RESUMO
Interleukin (IL)-9 is present in atopic dermatitis (AD) lesions and is considered to be mainly produced by skin-homing T cells expressing the cutaneous lymphocyte-associated antigen (CLA). However, its induction by AD-associated triggers remains unexplored. Circulating skin-tropic CLA+ and extracutaneous/systemic CLA- memory T cells cocultured with autologous lesional epidermal cells from AD patients were activated with house dust mite (HDM) and staphylococcal enterotoxin B (SEB). Levels of AD-related mediators in response to both stimuli were measured in supernatants, and the cytokine response was associated with different clinical characteristics. Both HDM and SEB triggered heterogeneous IL-9 production by CLA+ and CLA- T cells in a clinically homogenous group of AD patients, which enabled patient stratification into IL-9 producers and non-producers, with the former group exhibiting heightened HDM-specific and total IgE levels. Upon allergen exposure, IL-9 production depended on the contribution of epidermal cells and class II-mediated presentation; it was the greatest cytokine produced and correlated with HDM-specific IgE levels, whereas SEB mildly induced its release. This study demonstrates that both skin-tropic and extracutaneous memory T cells produce IL-9 and suggests that the degree of allergen sensitization reflects the varied IL-9 responses in vitro, which may allow for patient stratification in a clinically homogenous population.
Assuntos
Dermatite Atópica , Enterotoxinas , Interleucina-9 , Células T de Memória , Dermatite Atópica/imunologia , Dermatite Atópica/metabolismo , Humanos , Interleucina-9/metabolismo , Feminino , Masculino , Adulto , Enterotoxinas/imunologia , Células T de Memória/imunologia , Células T de Memória/metabolismo , Pele/imunologia , Pele/metabolismo , Pyroglyphidae/imunologia , Animais , Imunoglobulina E/imunologia , Imunoglobulina E/sangue , Pessoa de Meia-Idade , Antígenos de Diferenciação de Linfócitos T/metabolismo , Adulto Jovem , Alérgenos/imunologia , Adolescente , Glicoproteínas de MembranaRESUMO
BACKGROUND: While the contribution of environmental factors including smoking, overweight and stress has been validated, data mining for the association between socioeconomic status (SES) and psoriasis prevalence has yielded contradicting observations. OBJECTIVE: To evaluate the association between psoriasis prevalence and SES. METHODS: This was a nationwide population-based cross-sectional retrospective study that included all patients insured by the "Clalit" Health Services (N=4,604,994). Univariable and multivariable logistic regression analyses were conducted to explore the association between psoriasis and SES while controlling for potential sociodemographic and clinical confounders. RESULTS: The study population included 129,855 patients with psoriasis and 4,475,139 individuals without psoriasis. Higher SES was associated with an increased prevalence of psoriasis; in a fully adjusted model, Clalit members within the highest SES were 1.43-fold more likely to have psoriasis (95% CI, 1.39-1.48; P< 0.001), and those at medium SES were 1.2-fold more likely to have psoriasis, compared to those at the lowest SES group (95% CI, 1.18-1.26; P< 0.001; P for linear trend <0.001). CONCLUSIONS: Positive correlation was found between SES and psoriasis prevalence. Further investigation is warranted to elucidate the factors accounting for this observation.
RESUMO
BACKGROUND: While B-cells have historically been implicated in allergy development, a growing body of evidence supports their role in atopic dermatitis (AD). B-cell differentiation across ages in AD, and its relation to disease severity scores, has not been well defined. OBJECTIVE: To compare the frequency of B-cell subsets in blood of 0-5, 6-11, 12-17, and ≥18 years old patients with AD versus age-matched controls. METHODS: Flow cytometry was used to measure B-cell subset frequencies in the blood of 27 infants, 17 children, 11 adolescents, and 31 adults with moderate-to-severe AD and age-matched controls. IgD/CD27 and CD24/CD38 core gating systems and an 11-color flow cytometry panel were used to determine frequencies of circulating B-cell subsets. Serum total and allergen-specific IgE (sIgEs) levels were measured using ImmunoCAP®. RESULTS: Adolescents with AD had lower frequencies of major B-cells subsets (p < .03). CD23 expression increased with age and was higher in AD compared to controls across all age groups (p < .04). In AD patients, multiple positive correlations were observed between IL-17-producing T-cells and B-cell subsets, most significantly non-switched memory (NSM) B-cells (r = .41, p = .0005). AD severity positively correlated with a list of B-cell subsets (p < .05). IL-9 levels gradually increased during childhood, reaching a peak in adolescence, paralleling allergen sensitization, particularly in severe AD. Principal component analysis of the aggregated environmental sIgE data showed that while controls across all ages tightly clustered together, adolescents with AD demonstrated distinct clustering patterns relative to controls. CONCLUSIONS: Multiple correlations between B-cells and T-cells, as well as disease severity measures, suggest a complex interplay of immune pathways in AD. Unique B-cell signature during adolescence, with concurrent allergen sensitization and IL-9 surge, point to a potentially wider window of opportunity to implement interventions that may prevent the progression of the atopic march.
RESUMO
Circulating skin-homing cutaneous lymphocyte-associated antigen (CLA)+ T cells constitute a small subset of human memory T cells involved in several aspects of atopic dermatitis: Staphylococcus aureus related mechanisms, the abnormal Th2 immune response, biomarkers, clinical aspects of the patients, pruritus, and the mechanism of action of targeted therapies. Superantigens, IL-13, IL-31, pruritus, CCL17 and early effects on dupilumab-treated patients have in common that they are associated with the CLA+ T cell mechanisms in atopic dermatitis patients. The function of CLA+ T cells corresponds with the role of T cells belonging to the skin-associated lymphoid tissue and could be a reason why they reflect different mechanisms of atopic dermatitis and many other T cell mediated skin diseases. The goal of this review is to gather all this translational information of atopic dermatitis pathology.
Assuntos
Dermatite Atópica , Humanos , Células T de Memória , Subpopulações de Linfócitos T , Antígenos de Diferenciação de Linfócitos T , Glicoproteínas de Membrana , Receptores de Retorno de Linfócitos , Pele/patologia , Prurido , Antígenos de NeoplasiasRESUMO
PURPOSE OF REVIEW: As we continue to unravel the pathophysiology and immune mechanisms underlying atopic dermatitis (AD), the emergence of targeted treatments has provided new options for management. Although there are available therapies targeting various immune pathways in AD, the precise pathogenic role of interleukin (IL)-17 in AD pathogenesis remains unclear. The objective of this review is to examine the existing data pertaining to the role of IL-17 in AD and shed light on the potential of targeting this pathway as a therapeutic approach in AD treatment. RECENT FINDINGS: IL-17 has a dual role of pro-inflammatory and immune protective function, making it an important player in several autoimmune and inflammatory conditions. The extent of IL-17 axis involvement in AD pathogenesis is still debatable. Emerging data show that Th17-related cytokines/chemokines are elevated in skin and sera samples of AD patients, with some articles reporting correlations with disease severity. Particularly increased Th17 signature in specific AD patient subsets, such as Asian-origin or pediatric patients, suggests that certain patients' disease presentations are more predominantly influenced by Th17, and, thus, they may benefit more from Th17 therapeutic targeting approaches. Lack of clinical efficacy with anti-Th17 biologics in AD patients, underscores the need to better elucidate the role of Th17 in AD pathogenesis, along with its utility in therapy. SUMMARY: The well established role of IL-17 in autoimmune disorders hints for its possible participation in AD disease pathogenesis. Subsequent investigations are needed to assess whether the targeting of specific IL-17 isoforms, homodimers, or heterodimers in specific subpopulations of AD can modify treatment outcomes.
Assuntos
Dermatite Atópica , Humanos , Criança , Dermatite Atópica/tratamento farmacológico , Interleucina-17 , Pele , Citocinas , ImunidadeRESUMO
OBJECTIVE: To examine the association between chronic spontaneous urticaria (CSU) and interstitial cystitis/bladder pain syndrome (IC/BPS). METHODS: A population-based retrospective cross-sectional study was performed using the Clalit Health Services medical database. The prevalence of CSU was compared between patients diagnosed with IC/BPS and age- and gender-matched controls. Univariate analysis was performed using Chi-square and Student t test and a multivariable analysis was performed using a logistic regression model. RESULTS: The study included 681 patients with IC/BPS and 3376 demographically matched controls. The mean age of IC/BPS patients was 60 years old. The prevalence of CSU among patients with IC/BPS was higher as compared to the control group (20% vs 13.7%; P <.001). The adjusted OR for CSU in patients with IC/BPS was 1.58 (95% CI 1.28-1.97). Female gender and Jewish ethnicity were associated with the coexistence of these disorders (OR 1.7 95% CI 1.36-2.13, and 1.6 95% CI 1.28-2, respectively). CONCLUSION: A significant association was found between IC/BPS and CSU. This finding may support the presence of allergic/immune components in the pathogenesis of IC/BPS.
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Urticária Crônica , Cistite Intersticial , Humanos , Feminino , Pessoa de Meia-Idade , Cistite Intersticial/complicações , Cistite Intersticial/epidemiologia , Cistite Intersticial/diagnóstico , Estudos Retrospectivos , Estudos Transversais , Modelos Logísticos , Urticária Crônica/complicaçõesRESUMO
BACKGROUND: Flow cytometry is a well-accepted approach for immune profiling; however, its value is restricted by the limited number of markers that can be analyzed simultaneously. Mass cytometry/CyTOF offers broad-scale immune characterization integrating large number of parameters. While partial blood phenotyping was reported in atopic dermatitis (AD), patients' comprehensive profiling, critical for leveraging new targeted treatments, is not available. IL-21 may be involved in inflammatory skin diseases but its role in AD is not well established. METHODS: We studied T-cell polarization in the blood of 20 moderate-to-severe AD and 15 controls. Using CyTOF and an unsupervised analysis, we measured the frequencies and mean metal intensities of activated polar CD4+ /CD8+ T-cell subsets. Immunohistochemistry, immunofluorescence, and qRT-PCR were used to analyze skin samples. RESULTS: Examining 24 surface, intracellular markers, and transcription factors, we identified six CD4+ and five CD8+ T-cell metaclusters. A CD4+ skin-homing IL-13+ monocytokine and a novel IL-13+ IL-21+ multicytokine metaclusters were increased in AD vs. controls (p < .01). While IL-13 signature characterized both clusters, levels were significantly higher in the IL-21+ group. Both clusters correlated with AD severity (r = 0.49, p = .029). Manual gating corroborated these results and identified additional multicytokine subsets in AD. Immunohistochemistry and immunofluorescence, validated by mRNA expression, displayed significantly increasedIL-21 counts and colocalization with IL-13/IL-4R in AD skin. CONCLUSION: A multicytokine signature characterizes moderate-to-severe AD, possibly explaining partial therapeutic responses to one cytokine targeting, particularly in severe patients. Prominent IL-21 signature in blood and skin hints for a potential pathogenic role of IL-21 in AD.
Assuntos
Dermatite Atópica , Interleucinas , Subpopulações de Linfócitos T , Citocinas , Dermatite Atópica/imunologia , Humanos , Interleucina-13 , Interleucinas/imunologia , Pele , Subpopulações de Linfócitos T/citologiaRESUMO
Physician rating of cutaneous erythema is central to clinical dermatological assessment as well as quantification of outcome measures in clinical trials in a number of dermatologic conditions. However, issues with inter-rater reliability and variability in the setting of higher Fitzpatrick skin types make visual erythema assessment unreliable. We developed and validated a computer-assisted image-processing algorithm (EQscore) to reliably quantify erythema (across a range of skin types) in the dermatology clinical setting. Our image processing algorithm evaluated erythema based upon green light suppression differentials between affected and unaffected skin. A group of four dermatologists used a 4-point Likert scale as a human evaluation of similar erythematous patch tests. The algorithm and dermatologist scores were compared across 164 positive patch test reactions. The intra-class correlation coefficient of groups and the correlation coefficient between groups were calculated. The EQscore was validated on and independent image set of psoriasis, minimal erythema dose testing and steroid-induced blanching images. The reliability of the erythema quantification method produced an intra-class correlation coefficient of 0.84 for the algorithm and 0.67 for dermatologists. The correlation coefficient between groups was 0.85. The EQscore demonstrated high agreement with clinical scoring and superior reliability compared with clinical scoring, avoiding the pitfalls of erythema underrating in the setting of pigmentation. The EQscore is easily accessible (http://lab.rockefeller.edu/krueger/EQscore), user-friendly, and may allow dermatologists to more readily and accurately rate the severity of dermatological conditions and the response to therapeutic treatments.
Assuntos
Algoritmos , Dermatite/diagnóstico por imagem , Eritema/diagnóstico por imagem , Processamento de Imagem Assistida por Computador , Índice de Gravidade de Doença , Biomarcadores , Cor , Humanos , Variações Dependentes do Observador , Testes do Emplastro , Fotografação , Reprodutibilidade dos Testes , Pele/diagnóstico por imagem , Pigmentação da PeleAssuntos
Fármacos Dermatológicos/administração & dosagem , Psoríase/tratamento farmacológico , Retinoides/administração & dosagem , Talidomida/análogos & derivados , Quimioterapia Combinada , Humanos , Masculino , Pessoa de Meia-Idade , Psoríase/patologia , Índice de Gravidade de Doença , Talidomida/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: The circulating immune phenotype was defined in adults and young children with early atopic dermatitis (AD), but chronologic changes in the blood of infants and children with AD through adolescence have not been explored. OBJECTIVE: We sought to compare immune activation and cytokine polarization in the blood of 0- to 5-year-old (n = 39), 6- to 11-year-old (n = 26), 12- to 17-year-old (n = 21) and 18-year-old or older (n = 43) patients with AD versus age-matched control subjects. METHODS: Flow cytometry was used to measure IFN-γ, IL-9, IL-13, IL-17, and IL-22 cytokine levels in CD4+/CD8+ T cells, with inducible costimulator molecule and HLA-DR defining midterm and long-term T-cell activation, respectively, within skin-homing/cutaneous lymphocyte antigen (CLA)+ versus systemic/CLA- T cells. Unsupervised clustering differentiated patients based on their blood biomarker frequencies. RESULTS: Although CLA+ TH1 frequencies were significantly lower in infants with AD versus all older patients (P < .01), frequencies of CLA+ TH2 T cells were similarly expanded across all AD age groups compared with control subjects (P < .05). After infancy, CLA- TH2 frequencies were increased in patients with AD in all age groups, suggesting systemic immune activation with disease chronicity. IL-22 frequencies serially increased from normal levels in infants to highly significant levels in adolescents and adults compared with levels in respective control subjects (P < .01). Unsupervised clustering aligned the AD profiles along an age-related spectrum from infancy to adulthood (eg, inducible costimulator molecule and IL-22). CONCLUSIONS: The adult AD phenotype is achieved only in adulthood. Unique cytokine signatures characterizing individual pediatric endotypes might require age-specific therapies. Future longitudinal studies, comparing the profile of patients with cleared versus persistent pediatric AD, might define age-specific changes that predict AD clearance.
Assuntos
Citocinas/imunologia , Dermatite Atópica/imunologia , Antígenos HLA-DR/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adolescente , Adulto , Criança , Pré-Escolar , Dermatite Atópica/patologia , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Células Th1/patologia , Células Th2/patologiaRESUMO
BACKGROUND: Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD. OBJECTIVE: To analyze blood inflammatory proteins of early pediatric AD. METHODS: Using high-throughput proteomics (proximity extension assay), we assessed 257 inflammatory and cardiovascular risk proteins in the blood of 30 children with moderate to severe AD younger than 5 years of age (within 6 months of onset) compared with age-matched pediatric control individuals and adult patients with AD. RESULTS: In pediatric AD blood, T helper (Th) type 2 (CCL13, CCL22) and Th17 (peptidase inhibitor-3/elafin) markers were increased, together with markers of tissue remodeling (matrix metalloproteinases 3/9/10, urokinase receptor), endothelial activation (E-selectin), T-cell activation (IL2RA), neutrophil activation (myeloperoxidase), lipid metabolism (FABP4), and growth factors (FGF21, transforming growth factor-α). Total numbers of dysregulated proteins were smaller in pediatric AD (n = 22) than in adult AD (n = 61). Clinical severity scores were positively correlated with receptors for interleukins 33 and 36 and inversely correlated with some Th1 markers (interferon gamma, CXCL11). LIMITATIONS: Different baseline expression levels in healthy pediatric vs adult samples. CONCLUSIONS: Within months of pediatric AD onset, systemic immune activation is present, with Th2/Th17 skewing but otherwise different proteomic patterns from adult AD. Future correlation of proteomic patterns with disease course, comorbidity development, and drug response may yield predictive biomarkers.
Assuntos
Quimiocinas/sangue , Dermatite Atópica/sangue , Elafina/sangue , Inflamação/sangue , Metaloproteinases da Matriz/sangue , Receptores de Interleucina/sangue , Fatores Etários , Biomarcadores/sangue , Estudos de Casos e Controles , Pré-Escolar , Doença Crônica , Dermatite Atópica/metabolismo , Selectina E/sangue , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Fatores de Crescimento de Fibroblastos/sangue , Humanos , Lactente , Subunidade alfa de Receptor de Interleucina-2/sangue , Masculino , Peroxidase/sangue , Proteoma/metabolismo , RNA Mensageiro/metabolismo , Índice de Gravidade de Doença , Fator de Crescimento Transformador alfa/sangueRESUMO
Recent research advancements indicate that atopic dermatitis (AD) is a complex disease characterized by different subtypes/phenotypes based on age, disease chronicity, ethnicity, filaggrin and IgE status, and underlying molecular mechanisms/endotypes. This heterogeneity advocates against the traditional "one-size-fits-all" therapeutic approaches still used to manage AD. Precision medicine approaches, striving for targeted, tailored, endotype-driven disease prevention and treatment, rely on detailed definitions of the disease's variability across different phenotypes. Studies have shown that AD harbors different endotypes across different age groups and ethnicities and according to IgE levels and filaggrin mutation status. These include European American versus Asian patients, children versus adults, intrinsic versus extrinsic (IgE status) disease, and patients with and without filaggrin mutations. Therapies targeting different cytokine axes and other mechanisms involved in disease pathogenesis, which are currently being tested for patients with AD across the disease spectrum, will expand our ability to dissect the relative contribution of each of these pathways to disease perpetuation.
Assuntos
Citocinas , Dermatite Atópica , Imunoglobulina E , Proteínas de Filamentos Intermediários , Mutação , Medicina de Precisão , Adolescente , Adulto , Fatores Etários , Criança , Pré-Escolar , Citocinas/genética , Citocinas/imunologia , Dermatite Atópica/classificação , Dermatite Atópica/etnologia , Dermatite Atópica/genética , Dermatite Atópica/terapia , Feminino , Proteínas Filagrinas , Humanos , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Lactente , Recém-Nascido , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/imunologia , MasculinoRESUMO
BACKGROUND: Peripheral blood skin-homing/cutaneous lymphocyte antigen (CLA)+ T cells emerge as biomarkers of cutaneous immune activation in patients with inflammatory skin diseases (atopic dermatitis [AD] and alopecia areata [AA]). However, blood phenotyping across these subsets is not yet available in patients with vitiligo. OBJECTIVE: We sought to measure cytokine production by circulating skin-homing (CLA+) versus systemic (CLA-) "polar" CD4+/CD8+ ratio and activated T-cell subsets in patients with vitiligo compared with patients with AA, AD, or psoriasis and control subjects. METHODS: Flow cytometry was used to measure levels of the cytokines IFN-γ, IL-13, IL-9, IL-17, and IL-22 in CD4+/CD8+ T cells in the blood of 19 patients with moderate-to-severe nonsegmental/generalized vitiligo, moderate-to-severe AA (n = 32), psoriasis (n = 24), or AD (n = 43) and control subjects (n = 30). Unsupervised clustering differentiated subjects into groups based on cellular frequencies. RESULTS: Patients with Vitiligo showed the highest CLA+/CLA- TH1/type 1 cytotoxic T-cell polarization, with parallel TH2/TH9/TH17/TH22 level increases to levels often greater than those seen in patients with AA, AD, or psoriasis (P < .05). Total regulatory T-cell counts were lower in patients with vitiligo than in control subjects and patients with AD or psoriasis (P < .001). Vitiligo severity correlated with levels of multiple cytokines (P < .1), whereas duration was linked with IFN-γ and IL-17 levels (P < .04). Patients and control subjects grouped into separate clusters based on blood biomarkers. CONCLUSIONS: Vitiligo is characterized by a multicytokine polarization among circulating skin-homing and systemic subsets, which differentiates it from other inflammatory/autoimmune skin diseases. Future targeted therapies should delineate the relative contribution of each cytokine axis to disease perpetuation.
Assuntos
Alopecia em Áreas/diagnóstico , Biomarcadores/sangue , Citocinas/sangue , Dermatite Atópica/diagnóstico , Pele/imunologia , Células Th1/imunologia , Vitiligo/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Progressão da Doença , Feminino , Citometria de Fluxo , Humanos , Inflamação , Masculino , Pessoa de Meia-Idade , Oligossacarídeos/metabolismo , Antígeno Sialil Lewis X/análogos & derivados , Antígeno Sialil Lewis X/metabolismo , Células Th2/imunologiaRESUMO
BACKGROUND: Atopic dermatitis (AD) predominantly affects young children, but our understanding of AD pathogenesis is based on skin and blood samples from long-standing adult AD. Genomic biopsy profiling from early pediatric AD showed significant Th2 and Th17/Th22-skewing, without the characteristic adult Th1 up-regulation. Because obtaining pediatric biopsies is difficult, blood gene expression profiling may provide a surrogate for the pediatric skin signature. OBJECTIVE: To define the blood profile and associated biomarkers of early moderate-to-severe pediatric AD. METHODS: We compared microarrays and reverse transcription polymerase chain reaction (RT-PCR) of blood cells from 28 AD children (<5 years and within 6 months of disease onset) to healthy control blood cells. Differentially expressed genes (DEGs) in blood (fold change [FCH] > 1.2 and false discovery rate [FDR] < 0.05) were then compared with skin DEGs. RESULTS: Eosinophil and Th2 markers (IL5RA, IL1RL1/ST2, HRH4, CCR3, SIGLEC8, PRSS33, CLC from gene arrays; IL13/IL4/CCL22 from RT-PCR) were up-regulated in early pediatric AD blood, whereas IFNG/Th1 was decreased. Th1 markers were negatively correlated with clinical severity (EASI, pruritus, transepidermal water loss [TEWL]), whereas Th2/Th17-induced interleukin (IL)-19 was positively correlated with SCORAD. Although a few RT-PCR-defined immune markers (IL-13/CCL22) were increased in blood, as previously also reported for skin, minimal overlap based on gene array DEGs was seen. CONCLUSION: The whole blood signature of early moderate-to-severe pediatric AD blood cells show predominantly a Th2/eosinophil profile; however, markers largely differ from the skin profile. Given their complementarity, pooling of biomarkers from blood and skin may improve profiling and predictions, providing insight regarding disease course, allergic comorbidity development, and response to systemic medications.
Assuntos
Dermatite Atópica/genética , Pele/metabolismo , Transcriptoma , Idade de Início , Biomarcadores/análise , Biópsia , Pré-Escolar , Dermatite Atópica/sangue , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Leucócitos Mononucleares/metabolismo , MasculinoRESUMO
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 , Proteínas Filagrinas , 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 JovemRESUMO
The ichthyoses are rare skin disorders with immune and barrier aberrations. Identifying blood phenotypes may advance targeted therapeutics. We aimed to compare frequencies of skin homing/cutaneous lymphocyte antigen (+) versus systemic/cutaneous lymphocyte antigen (-) "polar" CD4+/CD8+ and activated T-cell subsets in ichthyosis versus atopic dermatitis, psoriasis, and control blood, with appropriate clinical correlations. Flow cytometry was used to measure IFN-γ, IL-13, IL-9, IL-17, and IL-22 cytokines in CD4+/CD8+ T cells, with inducible co-stimulator molecule and HLA-DR defining mid- and long-term T-cell activation, respectively. We compared peripheral blood from 47 patients with ichthyosis (congenital ichthyosiform erythroderma, lamellar ichthyosis, epidermolytic ichthyosis, and Netherton syndrome) with 43 patients with atopic dermatitis and 24 patients with psoriasis and 59 age-matched controls. Clinical measures included the ichthyosis severity score, with subsets for erythema and scaling, transepidermal water loss, and pruritus. All ichthyoses had excessive inducible co-stimulator molecule activation (P < 0.001), particularly epidermolytic ichthyosis. Significantly elevated IL-17- (P < 0.05) and IL-22-producing (P < 0.01) T cells characterized ichthyoses, mainly Netherton syndrome and congenital ichthyosiform erythroderma (P < 0.05). Increased T helper 2/cytotoxic T cell 2/T helper 9 (P < 0.05) and similar IFN-γ frequencies (P > 0.1) versus controls were also noted. IL-17/IL-22-producing cells clustered with clinical measures, whereas IFN-γ clustered with age. Our data show peripheral blood IL-17/IL-22 activation across the ichthyoses, correlating with clinical measures. Targeted therapies should dissect the relative contribution of polar cytokines to disease pathogenesis.
Assuntos
Citocinas/sangue , Ictiose/imunologia , Ativação Linfocitária/imunologia , Células Th17/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos de Diferenciação de Linfócitos T/sangue , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Citometria de Fluxo , Humanos , Ictiose/sangue , Ictiose/patologia , Imuno-Histoquímica , Lactente , Masculino , Pessoa de Meia-Idade , Células Th17/metabolismo , Adulto JovemRESUMO
BACKGROUND: Liver X receptors (LXRs) are involved in maintaining epidermal barrier and suppressing inflammatory responses in model systems. The LXR agonist VTP-38543 showed promising results in improving barrier function and inflammatory responses in model systems. OBJECTIVE: To assess the safety, tolerability, cellular and molecular changes, and clinical efficacy of the topical VTP-38543 in adults with mild to moderate atopic dermatitis (AD). METHODS: A total of 104 ambulatory patients with mild to moderate AD were enrolled in this randomized, double-blind, vehicle-controlled trial between December 2015 and September 2016. VTP-38543 cream in 3 concentrations (0.05%, 0.15%, and 1.0%) or placebo was applied twice daily for 28 days. Pretreatment and posttreatment skin biopsy specimens were obtained from a subset of 33 patients. Changes in SCORing of Atopic Dermatitis, Eczema Area and Severity Index, Investigator's Global Assessment, and tissue biomarkers (by real-time polymerase chain reaction and immunostaining) were evaluated. RESULTS: Topical VTP-38543 was safe and well tolerated. VTP-38543 significantly increased messenger RNA (mRNA) expression of epidermal barrier differentiation (loricrin and filaggrin, P = .02) and lipid (adenosine triphosphate-binding cassette subfamily G member 1 and sterol regulatory element binding protein 1c, P < .01) measures and reduced epidermal hyperplasia markers (thickness, keratin 16 mRNA). VTP-38543 nonsignificantly suppressed cellular infiltrates and down-regulated mRNA expression of several TH17/TH22-related (phosphatidylinositol 3, S100 calcium-binding protein A12) and innate immunity (interleukin 6) markers. CONCLUSION: Topical VTP-38543 is safe and well tolerated. Its application led to improvement in barrier differentiation and lipids. Longer-term studies are needed to clarify whether a barrier-based approach can induce meaningful suppression of immune abnormalities. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02655679.
Assuntos
Anti-Inflamatórios/uso terapêutico , Dermatite Atópica/tratamento farmacológico , Epiderme/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Receptores X do Fígado/agonistas , RNA Mensageiro/agonistas , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/imunologia , Administração Cutânea , Adulto , Transporte Biológico/efeitos dos fármacos , Transporte Biológico/imunologia , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Dermatite Atópica/patologia , Método Duplo-Cego , Epiderme/imunologia , Epiderme/patologia , Feminino , Proteínas Filagrinas , Regulação da Expressão Gênica/imunologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Proteínas de Filamentos Intermediários/genética , Proteínas de Filamentos Intermediários/imunologia , Queratina-16/genética , Queratina-16/imunologia , Receptores X do Fígado/genética , Receptores X do Fígado/imunologia , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/imunologia , Proteína S100A12/genética , Proteína S100A12/imunologia , Índice de Gravidade de Doença , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/imunologia , Resultado do TratamentoRESUMO
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 Th17RESUMO
Atopic dermatitis (AD) is increasingly recognized as a complex, inflammatory skin disease involving interplay of multiple elements. This article notes key advances in understanding of immune dysregulation, skin barrier dysfunction, environmental, genetic, and microbial influences orchestrating disease pathogenesis, and the relevance of therapeutic interventions in each area. Accumulating evidence and the discovery of new T-cell subsets has matured AD as a multiple-cytokine-axes-driven disorder, evolved from the widely held belief of it being a biphasic Th1/Th2 disease. These new insights have led to active trials testing multiple, targeted therapeutics with better efficacy and safety-profiles.