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1.
Artigo em Inglês | MEDLINE | ID: mdl-33453290

RESUMO

BACKGROUND: Although atopic dermatitis (AD) often presents in infancy and persists into adulthood, comparative characterization of AD skin among different pediatric age groups is lacking. OBJECTIVE: We sought to define skin biopsy profiles of lesional and nonlesional AD across different age groups (0-5-year-old infants with disease duration <6 months, 6-11-year-old children, 12-17-year-old adolescents, ≥18-year-old adults) versus age-appropriate controls. METHODS: We performed gene expression analyses by RNA-sequencing and real-time PCR (RT-PCR) and protein expression analysis using immunohistochemistry. RESULTS: TH2/TH22 skewing, including IL-13, CCL17/thymus and activation-regulated chemokine, IL-22, and S100As, characterized the common AD signature, with a global pathway-level enrichment across all ages. Nevertheless, specific cytokines varied widely. For example, IL-33, IL-1RL1/IL-33R, and IL-9, often associated with early atopic sensitization, showed greatest upregulations in infants. TH17 inflammation presented a 2-peak curve, with highest increases in infants (including IL-17A and IL-17F), followed by adults. TH1 polarization was uniquely detected in adults, even when compared with adolescents, with significant upregulation in adults of IFN-γ and CXCL9/CXCL10/CXCL11. Although all AD age groups had barrier abnormalities, only adults had significant decreases in filaggrin expression. Despite the short duration of the disease, infant AD presented robust downregulations of multiple barrier-related genes in both lesional and nonlesional skin. Clinical severity scores significantly correlated with TH2/TH22-related markers in all pediatric age groups. CONCLUSIONS: The shared signature of AD across ages is TH2/TH22-skewed, yet differential expression of specific TH2/TH22-related genes, other TH pathways, and barrier-related genes portray heterogenetic, age-specific molecular fingerprints.

2.
Artigo em Inglês | MEDLINE | ID: mdl-33516871

RESUMO

Atopic dermatitis (AD) is a common yet complex skin disease, posing a therapeutic challenge with increasingly recognized different phenotypes among variable patient populations. Because therapeutic response may vary on the basis of heterogeneous clinical and molecular phenotypes, a shift toward precision medicine approaches may improve AD management. Herein, we will consider biomarkers as potential instruments in the toolbox of precision medicine in AD and will review the process of biomarker development and validation, the opinion of AD experts on the use of biomarkers, types of biomarkers, encompassing biomarkers that may improve AD diagnosis, biomarkers reflecting disease severity, and those potentially predicting AD development, concomitant atopic diseases, or therapeutic response, and current practice of biomarkers in AD. We found that chemokine C-C motif ligand 17/thymus and activation-regulated chemokine, a chemoattractant of TH2 cells, has currently the greatest evidence for robust correlation with AD clinical severity, at both baseline and during therapy, by using the recommendations, assessment, development, and evaluation approach. Although the potential of biomarkers in AD is yet to be fully elucidated, due to the complexity of the disease, a comprehensive approach taking into account both clinical and reliable, AD-specific biomarker evaluations would further facilitate AD research and improve patient management.

3.
J Biomed Opt ; 25(11)2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33247560

RESUMO

SIGNIFICANCE: Melanoma is a deadly cancer that physicians struggle to diagnose early because they lack the knowledge to differentiate benign from malignant lesions. Deep machine learning approaches to image analysis offer promise but lack the transparency to be widely adopted as stand-alone diagnostics. AIM: We aimed to create a transparent machine learning technology (i.e., not deep learning) to discriminate melanomas from nevi in dermoscopy images and an interface for sensory cue integration. APPROACH: Imaging biomarker cues (IBCs) fed ensemble machine learning classifier (Eclass) training while raw images fed deep learning classifier training. We compared the areas under the diagnostic receiver operator curves. RESULTS: Our interpretable machine learning algorithm outperformed the leading deep-learning approach 75% of the time. The user interface displayed only the diagnostic imaging biomarkers as IBCs. CONCLUSIONS: From a translational perspective, Eclass is better than convolutional machine learning diagnosis in that physicians can embrace it faster than black box outputs. Imaging biomarkers cues may be used during sensory cue integration in clinical screening. Our method may be applied to other image-based diagnostic analyses, including pathology and radiology.

5.
Allergy ; 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32639640

RESUMO

BACKGROUND: Skin biopsies promote our understanding of atopic dermatitis/AD pathomechanisms in infants/toddlers with early-onset AD, but are not feasible in pediatric populations. Tape strips are an emerging, minimally invasive alternative, but global transcriptomic profiling in early pediatric AD is lacking. We aimed to provide global lesional and nonlesional skin profiles of infants/toddlers with recent-onset, moderate-to-severe AD using tape strips. METHODS: Sixteen tape strips were collected for RNA-seq profiling from 19 infants/toddlers (<5 years old; lesional and nonlesional) with early-onset moderate-to-severe AD (≤6 months) and 17 healthy controls. RESULTS: We identified 1829 differentially expressed genes/DEGs in lesional AD and 662 DEGs in nonlesional AD, vs healthy skin (fold-change ≥2, FDR <0.05), with 100% sample recovery. Both lesional and nonlesional skin showed significant dysregulations of Th2 (CCL17 and IL4R) and Th22/Th17 (IL36G, CCL20, and S100As)-related genes, largely lacking significant Th1-skewing. Significant down-regulation of terminal differentiation (FLG and FLG2), lipid synthesis/metabolism (ELOVL3 and FA2H), and tight junction (CLDN8) genes were primarily seen in lesional AD. Significant negative correlations were identified between Th2 measures and epidermal barrier gene-subsets and individual genes (FLG with IL-4R and CCL17; r < -0.4, P < .05). Significant correlations were also identified between clinical measures (body surface area/BSA, pruritus ADQ, and transepidermal water loss/TEWL) with immune and barrier mRNAs in lesional and/or nonlesional AD (FLG/FLG2 with TEWL; r < -0.4, P < .05). CONCLUSION: RNA-seq profiling using tape strips in early-onset pediatric AD captures immune and barrier alterations in both lesional and nonlesional skin. Tape strips provide insight into disease pathomechanisms and cutaneous disease activity.

6.
J Am Acad Dermatol ; 2020 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-32376430

RESUMO

BACKGROUND: Although there is increased understanding of the alopecia areata (AA) pathogenesis based on studies in scalp tissues, little is known about its systemic profile. OBJECTIVE: To evaluate the blood proteomic signature of AA and determine biomarkers associated with increased disease severity. METHODS: In a cross-sectional study, we assessed 350 inflammatory and cardiovascular proteins using OLINK high-throughput proteomics in patients with moderate to severe AA (n = 35), as compared with healthy individuals (n = 36), patients with moderate to severe psoriasis (n = 19), and those with atopic dermatitis (n = 49). RESULTS: Seventy-four proteins were significantly differentially expressed between AA and control individuals (false discovery rate, <.05) including innate immunity (interleukin [IL] 6/IL-8), T helper (Th) type 1 (interferon [IFN] γ/CXCL9/CXCL10/CXCL11), Th2 (CCL13/CCL17/CCL7), Th17 (CCL20/PI3/S100A12), and cardiovascular-risk proteins (OLR1/OSM/MPO/PRTN3). Eighty-six biomarkers correlated with AA clinical severity (P < .05), including Th1/Th2, and cardiovascular/atherosclerosis-related proteins, including SELP/PGLYRP1/MPO/IL-18/OSM (P < .05). Patients with AA totalis/universalis showed the highest systemic inflammatory tone, including cardiovascular risk biomarkers, compared to control individuals and even to patients with atopic dermatitis and those with psoriasis. The AA profile showed some Th1/Th2 differences in the setting of concomitant atopy. LIMITATIONS: Our analysis was limited to 350 proteins. CONCLUSION: This study defined the abnormalities of moderate to severe AA and associated circulatory biomarkers. It shows that AA has systemic immune, cardiovascular, and atherosclerosis biomarker dysregulation, suggesting the need for systemic treatment approaches.

7.
J Allergy Clin Immunol Pract ; 8(4): 1323-1328.e1, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32036002

RESUMO

BACKGROUND: Evidence of TH1/IFN-γ overactivation as a major pathogenic driver somewhat conflicts with data supporting robust allergic background in patients with alopecia areata (AA). Previous investigations of immunological dysregulations show that both TH1- and TH2-related markers are overexpressed in AA. Clinical correlations in large populations may shed light on the immune pathways most likely to result in the clinical phenotype of AA. OBJECTIVE: To investigate the atopic comorbidities among patients with AA in a large population-based study. METHODS: This is a cross-sectional retrospective study of patients with AA and a matched comparison group, analyzing the associations between AA and 4 atopic comorbidities: asthma, atopic dermatitis (AD), allergic rhinitis, and allergic conjunctivitis. χ2 and t tests were used for univariate analysis, and logistic regression model was used for multivariate analysis. The study was performed using the computerized database of the Clalit Health Services, encompassing more than 4.4 million subjects. RESULTS: The study population included 51,561 patients with AA and 51,410 matched control subjects. The prevalence of asthma (7.8% vs 6.5%; odds ratio [OR], 1.22; 95% CI, 1.17-1.28; P < .001), AD (3.9% vs 2.6%; OR, 1.55; 95% CI, 1.44-1.66; P < .001), allergic rhinitis (16.0% vs 12.8%; OR, 1.29; 95% CI, 1.25-1.34; P < .001), and allergic conjunctivitis (23.5% vs 19.6%; OR, 1.27; 95% CI, 1.23-1.30; P < .001) was significantly higher among patients with AA as compared with matched control subjects. Patients with AA also had a significantly higher probability of having more than 1 atopic comorbidity, with increasing OR as the number of concomitant atopic conditions increased. CONCLUSIONS: Our analysis supports the previous literature and provides strong generalizability of significant atopy in patients with AA, suggesting TH2 pathogenicity in AA, and challenging the traditional view of AA as a single-axis, TH1-centered disease.

8.
Ann Allergy Asthma Immunol ; 124(1): 28-35, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31622669

RESUMO

OBJECTIVE: Atopic dermatitis (AD) is an increasingly common inflammatory skin disease undergoing significant revolution in recent years. New data on disease pathogenesis advanced the developments of novel therapeutics, mainly for patients with moderate to severe conditions, for whom treatment options have been largely insufficient for many years. DATA SOURCES: Review of recent studies investigating systemic treatments for AD. STUDY SELECTIONS: Relevant literature concerning novel therapeutics for AD beyond targeted monoclonal antibodies antagonizing selectively interleukin (IL)-4 or IL-13 was obtained from a PubMed and clinicaltrials.gov search and summarized. RESULTS: Multiple clinical trials of both nonspecific as well as specific agents revealed favorable outcomes in AD, including JAK inhibitors, a dual JAK/SYK inhibitor, a histamine H4R antagonist, antagonists of the TSLP/OX40L axis, an IL-22 inhibitor, and IL-33 and IL-17C antagonists. Importantly, negative trials were published as well (eg, phosphodiesterase 4 inhibitor, apremilast). CONCLUSION: In this rapidly evolving field of AD treatments, a completely new treatment paradigm will be available in the near future.


Assuntos
Citocinas/antagonistas & inibidores , Dermatite Atópica/tratamento farmacológico , Antagonistas dos Receptores Histamínicos/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/antagonistas & inibidores , Dermatite Atópica/imunologia , Humanos , Interleucina-13/antagonistas & inibidores , Interleucina-4/antagonistas & inibidores , Pele/patologia
9.
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
10.
J Am Acad Dermatol ; 83(1): 63-70, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31870914

RESUMO

BACKGROUND: Granuloma annulare (GA) is an inflammatory skin disorder. Localized GA is often self-resolving, but generalized GA is often recalcitrant to treatments. There are no targeted treatments for GA, largely due to lack of mechanistic understanding. Recently, tumor necrosis factor antagonism showed promise in GA, suggesting an underlying immune pathogenesis. OBJECTIVE: To elucidate the immune pathogenesis and identify potential therapeutic targets for GA. METHODS: Lesional and nonlesional skin biopsy samples were obtained from patients with GA and evaluated for a large array of inflammatory markers compared with inflammatory markers from normal skin of healthy individuals. RESULTS: We found differential expression of many inflammatory genes compared with normal skin. These genes were associated with T-helper (Th) cell type 1/innate immunity (tumor necrosis factor-α, interleukin [IL]-1ß, IL-12/23p40, signal transducer and activator of transcription 1, chemokine [C-X-C motif] ligand 9/10), Janus kinase signaling, and Th2 (IL-4, IL-31, chemokine (C-C motif) ligands 17 and 18; P < .05). Unexpectedly, IL-4 showed significant upregulation in GA lesional skin vs control skin (15,600-fold change). LIMITATIONS: Limited sample size. CONCLUSIONS: Our findings shed light on the inflammatory pathways of GA, supporting the notion that immune mechanisms could be driving disease, as suggested by the promising data of tumor necrosis factor-α inhibitors in GA. The significant Janus kinase and particularly Th2 signaling in GA advocates for the investigation of specific Janus kinase- and Th2- targeted drug therapy.

11.
Dermatol Clin ; 37(2): 205-213, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30850043

RESUMO

The evolving discoveries in atopic dermatitis (AD) shed light on disease pathogenesis and allow better management of patients. Dupiluamab was the first targeted agent approved for AD, proving for the first time AD can be treated with a single cytokine antagonism. Nevertheless, because not all patients respond to dupilumab and AD has a heterogeneous phenotype, more treatment options are much needed. This article reviews recent and exciting developments in AD, because ongoing or pipeline clinical trials for AD will ultimately expand and redefine a novel treatment paradigm for this common disease.


Assuntos
Inibidores de Calcineurina/uso terapêutico , Citocinas/antagonistas & inibidores , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Glucocorticoides/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Administração Cutânea , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Compostos de Boro/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Citocinas/imunologia , Dermatite Atópica/imunologia , Emolientes/uso terapêutico , Humanos , Microbiota , Linfócitos T Auxiliares-Indutores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia , Ustekinumab/uso terapêutico
13.
J Allergy Clin Immunol ; 143(2): 604-618, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29803800

RESUMO

BACKGROUND: Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy. OBJECTIVE: We sought to profile the molecular fingerprint of the most common orphan ichthyoses. METHODS: Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age-matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). RESULTS: Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL-17 and TNF-α-coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity-related manner, patients with Netherton syndrome showed the greatest T-cell activation (inducible costimulator [ICOS]) and a broader immune phenotype with TH1/IFN-γ, OASL, and TH2/IL-4 receptor/IL-5 skewing, although less than seen in patients with AD (all P < .05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL-17-regulated gene expression (IL17F and IL36A/IL36B/IL36G). CONCLUSION: Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis-like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL-17/IL-36-targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis.


Assuntos
Ictiose/imunologia , Síndrome de Netherton/imunologia , Linfócitos T/imunologia , Células Th17/imunologia , Junções Íntimas/genética , Adolescente , Adulto , Idoso , Criança , Impressões Digitais de DNA , Feminino , Genoma , Humanos , Ictiose/genética , Interleucina-1/genética , Interleucina-17/genética , Metabolismo dos Lipídeos/genética , Ativação Linfocitária , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Síndrome de Netherton/genética , Transcriptoma , Adulto Jovem
14.
Curr Opin Allergy Clin Immunol ; 18(4): 356-364, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29870461

RESUMO

PURPOSE OF REVIEW: To evaluate the treatment revolution atopic dermatitis, the most common inflammatory skin disease, has been going through in recent years, thanks to breakthroughs in disease understanding, delineating the immune fingerprint of atopic dermatitis. RECENT FINDINGS: The treatment for moderate-to-severe atopic dermatitis patients has been largely unchanged for decades and relied on broad-acting immunosuppressants. A huge unmet need existed for effective, well tolerated and narrow-targeted therapeutics. Multiple therapies, targeting various aspects of the complex immune activation of atopic dermatitis, are now assessed in clinical trials, and hold promise for a new era in the treatment of atopic dermatitis, comparable with the treatment shift seen for psoriasis in the last decade. The first effective monoclonal antibody licensed for the treatment of atopic dermatitis, dupilumab, not only offers a much-needed systemic agent for moderate-to-severe patients but also provides strong evidence for the potential role of other monoclonal antibodies in disease management. SUMMARY: In this rapidly changing field, new atopic dermatitis-targeted monoclonal antibodies will be reviewed in light of the recently discovered pathomechanisms of the disease.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Citocinas/antagonistas & inibidores , Dermatite Atópica/tratamento farmacológico , Fármacos Dermatológicos/uso terapêutico , Subpopulações de Linfócitos T/efeitos dos fármacos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Ensaios Clínicos como Assunto , Citocinas/imunologia , Dermatite Atópica/diagnóstico , Dermatite Atópica/imunologia , Fármacos Dermatológicos/farmacologia , Antagonistas dos Receptores Histamínicos/farmacologia , Antagonistas dos Receptores Histamínicos/uso terapêutico , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/imunologia , Receptores Histamínicos H4/antagonistas & inibidores , Receptores Histamínicos H4/imunologia , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Pele/imunologia , Subpopulações de Linfócitos T/imunologia , Resultado do Tratamento
15.
J Am Acad Dermatol ; 78(3): 498-505.e2, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29066275

RESUMO

BACKGROUND: The immune abnormalities underlying the ichthyoses are poorly understood. OBJECTIVE: To determine the immunophenotype of an ichthyosis resulting from mutations in the spectrin repeat 6 (SR6) domain of desmoplakin gene (DSP) and target therapy on the basis of molecular pathogenesis. METHODS: Immunophenotyping was performed by using the blood and skin of a girl with SR6 region DSP mutations causing erythroderma/ichthyosis and cardiomyopathy. RESULTS: On the basis of the discovery of T helper 1 and T helper 17/interleukin 23 skewing in the skin and T helper 17/interleukin 22 skewing in blood, ustekinumab therapy was initiated. Ustekinumab was also administered to a boy with an SR6 region DSP mutation and ichthyosis without cardiomyopathy. Both children responded despite previous poor responses to immunosuppressants and retinoids. LIMITATIONS: Small number of patients and immunophenotyping in only 1 patient. CONCLUSION: An understanding of the molecular basis of inflammation in rare cutaneous disorders can lead to targeted therapy, which promises to be more beneficial than broad immunosuppressants.


Assuntos
Fármacos Dermatológicos/uso terapêutico , Desmoplaquinas/genética , Ictiose/tratamento farmacológico , Ictiose/genética , Ustekinumab/uso terapêutico , Cardiomiopatias/genética , Criança , Dermatite/genética , Dermatite Esfoliativa/genética , Feminino , Genótipo , Humanos , Hipersensibilidade/genética , Ictiose/imunologia , Imunofenotipagem , Masculino , Mutação , Síndrome , Células Th1 , Células Th17
17.
Clin Dermatol ; 35(4): 387-397, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28709570

RESUMO

Atopic dermatitis (AD), the most prevalent inflammatory skin disease, is characterized by robust T-cell activation. The disease has several subtypes, all having a common T helper type 2 (Th2)/Th22 polarization, but it also displays differential immune skewing, such as increased Th17/interleukin 23 skewing in the skin of intrinsic, Asian, and early pediatric AD patients. Current systemic treatments for moderate to severe AD are largely unsatisfactory, associated with significant adverse effects and low compliance. A large unmet need exists for better therapeutics for moderate to severe AD. The translational revolution, first transforming the psoriasis treatment paradigm, is now becoming applicable for AD, with multiple targeted drugs being investigated in trials. The new treatments often have increased tolerability and specificity and higher efficacy compared with conventional treatments. The clinical testing of these targeted drugs can also provide an opportunity to further elucidate AD pathogenesis by dissecting the contribution of specific cytokines to the disease phenotype. By reviewing developing therapeutics for AD according to their pathway-specific mechanisms, this contribution also outlines the complex molecular characteristics of AD.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Dermatite Atópica/terapia , Fármacos Dermatológicos/uso terapêutico , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Dermatite Atópica/imunologia , Humanos , Células Th17/imunologia
18.
Adv Ther ; 34(7): 1594-1609, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28646393

RESUMO

Alopecia areata (AA), a prevalent inflammatory cause of hair loss, lacks FDA-approved therapeutics for extensive cases, which are associated with very poor rates of spontaneous hair regrowth and major psychological distress. Current treatments for severe cases include broad immune-suppressants, which are associated with significant adverse effects, precluding long-term use, with rapid hair loss following treatment termination. As a result of the extent of the disease in severe cases, topical contact sensitizers and intralesional treatments are of limited use. The pathogenesis of AA is not yet fully understood, but recent investigations of the immune activation in AA skin reveal Th1/IFN-γ, as well as Th2, PDE4, IL-23, and IL-9 upregulations. Tissue analyses of both animal models and human lesions following broad-acting and cytokine-specific therapeutics (such as JAK inhibitors and ustekinumab, respectively) provide another opportunity for important insights into the pathogenesis of AA. As reviewed in this paper, numerous novel therapeutics are undergoing clinical trials for AA, emphasizing the potential transformation of the clinical practice of AA, which is currently lacking. Dermatologists are already familiar with the revolution in disease management of psoriasis, stemming from better understanding of immune dysregulations, and atopic dermatitis will soon follow a similar path. In light of these recent developments, the therapeutic arena of AA treatments is finally getting more exciting. AA will join the lengthening list of dermatologic diseases with mechanism-targeted drugs, thus changing the face of AA.


Assuntos
Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/imunologia , Fármacos Dermatológicos/uso terapêutico , Imunossupressores/uso terapêutico , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos
19.
J Allergy Clin Immunol ; 139(1): 152-165, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27554821

RESUMO

BACKGROUND: The ichthyoses are rare genetic disorders associated with generalized scaling, erythema, and epidermal barrier impairment. Pathogenesis-based therapy is largely lacking because the underlying molecular basis is poorly understood. OBJECTIVE: We sought to characterize molecularly cutaneous inflammation and its correlation with clinical and barrier characteristics. METHODS: We analyzed biopsy specimens from 21 genotyped patients with ichthyosis (congenital ichthyosiform erythroderma, n = 6; lamellar ichthyosis, n = 7; epidermolytic ichthyosis, n = 5; and Netherton syndrome, n = 3) using immunohistochemistry and RT-PCR and compared them with specimens from healthy control subjects, patients with atopic dermatitis (AD), and patients with psoriasis. Clinical measures included the Ichthyosis Area Severity Index (IASI), which integrates erythema (IASI-E) and scaling (IASI-S); transepidermal water loss; and pruritus. RESULTS: Ichthyosis samples showed increased epidermal hyperplasia (increased thickness and keratin 16 expression) and T-cell and dendritic cell infiltrates. Increases of general inflammatory (IL-2), innate (IL-1ß), and some TH1/interferon (IFN-γ) markers in patients with ichthyosis were comparable with those in patients with psoriasis or AD. TNF-α levels in patients with ichthyosis were increased only in those with Netherton syndrome but were much lower than in patients with psoriasis and those with AD. Expression of TH2 cytokines (IL-13 and IL-31) was similar to that seen in control subjects. The striking induction of IL-17-related genes or markers synergistically induced by IL-17 and TNF-α (IL-17A/C, IL-19, CXCL1, PI3, CCL20, and IL36G; P < .05) in patients with ichthyosis was similar to that seen in patients with psoriasis. IASI and IASI-E scores strongly correlated with IL-17A (r = 0.74, P < .001) and IL-17/TNF-synergistic/additive gene expression. These markers also significantly correlated with transepidermal water loss, suggesting a link between the barrier defect and inflammation in patients with ichthyosis. CONCLUSION: Our data associate a shared TH17/IL-23 immune fingerprint with the major orphan forms of ichthyosis and raise the possibility of IL-17-targeting strategies.


Assuntos
Ictiose/imunologia , Interleucina-17/imunologia , Interleucina-23/imunologia , Adolescente , Adulto , Idoso , Criança , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Feminino , Expressão Gênica , Humanos , Ictiose/genética , Interleucina-17/genética , Interleucina-23/genética , Masculino , Pessoa de Meia-Idade , Psoríase/genética , Psoríase/imunologia , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Pele/imunologia , Adulto Jovem
20.
J Allergy Clin Immunol ; 140(1): 134-144.e9, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27965110

RESUMO

BACKGROUND: B cells undergo maturation and class-switching in response to antigen exposure and T-cell help. Early B-cell differentiation has not been defined in patients with early-onset atopic dermatitis (AD). OBJECTIVE: We sought to define the frequency of B-cell subsets associated with progressive B-cell maturation and IgE class-switching. METHODS: We studied 27 children and 34 adults with moderate-to-severe AD (mean SCORAD score, 55 and 65, respectively) and age-matched control subjects (15 children and 27 adults). IgD/CD27 and CD24/CD38 core gating systems and an 11-color flow cytometric panel were used to determine the frequencies of circulating B-cell subsets. Serum total and allergen-specific IgE (sIgE) levels were measured by using ImmunoCAP. RESULTS: Compared with adults, children showed T-cell predominance in the skin. Circulating CD19+CD20+ B-cell counts were lower in patients with pediatric AD than in control subjects (24% vs 33%, P = .04), whereas CD3+ T-cell counts were higher (62% vs 52%, P = .05). A decreased B-cell/T-cell lymphocyte ratio with age was observed only in pediatric control subjects (r = -0.48, P = .07). In pediatric patients with AD, a positive correlation was observed between B-cell/T-cell ratio and nonswitched memory B-cell counts (r = 0.42, P = .03). Higher frequencies of positive sIgE levels were seen in pediatric patients with AD (P < .0001). Diverse sIgE levels correlated with SCORAD scores and age of pediatric patients with AD (P < .01). Positive correlations were observed between activated B-cell and memory T-cell counts (P < .02). In patients with AD, IgE sensitization to most allergens clustered with age, TH1, TH2, total IgE levels, and B-cell memory subsets. CONCLUSIONS: Peripheral B and T cells are altered in pediatric patients with early AD, but T cells predominate in skin lesions.


Assuntos
Subpopulações de Linfócitos B/imunologia , Dermatite Atópica/imunologia , Adulto , Envelhecimento/imunologia , Alérgenos/imunologia , Pré-Escolar , Dermatite Atópica/sangue , Feminino , Humanos , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Lactente , Masculino , Pessoa de Meia-Idade , Pele/citologia , Pele/imunologia , Linfócitos T/imunologia
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