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1.
Artigo em Inglês | MEDLINE | ID: mdl-32296882

RESUMO

PURPOSE: The purpose of this study was to investigate the prognostic value of whole-body metabolic tumor volume (MTV) and other metabolic tumor parameters, obtained from baseline and first restaging 18F-FDG PET/CT scans in melanoma patients treated with immune checkpoint inhibitors (ICIs). METHODS: Eighty-five consecutive melanoma patients (M, 57; F, 28) treated with ICIs who underwent PET/CT scans before and approximately 3 months after the start of immunotherapy were retrospectively enrolled. Metabolic tumor parameters including MTV for all melanoma lesions were measured on each scan. A Cox proportional hazards model was used for univariate and multivariate analyses of metabolic parameters combined with known clinical prognostic factors associated with overall survival (OS). Kaplan-Meier curves for patients dichotomized based on median values of imaging parameters were generated. RESULTS: The median OS time in all patients was 45 months (95% CI 24-45 months). Univariate analysis demonstrated that MTV obtained from first restaging PET/CT scans (MTVpost) was the strongest prognostic factor for OS among PET/CT parameters (P < 0.0001). The median OS in patients with high MTVpost (≥ 23.44) was 16 months (95% CI 12-32 months) as compared with more than 60 months in patients with low MTVpost (< 23.44) (P = 0.0003). A multivariate model including PET/CT parameters and known clinical prognostic factors revealed that MTVpost and the presence of central nervous system lesions were independent prognostic factors for OS (P = 0.0004, 0.0167, respectively). One pseudoprogression case (1.2%) was seen in this population and classified into the high MTVpost group. CONCLUSION: Whole-body metabolic tumor volume from PET scan acquired approximately 3 months following initiation of immunotherapy (MTVpost) is a strong prognostic indicator of OS in melanoma patients. Although the possibility of pseudoprogression must be considered whenever evaluating first restaging PET imaging, it only occurred in 1 patient in our cohort.

2.
ACR Open Rheumatol ; 2(4): 197-206, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32198914

RESUMO

OBJECTIVE: The objective of this study is to evaluate racial/ethnic differences in disease manifestations and survival in a US cohort of patients with systemic sclerosis (SSc), with a focus on Asian patients. METHODS: A retrospective cohort study was conducted among Kaiser Permanente Northern California adults with an incident SSc diagnosis by a rheumatologist from 2007 to 2016, confirmed by a chart review to fulfill 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria. Self-reported race/ethnicity was categorized as non-Hispanic white, Asian, Hispanic, and black. Disease manifestations and survival were compared, using white patients as the reference. RESULTS: A total of 609 patients with incident SSc were identified: 89% were women, and 81% had limited cutaneous SSc, with a mean age at diagnosis of 55.4 ± 14.8 years. The racial/ethnic distribution was 51% non-Hispanic white (n = 310), 25% Hispanic (n = 154), 16% Asian (n = 96), and 8% black (n = 49). Compared with white patients, black patients had a greater prevalence of diffuse disease (14.5% vs. 44.9%; P < 0.001), and Asians had higher rates of anti-U1-RNP antibodies (32.1% vs. 11.9%; P = 0.005). Nine-year overall survival rates following SSc diagnosis were lower in Asian (52.3%), black (52.2%), and Hispanic patients (68.2%) compared with white patients (75.8%). Pulmonary hypertension and infections were the leading causes of death in Asian patients. Asian race was associated with higher mortality on univariable (hazard ratio [HR] 1.83 [95% confidence interval (CI) 1.08-2.99]; P = 0.020) and multivariable analyses (HR 1.80 [95% CI 0.99-3.16]; P = 0.047) when adjusting for age, sex, body mass index, cutaneous subtype, smoking status, interstitial lung disease, pulmonary hypertension, renal crisis, and malabsorption syndrome. CONCLUSION: Asian patients with SSc in this US cohort had increased mortality compared with white patients. These patients warrant close monitoring for disease progression.

3.
Cancer Cell ; 32(1): 27-41.e4, 2017 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-28625481

RESUMO

Here, we define the landscape and dynamics of active regulatory DNA in cutaneous T cell lymphoma (CTCL) by ATAC-seq. Analysis of 111 human CTCL and control samples revealed extensive chromatin signatures that distinguished leukemic, host, and normal CD4+ T cells. We identify three dominant patterns of transcription factor (TF) activation that drive leukemia regulomes, as well as TF deactivations that alter host T cells in CTCL patients. Clinical response to histone deacetylase inhibitors (HDACi) is strongly associated with a concurrent gain in chromatin accessibility. HDACi causes distinct chromatin responses in leukemic and host CD4+ T cells, reprogramming host T cells toward normalcy. These results provide a foundational framework to study personal regulomes in human cancer and epigenetic therapy.


Assuntos
Cromatina/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica , Inibidores de Histona Desacetilases/uso terapêutico , Linfoma Cutâneo de Células T/genética , Cromatina/química , Análise por Conglomerados , Epigenômica , Humanos , Linfoma Cutâneo de Células T/tratamento farmacológico , RNA Mensageiro/metabolismo
4.
Cell Syst ; 1(1): 51-61, 2015 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-26251845

RESUMO

Here we survey variation and dynamics of active regulatory elements genome-wide using longitudinal samples from human individuals. We applied Assay of Transposase Accessible Chromatin with sequencing (ATAC-seq) to map chromatin accessibility in primary CD4+ T cells isolated from standard blood draws of 12 healthy volunteers over time, from cancer patients, and during T cell activation. Over 4,000 predicted regulatory elements (7.2%) showed reproducible variation in accessibility between individuals. Gender was the most significant attributable source of variation. ATAC-seq revealed previously undescribed elements that escape X chromosome inactivation and predicted gender-specific gene regulatory networks across autosomes, which coordinately affect genes with immune function. Noisy regulatory elements with personal variation in accessibility are significantly enriched for autoimmune disease loci. Over one third of regulome variation lacked genetic variation in cis, suggesting contributions from environmental or epigenetic factors. These results refine concepts of human individuality and provide a foundational reference for comparing disease-associated regulomes.

5.
PLoS One ; 9(11): e111255, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25369198

RESUMO

Mutations in the caspase recruitment domain, family member 14 (CARD14) gene have recently been described in psoriasis patients, and explain the psoriasis susceptibility locus 2 (PSORS2). CARD14 is a scaffolding protein that regulates NF-κB activation, and psoriasis-associated CARD14 mutations lead to enhanced NF-κB signaling. CARD14 is expressed mainly in epidermal keratinocytes, but also in unidentified dermal cells. In this manuscript, the identity of the dermal cell types expressing CARD14, as well the potential functional consequence of overactive CARD14 in these dermal cell types, was determined. Using two-color immunofluorescence, dermal CARD14 did not co-localize with T-cells, dendritic cells, or macrophages. However, dermal CARD14 did highly co-localize with CD31(+) endothelial cells (ECs). CARD14 was also expressed non-dermal endothelial cells, such as aortic endothelial cells, which may indicate a role of CARD14(+)ECs in the systemic inflammation and cardiovascular comorbidities associated with psoriasis. Additionally, phosphorylated NF-κB was found in psoriatic CARD14(+) CD31(+) ECs, demonstrating this pathway is active in dermal ECs in psoriasis. Transfection of dermal ECs with psoriasis-associated CARD14 mutations resulted in increased expression of several chemokines, including CXCL10, IL-8, and CCL2. These results provide preliminary evidence that CARD14 expression in ECs may contribute to psoriasis through increased expression of chemokines and facilitating recruitment of immune cells into skin.


Assuntos
Proteínas Adaptadoras de Sinalização CARD/metabolismo , Células Endoteliais/metabolismo , Guanilato Ciclase/metabolismo , Proteínas de Membrana/metabolismo , Psoríase/patologia , Proteínas Adaptadoras de Sinalização CARD/genética , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiocina CXCL10/metabolismo , Derme/citologia , Células Endoteliais/citologia , Guanilato Ciclase/genética , Humanos , Interleucina-8/metabolismo , Queratinócitos/metabolismo , Proteínas de Membrana/genética , Monócitos/imunologia , Monócitos/metabolismo , Mutação , NF-kappa B/metabolismo , Fosforilação , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Psoríase/metabolismo , RNA Mensageiro/metabolismo , Transdução de Sinais , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transcriptoma , Transfecção
6.
Nat Methods ; 10(12): 1213-8, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24097267

RESUMO

We describe an assay for transposase-accessible chromatin using sequencing (ATAC-seq), based on direct in vitro transposition of sequencing adaptors into native chromatin, as a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq captures open chromatin sites using a simple two-step protocol with 500-50,000 cells and reveals the interplay between genomic locations of open chromatin, DNA-binding proteins, individual nucleosomes and chromatin compaction at nucleotide resolution. We discovered classes of DNA-binding factors that strictly avoided, could tolerate or tended to overlap with nucleosomes. Using ATAC-seq maps of human CD4(+) T cells from a proband obtained on consecutive days, we demonstrated the feasibility of analyzing an individual's epigenome on a timescale compatible with clinical decision-making.


Assuntos
Proteínas de Ligação a DNA/química , Epigenômica , Nucleossomos/química , Linfócitos T CD4-Positivos/citologia , Separação Celular , Cromatina/química , Biologia Computacional/métodos , Dimerização , Elementos Facilitadores Genéticos , Citometria de Fluxo/métodos , Humanos , Interleucina-2/genética , Reação em Cadeia da Polimerase/métodos , Fatores de Transcrição/química
7.
J Invest Dermatol ; 133(7): 1742-51, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23407402

RESUMO

Our group recently described a population of antigen-presenting cells that appear to be critical in psoriasis pathogenesis, termed inflammatory myeloid dendritic cells (CD11c(+)/blood dendritic cell (DC) antigen 1(-)). Triggering receptor expressed on myeloid cells type-1 (TREM-1) signaling was a major canonical pathway in the published transcriptome of these cells. TREM-1 is a member of the Ig superfamily, active through the DAP12 signaling pathway, with an unknown ligand. Activation through TREM-1 induces inflammatory cytokines, including IL-8, MCP/CCL2, and tumor necrosis factor. We now show that TREM-1 was expressed in the skin of healthy and psoriatic patients, and there was increased soluble TREM-1 in the circulation of psoriasis patients. In psoriasis lesions, TREM-1 was colocalized with DCs, as well as CD31(+) endothelial cells. TREM-1 expression was reduced with successful narrow band UVB (NB-UVB), etanercept, and anti-IL-17 treatments. An in vitro model of peptidoglycan-activated monocytes as inflammatory myeloid DCs was developed to study TREM-1 blockade, and treatment with a TREM-1 blocking chimera decreased allogeneic T-helper type 17 cell activation, as well as IL-17 production. Furthermore, TREM-1 blockade of ex vivo psoriatic DCs in an allogeneic mixed leukocyte reaction also showed a decrease in IL-17. Together, these data suggest that the TREM-1 signaling pathway may be a previously unidentified therapeutic target to prevent the effects of inflammatory myeloid DCs in psoriasis.


Assuntos
Células de Langerhans/metabolismo , Glicoproteínas de Membrana/antagonistas & inibidores , Glicoproteínas de Membrana/metabolismo , Psoríase/metabolismo , Psoríase/terapia , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Transdução de Sinais/fisiologia , Anti-Inflamatórios não Esteroides/uso terapêutico , Antígeno CD11c/metabolismo , Células Cultivadas , Citocinas/metabolismo , Etanercepte , Feminino , Humanos , Imunoglobulina G/uso terapêutico , Técnicas In Vitro , Interleucina-17/metabolismo , Células de Langerhans/imunologia , Células de Langerhans/patologia , Masculino , Pessoa de Meia-Idade , Monócitos/metabolismo , Monócitos/patologia , Psoríase/patologia , Receptores do Fator de Necrose Tumoral/uso terapêutico , Células Th17/metabolismo , Células Th17/patologia , Receptor Gatilho 1 Expresso em Células Mieloides , Terapia Ultravioleta
8.
Curr Opin Rheumatol ; 24(6): 597-601, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22907594

RESUMO

PURPOSE OF REVIEW: This review will provide the clinician with an update on the pathogenesis, clinical manifestations, and therapy for skin disease in dermatomyositis. Recent insights into the role for interferon in skin disease as well as the development and validation of quantitative tools to measure skin disease activity allow the possibility that, for the first time, dermatomyositis skin disease can serve as a valid outcome for clinical trials of targeted therapies. Also, the increasing appreciation of the heterogeneity of skin disease in dermatomyositis has already provided evidence that clinical subtypes of disease can provide important prognostic and diagnostic information to the clinician. RECENT FINDINGS: It is becoming apparent that the skin inflammation alone has implications for systemic and malignancy risk in dermatomyositis patients, and that there may be several pathogenic similarities between muscle and skin inflammation in dermatomyositis. Recent data on therapy for calcinosis cutis highlights that more prospective studies are needed to evaluate how best to manage all manifestations of skin inflammation in dermatomyositis. SUMMARY: A more careful description and classification of skin disease in dermatomyositis may allow the clinician to predict more accurately which patients will be at higher risk for cancer, lung disease, or muscle inflammation. In addition, given the similarities in perturbed gene expression between skin and muscle tissue, it is likely that analysis of a more readily evaluable target organ such as skin might shed light on mechanisms of disease propagation throughout the body.


Assuntos
Dermatomiosite/complicações , Dermatopatias/complicações , Autoimunidade , Calcinose/imunologia , Calcinose/patologia , Calcinose/terapia , Dermatomiosite/diagnóstico , Dermatomiosite/terapia , Humanos , Seleção de Pacientes , Prognóstico , Índice de Gravidade de Doença , Transdução de Sinais , Dermatopatias/diagnóstico , Dermatopatias/terapia
9.
J Invest Dermatol ; 130(10): 2412-22, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20555352

RESUMO

Macrophages are important cells of the innate immune system, and their study is essential to gain greater understanding of the inflammatory nature of psoriasis. We used immunohistochemistry and double-label immunofluorescence to characterize CD163(+) macrophages in psoriasis. Dermal macrophages were increased in psoriasis compared with normal skin and were identified by CD163, RFD7, CD68, lysosomal-associated membrane protein 2 (LAMP2), stabilin-1, and macrophage receptor with collagenous structure (MARCO). CD163(+) macrophages expressed C-lectins CD206/macrophage mannose receptor and CD209/DC-SIGN, as well as costimulatory molecules CD86 and CD40. They did not express mature dendritic cell (DC) markers CD208/DC-lysosomal-associated membrane glycoprotein, CD205/DEC205, or CD83. Microarray analysis of in vitro-derived macrophages treated with IFN-γ showed that many of the genes upregulated in macrophages were found in psoriasis, including STAT1, CXCL9, Mx1, and HLA-DR. CD163(+) macrophages produced inflammatory molecules IL-23p19 and IL-12/23p40 as well as tumor necrosis factor (TNF) and inducible nitric oxide synthase (iNOS). These data show that CD163 is a superior marker of macrophages, and identifies a subpopulation of "classically activated" macrophages in psoriasis. We conclude that macrophages are likely to contribute to the pathogenic inflammation in psoriasis, a prototypical T helper 1 (Th1) and Th17 disease, by releasing key inflammatory products.


Assuntos
Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Biomarcadores/metabolismo , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Psoríase/imunologia , Receptores de Superfície Celular/metabolismo , Biópsia , Células Cultivadas , Quimiocina CXCL9/genética , Células Dendríticas/metabolismo , Imunofluorescência , Proteínas de Ligação ao GTP/genética , Expressão Gênica/imunologia , Antígenos HLA-DR/genética , Humanos , Interferon gama/genética , Lectinas Tipo C/metabolismo , Macrófagos/citologia , Proteínas de Resistência a Myxovirus , Fator de Transcrição STAT1/genética
10.
J Allergy Clin Immunol ; 125(6): 1261-1268.e9, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20471070

RESUMO

BACKGROUND: Previous work has identified CD11c(+)CD1c(-) dendritic cells (DCs) as the major "inflammatory" dermal DC population in patients with psoriasis vulgaris and CD1c(+) DCs as the "resident" cutaneous DC population. OBJECTIVE: We sought to further define molecular differences between these 2 myeloid dermal DC populations. METHODS: Inflammatory and resident DCs were single-cell sorted from lesional skin biopsy specimens of patients with psoriasis, and the transcriptome of CD11c(+)CD1c(-) versus CD1c(+) DCs was determined. Results were confirmed with RT-PCR, flow cytometry, immunohistochemistry, and double-labeled immunofluorescence. Human keratinocytes were cultured for functional studies. RESULTS: TNF-related apoptosis-inducing ligand (TRAIL), Toll-like receptors 1 and 2, S100A12/ENRAGE, CD32, and many other inflammatory products were differentially expressed in inflammatory DCs compared with resident DCs. Flow cytometry and immunofluorescence confirmed higher protein expression on CD1c(-) versus CD1c(+) DCs. TRAIL receptors, death receptor 4, and decoy receptor 2 were expressed in keratinocytes and dermal cells. In vitro culture of keratinocytes with TRAIL induced CCL20 chemokine. CONCLUSIONS: CD11c(+)CD1c(-) inflammatory DCs in psoriatic lesional skin express a wide range of inflammatory molecules compared with skin-resident CD1c(+) DCs. Some molecules made by inflammatory DCs, including TRAIL, could have direct effects on keratinocytes or other skin cell types to promote disease pathogenesis.


Assuntos
Biomarcadores/metabolismo , Células de Langerhans/metabolismo , Psoríase/diagnóstico , Psoríase/imunologia , Ligante Indutor de Apoptose Relacionado a TNF/metabolismo , Antígenos CD/genética , Antígenos CD/metabolismo , Diferenciação Celular , Separação Celular , Células Cultivadas , Quimiocina CCL20/biossíntese , Quimiocina CCL20/genética , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Inflamação , Queratinócitos/imunologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Células de Langerhans/imunologia , Células de Langerhans/patologia , Análise em Microsséries , Psoríase/patologia , Proteínas S100/biossíntese , Proteínas S100/genética , Receptores Chamariz do Fator de Necrose Tumoral/biossíntese , Receptores Chamariz do Fator de Necrose Tumoral/genética
11.
PLoS One ; 5(4): e10247, 2010 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-20422035

RESUMO

BACKGROUND: Our objective was to develop a consistent molecular definition of psoriasis. There have been several published microarray studies of psoriasis, and we compared disease-related genes identified across these different studies of psoriasis with our own in order to establish a consensus. METHODOLOGY/PRINCIPAL FINDINGS: We present a psoriasis transcriptome from a group of 15 patients enrolled in a clinical study, and assessed its biological validity using a set of important pathways known to be involved in psoriasis. We also identified a key set of cytokines that are now strongly implicated in driving disease-related pathology, but which are not detected well on gene array platforms and require more sensitive methods to measure mRNA levels in skin tissues. Comparison of our transcriptome with three other published lists of psoriasis genes showed apparent inconsistencies based on the number of overlapping genes. We extended the well-established approach of Gene Set Enrichment Analysis (GSEA) to compare a new study with these other published list of differentially expressed genes (DEG) in a more comprehensive manner. We applied our method to these three published psoriasis transcriptomes and found them to be in good agreement with our study. CONCLUSIONS/SIGNIFICANCE: Due to wide variability in clinical protocols, platform and sample handling, and subtle disease-related signals, intersection of published DEG lists was unable to establish consensus between studies. In order to leverage the power of multiple transcriptomes reported by several laboratories using different patients and protocols, more sophisticated methods like the extension of GSEA presented here, should be used in order to overcome the shortcomings of overlapping individual DEG approach.


Assuntos
Perfilação da Expressão Gênica/estatística & dados numéricos , Psoríase/genética , Ensaios Clínicos como Assunto , Etanercepte , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Humanos , Imunoglobulina G/uso terapêutico , Métodos , Variações Dependentes do Observador , Psoríase/tratamento farmacológico , RNA Mensageiro/análise , Receptores do Fator de Necrose Tumoral/uso terapêutico
13.
Am J Respir Cell Mol Biol ; 42(1): 32-9, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19372243

RESUMO

Sarcoidosis is a noncaseating granulomatous disease, likely of autoimmune etiology, that causes inflammation and tissue damage in multiple organs, most commonly the lung, but also skin, and lymph nodes. Reduced dendritic cell (DC) function in sarcoidosis peripheral blood compared with peripheral blood from control subjects suggests that blunted end organ cellular immunity may contribute to sarcoidosis pathogenesis. Successful treatment of sarcoidosis with tumor necrosis factor (TNF) inhibitors, which modulate DC maturation and migration, has also been reported. Together, these observations suggest that DCs may be important mediators of sarcoidosis immunology. This review focuses on the phenotype and function of DCs in the lung, skin, blood, and lymph node of patients with sarcoidosis. We conclude that DCs in end organs are phenotypically and functionally immature (anergic), while DCs in the lymph node are mature and polarize pathogenic Th1 T cells. The success of TNF inhibitors is thus likely secondary to inhibition of DC-mediated Th1 polarization in the lymph node.


Assuntos
Células Dendríticas/patologia , Sarcoidose/fisiopatologia , Líquido da Lavagem Broncoalveolar , Proliferação de Células , Sobrevivência Celular , Citocinas/metabolismo , Células Dendríticas/citologia , Granuloma/patologia , Humanos , Inflamação , Linfonodos/patologia , Ativação Linfocitária , Macrófagos/metabolismo , Modelos Biológicos , Alvéolos Pulmonares/metabolismo , Células Th1/citologia
14.
J Allergy Clin Immunol ; 124(5): 1022-10.e1-395, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19895991

RESUMO

BACKGROUND: TNF inhibitors have revolutionized the treatment of psoriasis vulgaris as well as psoriatic and rheumatoid arthritis and Crohn disease. Despite our understanding that these agents block TNF, their complex mechanism of action in disease resolution is still unclear. OBJECTIVE: To analyze globally the genomic effects of TNF inhibition in patients with psoriasis, and to compare genomic profiles of patients who responded or did not respond to treatment. METHODS: In a clinical trial using etanercept TNF inhibitor to treat psoriasis vulgaris (n = 15), Affymetrix gene arrays were used to analyze gene profiles in lesional skin at multiple time points during drug treatment (baseline and weeks 1, 2, 4, and 12) compared with nonlesional skin. Patients were stratified as responders (n = 11) or nonresponders (n = 4) on the basis of histologic disease resolution. Cluster analysis was used to define gene sets that were modulated with similar magnitude and velocity over time. RESULTS: In responders, 4 clusters of downregulated genes and 3 clusters of upregulated genes were identified. Genes downmodulated most rapidly reflected direct inhibition of myeloid lineage immune genes. Upregulated genes included the stable dendritic cell population genes CD1c and CD207 (langerin). Comparison of responders and nonresponders revealed rapid downmodulation of innate IL-1beta and IL-8 sepsis cascade cytokines in both groups, but only responders downregulated IL-17 pathway genes to baseline levels. CONCLUSION: Although both responders and nonresponders to etanercept inactivated sepsis cascade cytokines, response to etanercept is dependent on inactivation of myeloid dendritic cell genes and inactivation of the T(H)17 immune response.


Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Células Dendríticas/efeitos dos fármacos , Imunoglobulina G/uso terapêutico , Interleucina-17/imunologia , Células Mieloides/efeitos dos fármacos , Psoríase/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Anti-Inflamatórios não Esteroides/administração & dosagem , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Regulação para Baixo/imunologia , Etanercepte , Expressão Gênica/efeitos dos fármacos , Perfilação da Expressão Gênica , Humanos , Imunoglobulina G/administração & dosagem , Interferon gama/antagonistas & inibidores , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/antagonistas & inibidores , Interleucina-17/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-8/antagonistas & inibidores , Interleucina-8/imunologia , Interleucina-8/metabolismo , Células Mieloides/imunologia , Células Mieloides/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Psoríase/genética , Psoríase/imunologia , Receptores do Fator de Necrose Tumoral/administração & dosagem , Transdução de Sinais , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética , Regulação para Cima/imunologia
15.
J Allergy Clin Immunol ; 123(6): 1244-52.e2, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19439349

RESUMO

BACKGROUND: Psoriasis and atopic dermatitis (AD) are common inflammatory skin diseases. An upregulated TH17/IL-23 pathway was demonstrated in psoriasis. Although potential involvement of TH17 T cells in AD was suggested during acute disease, the role of these cells in chronic AD remains unclear. OBJECTIVE: To examine differences in IL-23/TH17 signal between these diseases and establish relative frequencies of T-cell subsets in AD. METHODS: Skin biopsies and peripheral blood were collected from patients with chronic AD (n = 12) and psoriasis (n = 13). Relative frequencies of CD4+ and CD8+ T-cell subsets within these 2 compartments were examined by intracellular cytokine staining and flow cytometry. RESULTS: In peripheral blood, no significant difference was found in percentages of different T-cell subsets between these diseases. In contrast, psoriatic skin had significantly increased frequencies of TH1 and TH17 T cells compared with AD, whereas TH2 T cells were significantly elevated in AD. Distinct IL-22-producing CD4+ and CD8+ T-cell populations were significantly increased in AD skin compared with psoriasis. IL-22+CD8+ T-cell frequency correlated with AD disease severity. CONCLUSION: Our data established that T cells could independently express IL-22 even with low expression levels of IL-17. This argues for a functional specialization of T cells such that "T17" and "T22" T-cells may drive different features of epidermal pathology in inflammatory skin diseases, including induction of antimicrobial peptides for "T17" T cells and epidermal hyperplasia for "T22" T-cells. Given the clinical correlation with disease severity, further characterization of "T22" T cells is warranted, and may have future therapeutic implications.


Assuntos
Dermatite Atópica/imunologia , Interleucina-23/metabolismo , Interleucinas/metabolismo , Psoríase/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Doença Crônica , Dermatite Atópica/metabolismo , Humanos , Interleucina-17/imunologia , Interleucina-17/metabolismo , Interleucina-23/imunologia , Interleucinas/imunologia , Pessoa de Meia-Idade , Psoríase/metabolismo , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo
16.
J Invest Dermatol ; 129(10): 2451-62, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19387481

RESUMO

To determine the phenotype and function of myeloid dendritic cells (DCs) from human cutaneous squamous-cell carcinoma (SCC), we studied their surface marker expression and allo-stimulatory potential ex vivo. There were abundant CD11c(+) myeloid DCs, as well as TNF and inducible nitric oxide synthase (iNOS)-producing DCs, in and around SCC tumor nests. Although myeloid DCs from SCC, adjacent non-tumor-bearing skin, and normal skin, were phenotypically similar by flow cytometry, and there was a pronounced genomic signature of mature DCs in SCC, they showed different T-cell stimulatory potential in an allogeneic mixed leukocyte reaction. Myeloid DCs from SCC were less potent stimulators of allogeneic T-cell proliferation than DCs from non-tumor-bearing skin. Culture with a DC-maturing cytokine cocktail (IL-1beta, IL-6, TNF-alpha, and PGE(2)) enhanced stimulatory potential in DCs from non-tumor-bearing skin, whereas SCC-associated DCs remained poor stimulators of T-cell proliferation. The microenvironment associated with SCC showed expression of TGF-beta, IL-10, and VEGF-A, factors capable of suppressing the DC function. These findings indicate that CD11c(+)/HLA-DR(hi) DCs from SCC are mature, but are not potent stimulators of T-cell proliferation compared with phenotypically similar DCs isolated from non-tumor-bearing skin. Identification of mechanisms responsible for suppression of tumor-associated DCs may provide insight into the evasion of immunosurveillance by SCC.


Assuntos
Proliferação de Células , Células Dendríticas/patologia , Neoplasias de Células Escamosas/patologia , Neoplasias Cutâneas/patologia , Linfócitos T/patologia , Antígenos CD1/metabolismo , Células Cultivadas , Células Dendríticas/metabolismo , Antígenos HLA-DR/metabolismo , Humanos , Células de Langerhans/metabolismo , Células de Langerhans/patologia , Lectinas Tipo C/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias de Células Escamosas/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Receptores Imunológicos/metabolismo , Neoplasias Cutâneas/metabolismo , Linfócitos T/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
17.
J Invest Dermatol ; 129(1): 79-88, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18633443

RESUMO

Myeloid dermal dendritic cells (DCs) accumulate in chronically inflamed tissues such as psoriasis. The importance of these cells for psoriasis pathogenesis is suggested by comparative T-cell and DC-cell counts, where DCs outnumber T cells. We have previously identified CD11c(+)-blood dendritic cell antigen (BDCA)-1(+) cells as the main resident dermal DC population found in normal skin. We now show that psoriatic lesional skin has two populations of dermal DCs: (1) CD11c(+)BDCA-1(+) cells, which are phenotypically similar to those contained in normal skin and (2) CD11c(+)BDCA-1(-) cells, which are phenotypically immature and produce inflammatory cytokines. Although BDCA-1(+) DCs are not increased in number in psoriatic lesional skin compared with normal skin, BDCA-1(-) DCs are increased 30-fold. For functional studies, we FACS-sorted psoriatic dermal single-cell suspensions to isolate these two cutaneous DC populations, and cultured them as stimulators in an allogeneic mixed leukocyte reaction. Both BDCA-1(+) and BDCA-1(-) myeloid dermal DC populations induced T-cell proliferation, and polarized T cells to become T helper 1 (Th1) and T helper 17 (Th17) cells. In addition, psoriatic dermal DCs induced a population of activated T cells that simultaneously produced IL-17 and IFN-gamma, which was not induced by normal skin dermal DCs. As psoriasis is believed to be a mixed Th17/Th1 disease, it is possible that induction of these IL-17(+)IFN-gamma(+) cells is pathogenic. These cytokines, the T cells that produce them, and the inducing inflammatory DCs may all be important new therapeutic targets in psoriasis.


Assuntos
Células Dendríticas/citologia , Interleucina-17/metabolismo , Psoríase/diagnóstico , Psoríase/imunologia , Células Th1/imunologia , Antígeno CD11c/biossíntese , Separação Celular , Células Dendríticas/imunologia , Citometria de Fluxo , Humanos , Sistema Imunitário , Inflamação , Interferon gama/metabolismo , Leucócitos/metabolismo , Fenótipo , Pele/patologia , Linfócitos T/imunologia
18.
J Invest Dermatol ; 129(2): 302-8, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18685620

RESUMO

Dendritic cells (DCs) are a heterogeneous group of antigen-presenting leukocytes that are important in activation of both the innate and adaptive arms of the immune system. Although there are several different DC populations in the body, DCs are globally defined by their capacity for potent antigen presentation and naive T-cell activation. In noninflamed human skin during steady state, there are three main cutaneous DC populations: epidermal Langerhans cells, dermal myeloid DCs, and dermal plasmacytoid DCs. In psoriasis, a model for cutaneous inflammation, there is an additional population of myeloid dermal DCs--"inflammatory DCs"--which appears to be critical for disease pathogenesis.


Assuntos
Células Dendríticas/imunologia , Dermatite/imunologia , Pele/imunologia , Células Dendríticas/patologia , Dermatite/patologia , Humanos , Pele/patologia
19.
J Immunol ; 181(10): 7420-7, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18981165

RESUMO

The classical Th1/Th2 paradigm previously defining atopic dermatitis (AD) and psoriasis has recently been challenged with the discovery of Th17 T cells that synthesize IL-17 and IL-22. Although it is becoming evident that many Th1 diseases including psoriasis have a strong IL-17 signal, the importance of Th17 T cells in AD is still unclear. We examined and compared skin biopsies from AD and psoriasis patients by gene microarray, RT-PCR, immunohistochemistry, and immunofluorescence. We found a reduced genomic expression of IL-23, IL-17, and IFN-gamma in AD compared with psoriasis. To define the effects of IL-17 and IL-22 on keratinocytes, we performed gene array studies with cytokine-treated keratinocytes. We found lipocalin 2 and numerous other innate defense genes to be selectively induced in keratinocytes by IL-17. IFN-gamma had no effect on antimicrobial gene-expression in keratinocytes. In AD skin lesions, protein and mRNA expression of lipocalin 2 and other innate defense genes (hBD2, elafin, LL37) were reduced compared with psoriasis. Although AD has been framed by the Th1/Th2 paradigm as a Th2 polar disease, we present evidence that the IL-23/Th17 axis is largely absent, perhaps accounting for recurrent skin infections in this disease.


Assuntos
Dermatite Atópica/imunologia , Interleucina-23/biossíntese , Psoríase/imunologia , Proteínas da Fase Aguda/biossíntese , Proteínas da Fase Aguda/imunologia , Adolescente , Adulto , Idoso , Células Cultivadas , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Dermatite Atópica/metabolismo , Feminino , Imunofluorescência , Humanos , Imuno-Histoquímica , Interferon gama/biossíntese , Interferon gama/imunologia , Interleucina-17/biossíntese , Interleucina-17/imunologia , Interleucina-23/imunologia , Interleucinas/biossíntese , Interleucinas/imunologia , Queratinócitos/imunologia , Queratinócitos/metabolismo , Lipocalina-2 , Lipocalinas/biossíntese , Lipocalinas/imunologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas/imunologia , Psoríase/metabolismo , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo
20.
PLoS Genet ; 4(3): e1000041, 2008 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-18369459

RESUMO

A genome-wide association study was performed to identify genetic factors involved in susceptibility to psoriasis (PS) and psoriatic arthritis (PSA), inflammatory diseases of the skin and joints in humans. 223 PS cases (including 91 with PSA) were genotyped with 311,398 single nucleotide polymorphisms (SNPs), and results were compared with those from 519 Northern European controls. Replications were performed with an independent cohort of 577 PS cases and 737 controls from the U.S., and 576 PSA patients and 480 controls from the U.K.. Strongest associations were with the class I region of the major histocompatibility complex (MHC). The most highly associated SNP was rs10484554, which lies 34.7 kb upstream from HLA-C (P = 7.8x10(-11), GWA scan; P = 1.8x10(-30), replication; P = 1.8x10(-39), combined; U.K. PSA: P = 6.9x10(-11)). However, rs2395029 encoding the G2V polymorphism within the class I gene HCP5 (combined P = 2.13x10(-26) in U.S. cases) yielded the highest ORs with both PS and PSA (4.1 and 3.2 respectively). This variant is associated with low viral set point following HIV infection and its effect is independent of rs10484554. We replicated the previously reported association with interleukin 23 receptor and interleukin 12B (IL12B) polymorphisms in PS and PSA cohorts (IL23R: rs11209026, U.S. PS, P = 1.4x10(-4); U.K. PSA: P = 8.0x10(-4); IL12B:rs6887695, U.S. PS, P = 5x10(-5) and U.K. PSA, P = 1.3x10(-3)) and detected an independent association in the IL23R region with a SNP 4 kb upstream from IL12RB2 (P = 0.001). Novel associations replicated in the U.S. PS cohort included the region harboring lipoma HMGIC fusion partner (LHFP) and conserved oligomeric golgi complex component 6 (COG6) genes on chromosome 13q13 (combined P = 2x10(-6) for rs7993214; OR = 0.71), the late cornified envelope gene cluster (LCE) from the Epidermal Differentiation Complex (PSORS4) (combined P = 6.2x10(-5) for rs6701216; OR 1.45) and a region of LD at 15q21 (combined P = 2.9x10(-5) for rs3803369; OR = 1.43). This region is of interest because it harbors ubiquitin-specific protease-8 whose processed pseudogene lies upstream from HLA-C. This region of 15q21 also harbors the gene for SPPL2A (signal peptide peptidase like 2a) which activates tumor necrosis factor alpha by cleavage, triggering the expression of IL12 in human dendritic cells. We also identified a novel PSA (and potentially PS) locus on chromosome 4q27. This region harbors the interleukin 2 (IL2) and interleukin 21 (IL21) genes and was recently shown to be associated with four autoimmune diseases (Celiac disease, Type 1 diabetes, Grave's disease and Rheumatoid Arthritis).


Assuntos
Artrite Psoriásica/genética , Artrite Psoriásica/imunologia , Psoríase/genética , Psoríase/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoimunidade/genética , Estudos de Casos e Controles , Criança , Cromossomos Humanos Par 13/genética , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 4/genética , Estudos de Coortes , Feminino , Genes MHC Classe I , Predisposição Genética para Doença , Genoma Humano , Humanos , Subunidade p40 da Interleucina-12/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Receptores de Interleucina/genética
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