Humanos , Interleucina-17/genética , Interleucina-17/imunologia , Síndrome de Job/genética , Síndrome de Job/patologia , Queratinócitos/patologia , Masculino , Camundongos , Camundongos Transgênicos , Fator de Necrose Tumoral alfa/genética
6.
JCI Insight ; 3(9)2018 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-29720571

RESUMO

The underlying pathology of atopic dermatitis (AD) includes impaired skin barrier function, susceptibility to Staphylococcus aureus skin infection, immune dysregulation, and cutaneous dysbiosis. Our recent investigation into the potential role of Gram-negative skin bacteria in AD revealed that isolates of one particular commensal, Roseomonas mucosa, collected from healthy volunteers (HVs) improved outcomes in mouse and cell culture models of AD. In contrast, isolates of R. mucosa from patients with AD worsened outcomes in these models. These preclinical results suggested that interventions targeting the microbiome could provide therapeutic benefit for patients with AD. As a first test of this hypothesis in humans, 10 adult and 5 pediatric patients were enrolled in an open-label phase I/II safety and activity trial (the Beginning Assessment of Cutaneous Treatment Efficacy for Roseomonas in Atopic Dermatitis trial; BACTERiAD I/II). Treatment with R. mucosa was associated with significant decreases in measures of disease severity, topical steroid requirement, and S. aureus burden. There were no adverse events or treatment complications. We additionally evaluated differentiating bacterial metabolites and topical exposures that may contribute to the skin dysbiosis associated with AD and/or influence future microbiome-based treatments. These early results support continued evaluation of R. mucosa therapy with a placebo-controlled trial.


Assuntos
Terapia Biológica , Dermatite Atópica/terapia , Disbiose/terapia , Methylobacteriaceae , Microbiota , Pele/microbiologia , Adolescente , Adulto , Animais , Terapia Biológica/efeitos adversos , Criança , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/genética , Dermatite Atópica/microbiologia , Disbiose/microbiologia , Feminino , Humanos , Masculino , Methylobacteriaceae/isolamento & purificação , Camundongos , Índice de Gravidade de Doença , Staphylococcus aureus/isolamento & purificação , Esteroides/uso terapêutico , Adulto Jovem
7.
Pathogens ; 6(2)2017 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-28587312

RESUMO

Autosomal dominant hyper IgE syndrome (AD-HIES) is a primary immunodeficiency caused by a loss-of-function mutation in the Signal Transducer and Activator of Transcription 3 (STAT3). This immune disorder is clinically characterized by increased susceptibility to cutaneous and sinopulmonary infections, in particular with Candida and Staphylococcus aureus. It has recently been recognized that the skin microbiome of patients with AD-HIES is altered with an overrepresentation of certain Gram-negative bacteria and Gram-positive staphylococci. However, these alterations have not been characterized at the species- and strain-level. Since S. aureus infections are influenced by strain-specific expression of virulence factors, information on colonizing strain characteristics may provide insights into host-pathogen interactions and help guide management strategies for treatment and prophylaxis. The aim of this study was to determine whether the immunodeficiency of AD-HIES selects for unique strains of colonizing S. aureus. Using multi-locus sequence typing (MLST), protein A (spa) typing, and PCR-based detection of toxin genes, we performed a detailed analysis of the S. aureus isolates (n = 13) found on the skin of twenty-one patients with AD-HIES. We found a low diversity of sequence types, and an abundance of strains that expressed methicillin resistance, Panton-Valentine leukocidin (PVL), and staphylococcal enterotoxins K and Q (SEK, SEQ). Our results indicate that patients with AD-HIES may often carry antibiotic-resistant strains that harbor key virulence factors.

8.
Immunol Lett ; 172: 106-12, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26916143

RESUMO

The SV-40-transformed MH-S cell line maintains some, but not all, features of primary alveolar macrophages (AMs) from BALB/c mice. We show here that MH-S cells produce inflammatory cytokines IL-6 and CXCL10 in response to challenge with Gram-positive Lactobacillus reuteri, and to TLR2 and NOD2 ligands Pam3CSK4 and MDP, respectively. In contrast, although wild-type AMs are infected in vivo by pneumonia virus of mice (PVM), no virus replication was detected in MH-S cells. Interestingly, the surface immunophenotype of MH-S cells (CD11c(+)Siglec F(-)) differs from that of wild-type AMs (CD11c(+) Siglec F(+)) and is similar to that of immature AMs isolated from granulocyte macrophage-colony stimulating factor (GM-CSF) gene-deleted mice; AMs from GM-CSF(-/-) mice also support PVM replication. However, MH-S cells do not express the GM-CSF receptor alpha chain (CD116) and do not respond to GM-CSF. Due to these unusual features, MH-S cells should be used with caution as experimental models of AMs.


Assuntos
Limosilactobacillus reuteri/imunologia , Macrófagos Alveolares/virologia , Infecções por Pneumovirus/imunologia , Pneumovirus/fisiologia , Animais , Linhagem Celular Transformada , Quimiocina CXCL10/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Interleucina-6/metabolismo , Lipopeptídeos/imunologia , Macrófagos Alveolares/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptor 2 Toll-Like/metabolismo , Replicação Viral
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