INTRODUÇÃO: A psoríase é doença inflamatória hiperproliferativa da pele, na qual mecanismos imunológicos são cruciais para o processo patogênico. O marcador CD57 denota inabilidade de replicação e imuno-senescência de células T CD8+, e sua expressão foi demonstrada em diversas condições inflamatórias. CD57 também pode ser expresso por células natural killer (NK), nas quais é considerado marcador de maturidade, por ser em geral adquirido pelas formas mais diferenciadas CD56+CD16+. A expressão de CD57 e outros receptores de células NK não foi amplamente investigada na psoríase. OBJETIVOS: Este estudo buscou examinar o fenótipo de células NK em biópsias de pele e células mononucleares do sangue periférico (CMSP) de pacientes com psoríase em relação a controles sadios. Este estudo investigou também o fenótipo e características funcionais de células T isoladas da pele lesional e não afetada de pacientes com psoríase. MÉTODOS: Foram isoladas células NK dos subtipos CD56+CD16- e CD56+CD16+ de pele lesional, não afetada e CMSP de pacientes com psoríase, comparadas com pele normal e CMSP de controles sadios. A expressão de CD57, NKG2A e NKG2C foi determinada nesses subtipos de células por citometria de fluxo. Células T CD4+ e CD8+ foram isoladas da pele lesional e não afetada de pacientes com psoríase, e a expressão de CD57 foi avaliada. Características funcionais de células T foram estudadas através da análise da secreção de diversas citocinas inflamatórias (IL-17A, IFN-\", IL-2, IL-33, TNF- #, IL-21, IL-22 and IL-27) produzidas por células T CD4+ e CD8+ isoladas por sorting celular, a partir de amostras de pele lesional e não afetada de pacientes com psoríase. RESULTADOS: Células NK isoladas das lesões de psoríase apresentaram um fenótipo particular, caracterizado por baixa expressão de CD57 e alta expressão de NKG2A na pele lesional e não afetada em relação aos controles. Em relação às células T, encontrouse frequência de células T CD4+CD57+ e CD8+CD57+ significativamente maior na pele não afetada em relação à pele lesional de pacientes com psoríase. Células T CD4+ isoladas por sorting celular a partir de amostras de pele lesional produziram níveis maiores de IL-17A, IL-22 e IFN-\" em relação às amostras de pele não afetada. Células T CD8+ isoladas da pele lesional secretaram maiores níveis de IL-17A, IFN-\", TNF-# e IL- 2 em relação à pele não afetada. CONCLUSÕES: Esses dados sugerem que células NK presentes nas lesões de psoríase apresentam fenótipo imaturo, que foi previamente associado a maiores capacidades funcionais, e poderiam ser implicadas na patogênese da psoríase. Em relação às células T, as características fenotípicas sugerem menor sobrevivência de células com baixa capacidade replicativa na pele lesional, pelo ambiente inflamatório local ou pelo alto turnover celular da psoríase / INTRODUCTION: Psoriasis is a hyper-proliferative inflammatory disease of the skin in which immunological mechanisms play a direct role in disease pathogenesis. CD57 is a marker of replicative inability and immunosenescence on CD8+ T cells and its expression is increased in a number of inflammatory conditions. CD57 is also expressed by NK cells and is considered a marker of NK cell maturity, being acquired by more differentiated CD56+CD16+ NK cells. The expression of CD57 and other NK cell markers in psoriasis has not been thoroughly investigated. OBJECTIVES: This study sought to examine the phenotype of NK cells in skin biopsies and peripheral blood mononuclear cells (PBMC) from patients with psoriasis and healthy controls. We also investigated the phenotype and functional characteristics of T cells from psoriasis patients, comparing lesional and unaffected skin. METHODS: CD56+CD16- and CD56+CD16+ NK cells were isolated from lesional skin, unaffected skin and PBMC of psoriasis patients, and normal skin and PBMC from healthy controls. The expression of CD57, NKG2A, and NKG2C was assessed by flow cytometry. CD57 expression was also determined on T cells from lesional and unaffected skin by flow cytometry. We assessed functional characteristics of T cells by evaluating the secretion of several inflammatory cytokines (IL-17A, IFN-\", IL- 2, IL-33, TNF-#, IL-21, IL-22 and IL-27), from cell-sorted purified CD4+ and CD8+ T cells isolated from lesional and unaffected skin of psoriasis patients, by multiplex assays. RESULTS: NK cells in psoriasis skin lesions exhibited a distinct phenotype, with CD57 expression significantly reduced and NKG2A expression increased on NK cells in lesional and unaffected skin compared to controls. In relation to T cells, we observed that the frequency of CD57+CD4+ and CD57+CD8+ T cells was significantly increased in unaffected skin of psoriasis patients compared to lesional skin. Sorted CD4+ T cells from psoriasis lesional skin produced higher levels of IL-17A, IL-22 and IFN-\" compared to unaffected skin. CD8+ T cells isolated from lesional skin produced higher levels of IL- 17A, IFN-\", TNF-# and IL-2 compared to unaffected skin. CONCLUSIONS: These data suggest that NK cells in psoriasis lesions exhibit an immature phenotype, that has been previously associated with higher functional abilities, and could implicate NK cells in psoriasis pathogenesis. For T cells, the findings of this study suggest lower survival of cells with low replicative ability in lesional skin, due to the local inflammatory environment or to the high cellular turnover in psoriasis

Orientador: Maria Helena Stangler Kraemer / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-14T09:37:26Z (GMT). No. of bitstreams: 1 Magalhaes_RenataFerreira_D.pdf: 45600840 bytes, checksum: c3be46b9fbfab6e5433e2e91db336bb3 (MD5) Previous issue date: 2009 / Resumo: Psoríase é uma dermatose inflamatória crônica, determinada por desregulação do sistema imune e associada a várias comorbidades. O marcador genético mais associado à psoríase em todas as populações é o HLA-CW06. Polimorfismos na região promotora do TNF-a, especialmente a troca de uma guanina por uma adenina nas posições -238 e -308 estão relacionados à alta produção de TNF-a e risco aumentado para psoríase nas populações caucasóides e não em asiáticos. Com o objetivo de determinar se polimorfismos destes genes podem ser fatores de risco para susceptibilidade ou gravidade da doença em pacientes brasileiros, foi realizado um estudo caso-controle com 69 pacientes com psoríase de início até 40 anos, com acompanhamento por dez anos para caracterização de sua evolução clínica em doença leve (grupo I) e grave (grupo II), e 70 indivíduos sadios. Foi feita a identificação dos alelos HLA classe I e II e SNPs da região promotora do TNF-a -238 e -308. Coletaram-se 10 mL de sangue periférico dos indivíduos e se realizou a extração do DNA através do método salting out. O DNA foi amplificado pela reação em cadeia da polimerase (PCR), com primers sequência-específica. As freqüências alélicas e gênicas foram estimadas por contagem direta e a comparação entre as frequências dos grupos foi efetuada por Teste de Fisher (programa GraphPad InStat 3.05). Dois métodos computacionais foram usados para determinar os haplótipos dos indivíduo: (1) o algoritmo ELB implementado pelo software Arlequin 3.1 e (2) um método de base coalescente implementado pelo software PHASE v2, e as freqüências de cada haplótipo foram comparadas por Teste de Fisher. No grupo II, observou-se maior associação com fatores desencadeantes como estresse, início na adolescência e predominância do sexo masculino. Pode-se sugerir que os alelos HLA-B*37, -Cw*06, -Cw*12 e -DRB1*07 foram associados ao curso mais grave da doença, enquanto - B*57 à doença mais leve. O aielo DRBT04 teve tendência a associação negativa. Ao se comparar o grupo I com o grupo II, o alelo HLA-B*37 pode ser interpretado como fator de mau prognóstico. Não houve diferença estatística entre polimorfismos da região promotora do TNF-a entre pacientes e controles. Este estudo apontou uma alta frequência do genótipo TNF-a -238 G/G {OFt 3,21; Cl:1,06-9,71; p=0,04), assim como do alelo -238 G, no grupo com doença mais grave e, ao contrário, o genótipo -238 G/A com frequência maior no grupo de boa evolução. O haplótipo -238A-308G mostrou frequência reduzida conferindo um efeito protetor. Estes dados não correspondem ao reportado para as populações caucasianas, considerando que a população brasileira é miscigenada. Polimorfismos dos SNPs do TNF-a não parecem ser um fator de susceptibilidade genética mais importante do que o já conhecido HLA-Cw*06 em pacientes brasileiros, mas podem ter relação com as manifestações e evolução da doença. / Abstract: Psoriasis is an erythematous, scaly inflammatory dermatosis with a complex immunologic basis. The strongest genetic marker for psoriasis is HLA-Cw*06. Polymorphisms in the TNF-a promoter region, especially replacement of guanine with adenine in positions -238 and -308 are related to higher TNF-a production and higher risk for psoriasis in Caucasoid populations, not found in Asians. We did a case-control study of 69 patients with psoriasis type I and 70 controls, characterized clinical progression along 10-years of follow-up in mild or severe disease and determined HLA class I, II and TNF-a SNPs -238 and -308 polymorphisms to demonstrate whether these polymorphisms may be genetic risk for susceptibility to psoriasis or severity of the disease in Brazilians. Peripheral blood (10 ml) was collected. Genomic DNA from both psoriasis patients and controls was isolated using a salting out procedure. Polymorphisms were identified by PCR/SSP. Alleles and genotypes frequencies were compared by Fisher's test (GraphPad InStat 3.05 software). Two computational methods were used to determine the haplotypes of each subject, without taking into account any prior information: (1) the ELB algorithm implemented by the ARLEQUIN 3.1 software and (2) a coalescence based method as implemented by the PHASE v2 software. The haplotype frequencies were compared between group pairs by Fisher's test. Severe disease was found more frequently in male patients, associated with environmental factors and onset at adolescence. It may be suggested that alleles HLA- B*37, -Cw*06, -Cw*12 and -DRB1*07 were associated with severe disease course, while -B"57 with mild disease. No statistical difference was found between the patients and controls regarding polymorphisms frequencies in TNF SNPs. This study pointed to a higher TNF-238 G/G genotype frequency (OR 3,21; Cl:1,06-8,71; p=0,04) in the group with severe disease and -238A-308G haplotype was found in reduced frequencies revealing a protective effect. These data do not correspond to those reported for the Caucasian population, considering that Brazilian population is admixed, and this is the first consideration about TNF-a SNPs in psoriasis in this population. Polymorphisms in the TNF-a SNPs do not seem to be a more important genetic risk factor for psoriasis than the already known Cw*06 in Brazilian patients, but these markers may be related to clinical manifestations. / Doutorado / Clinica Medica / Doutor em Clínica Médica

Background: It has been proposed that depression plays a role in how psoriasis affects quality of life. However, primary data are limited. Objective: To investigate the role depression plays in how patients experience psoriasis. Methods: Cross-sectional study conducted between January and May 2005. Recruitment of 265 adults with prevalent psoriasis through Internet advertisements. Standardized assessment of depressive symptoms, health-related quality of life (HRQL), illness-related stress, and clinical severity of psoriasis using validated scales. Results: Thirty-two percent of all participants screened positive for depression. We observed a graded relationship between depressive symptoms and HRQL impairment (p < 0.001). Only 16.5% of those with high depression scores were currently treated for depression. Both dissatisfaction with antipsoriatic treatment and illness-related stress were highly associated with depression. After adjustment for HRQL, patients with more severe psoriasis were less likely depressed, although this association failed to reach statistical significance (multiadjusted odds ratio 0.37; 95% CI 0.13–1.02; p = 0.06). Conclusion: Patients with high subjective distress and low objective measures of psoriasis should be evaluated for depression. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Background: According to current guidelines the cost of productivity loss should be considered in pharmacoeconomic analyses. The cost of health-related productivity loss in psoriasis patients is unknown. Objective: To estimate the cost of productivity loss in psoriasis and its association with health-related quality of life and clinical disease severity. Methods: Cross-sectional study, recruitment of adult participants through Internet advertisements. 201 (72.3%) out of 278 eligible participants completed the study. Health-related work productivity loss, quality of life and clinical severity of psoriasis were assessed by standardized instruments. Results: Indirect costs of productivity loss clearly exceed the total direct cost. In contrast to objective clinical disease severity, health-related quality of life (measured by the Dermatology Life Quality Index) is an independent predictor of work productivity. Conclusions: There is good reason to believe that intervention can reduce health-related productivity loss by improving patients’ quality of life. Savings from increased work productivity might offset comparatively high acquisition costs of biological agents. / Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

No description available.

<p>Kontaktna senzibilizacija, kao stanje specifične reaktivnosti kože, može biti egzogeni pokretač psorijaze. Rezultat je interakcije endogenih i egzogenih činioca. Jedan od najznačajnijih endogenih faktora kome se pripisuje uloga faktora rizika jeste pol. Cilj istraživanja bio je da se kod obolelih od psorijaze utvrdi učestalost i distribucija kontaktne senzibilizacije u odnosu na pol, razlike u distribuciji kontaktne senzibilizacije po polu&nbsp; između osoba obolelih od psorijaze i osoba pod sumnjom na postojanje kontaktnog alergijskog dermatitisa, povezanost kontaktne senzibilizacije i težine kliničkog nalaza i povezanost kontaktne senzibilizacije i dužine trajanja oboljenja. Hipoteza istraživanja polazila je od pretpostavke da je kontaktni alergijski dermatitis redak kod obolelih od psorijaze, jer hronična inflamacija u koži smanjuje njenu sposobnost specifične senzibilizacije a da je veća učestalost kontaktne senzibilizacije kod osoba ženskog pola rezultat egzogenog faktora tj.ekspozicije, kao i da je učestalost kontaktne senzibilizacije u pozitivnoj korelaciji sa težinom i dužinom trajanja oboljenja. Istaživanje je sprovedeno kod 176 ispitanika koji su bili podeljeni u dve grupe. Eksperimentalnu grupu su činili oboleli od psorijaze, a kontrolnu grupu ispitanici upućeni na alergolo&scaron;ko testiranje pod sumnjom na postojanje kontaktnog alergijskog dermatitisa. Obolelima od psorijaze je ocenjivana težine oboljenja PASI skorom, a svi ispitanici bili su alergolo&scaron;ki testirani epikutanim -pač testom. Pozitivni rezultati alergolo&scaron;kog testiranja su analizirani, u cilju utvrđivanja kliničke relevantnosti istih. Ispitanicima u grupi obolelih od psorijaze je testom skarifikacije određivano prisustvo ili odsustvo Koebnerovog izomorfnog podražajnog fenomena. Istraživanjem je utvrđeno, da se kontaktno reagovanje kod obolelih od psorijaze na najmanje jedan standardni alergen nije statistički značajno razlikovalo od reagovanja osoba kod kojih je postavljena sumnja na postojanje kontaktnog alergijskog dermatitisa, ali je senzitivnost izražena kroz prosečan broj pozitivnih testova po jednom ispitaniku bila statistički značajno niža kod obolelih od psorijaze. Poređenjem kontaktnog reagovanja mu&scaron;karaca i žena nisu utvrđene značajna razlike u reagovanju u odnosu na pol. Težina oboljenja nije uticala na učestalost kontaktne senzibilizacije kod obolelih od psorijaze, ali je učestalost kontaktne senzibilizacije bila u pozitivnoj korelaciji sa dužinom trajanja bolesti. Niža stopa kontaktnog reagovanja utvrđena je kod osoba obolelih od psorijaze koji su imali pozitivan Koebnerov fenomen u trenutku ispitivanja.</p> / <p>Contact sensitization as a state of specific skin reactivity may provoke psoriasis resulting from an interaction between extrinsic and intrinsic factors. One of the most significant factors characterized, as a risk factor, is the sex. The aim of this study was to determinate the frequency and distribution of contact sensitization in patients with&nbsp; psoriasis with respect to their sex, as well as the differences in the distribution of contact sensitization in both sexes, namely&nbsp; with patients with psoriasis and patients&nbsp; suspected to allergic contact dermatitis. Consequently, appropriate attention was paid to the correlation between contact sensitization and disease severity, and between contact sensitization and disease duration. Hypothesis were based on the assumption that allergic contact dermatitis is rare in&nbsp; patients with psoriasis, as a chronic inflammation of the skin reduces its ability specific sensitization, as well as that the higher frequency of contact sensitization in females represent a result of exogenous factors, i.e. exposition, and finally that there is a positive correlation between the incidence of contact sensitization and the disease severity, and contact sensitization and the disease duration. The study included 176 patients. They were divided into two groups: the study group included patients with psoriasis, while the control group included patients referred for allergy testing, since they were suspected to allergic contact dermatitis. The severity of psoriasis was evaluated by PASI score. Thereafter,&nbsp; each patient underwent patch testing. The positive results of patch tests were evaluated with the aim to define their clinical relevancy. Subjects from the group of psoriatic patients passed scarification test carried out to indicate the presence or absence of K&ouml;ebner isomorphic phenomenon. This research led us to the conclusion that the positive reaction of psoriatic patients to at least one standard allergen did not indicate a statistically significant different reaction when compared to the reaction of patients suspected to allergic contact dermatitis. From the other side, the sensitivity expressed through the average number of positive&nbsp; tests per one&nbsp; tested&nbsp; patients was&nbsp; significantly lower in&nbsp; patients&nbsp; with psoriasis. Comparison of the contact response of men and women showed no significant differences in response with respect to&nbsp; their sex. The&nbsp; disease severity did not influence the frequency of contact sensitization in patients&nbsp; with&nbsp; psoriasis. At&nbsp; the same time, the frequency of contact sensitization stood in a positive correlation with the duration of disease. The lower rate of contact sensitization was found in patients with psoriasis who have had a&nbsp; positive K&ouml;ebner phenomenon at&nbsp; the time of testing.</p>

Upon encounter of an antigen, epidermis-resident Langerhans cells (LCs) become activated and present the processed antigen to T cells of the draining lymph nodes, resulting in tolerogenic or inflammatory responses. In psoriasis plaques, skin homeostasis is disrupted and replaced by an inflammatory dermatitis. Topical application of the anti-viral compound, imiquimod, induces a psoriasiform inflammatory condition, partly driven by LC production of pro-inflammatory cytokines. Differentiation of the myeloid progenitor cell line, MUTZ-3, produces MUTZ-3 derived Langerhans cells (MUTZ-LCs) which can be used as an in vitro model of LCs. This project aimed to investigate the phenotype and function of imiquimod-treated MUTZ-LCs in monolayer cultures, co-culture with T cells and inserted into a 3D skin model. LC-related surface markers (HLA-DR, CD1a, CD207, CCR7) were upregulated in MUTZ-LCs after 7 days of differentiation with 40 ng/ml GM-CSF, 10 ng/ml TGF-β and 2.5 ng/ml TNF-α. Supernatants of imiquimod-treated monolayer cultures of MUTZ-LCs showed subtle concentrations of IL-6 and TNF-α, but not IL-23. mRNA expression showed no significant upregulation of IL-6, IL-23 or TNF-α after 24 h treatment with imiquimod. The presence of MUTZ-LCs in T cell co-cultures greatly increased the production of IL-2, but did not affect expression of CD25. After 16 h exposure to imiquimod, IL-6, IL-23 and TNF-α could not be detected in culture supernatants of a 3D model consisting of fibroblasts, keratinocytes and MUTZ-LCs. The model was devoid of fibroblasts after 19 days of culture, most likely compromising the immunocompetence, as LC migration in response to activation could not be detected. Further studies could refine and optimize the imiquimod-3D skin model, which has potential as a possible substitute for animal models in psoriasis research.

No / In recent years, different genes and proteins have been highlighted as potential biomarkers for psoriasis, one of the most common inflammatory skin diseases worldwide. However, most of these markers are not only psoriasis-specific but also found in other inflammatory disorders. We performed an unsupervised cluster analysis of gene expression profiles in 150 psoriasis patients and other inflammatory skin diseases (atopic dermatitis, lichen planus, contact eczema, and healthy controls). We identified a cluster of IL-17/tumor necrosis factor-alpha (TNFalpha)-associated genes specifically expressed in psoriasis, among which IL-36gamma was the most outstanding marker. In subsequent immunohistological analyses, IL-36gamma was confirmed to be expressed in psoriasis lesions only. IL-36gamma peripheral blood serum levels were found to be closely associated with disease activity, and they decreased after anti-TNFalpha-treatment. Furthermore, IL-36gamma immunohistochemistry was found to be a helpful marker in the histological differential diagnosis between psoriasis and eczema in diagnostically challenging cases. These features highlight IL-36gamma as a valuable biomarker in psoriasis patients, both for diagnostic purposes and measurement of disease activity during the clinical course. Furthermore, IL-36gamma might also provide a future drug target, because of its potential amplifier role in TNFalpha- and IL-17 pathways in psoriatic skin inflammation. / Deutsche Forschungsgemeinschaft (DFG) to JW (WE-4428), the René Touraine Foundation (for AD), and the PTJ reference number 0306v12 as part of the Technology and Innovation Program (TIP) North-Rhine Westphalia (gene expression analyses)

Drug repositioning can save considerable time and resources and significantly speed up the drug development process. The increasing availability of drug action and disease-associated transcriptome data makes it an attractive source for repositioning studies. Here, we have developed a transcriptome-guided approach for drug/biologics repositioning based on multi-layer self-organizing maps (ml-SOM). It allows for analyzing multiple transcriptome datasets by segmenting them into layers of drug action- and disease-associated transcriptome data. A comparison of expression changes in clusters of functionally related genes across the layers identifies “drug target” spots in disease layers and evaluates the repositioning possibility of a drug. The repositioning potential for two approved biologics drugs (infliximab and brodalumab) confirmed the drugs’ action for approved diseases (ulcerative colitis and Crohn’s disease for infliximab and psoriasis for brodalumab). We showed the potential efficacy of infliximab for the treatment of sarcoidosis, but not chronic obstructive pulmonary disease (COPD). Brodalumab failed to affect dysregulated functional gene clusters in Crohn’s disease (CD) and systemic juvenile idiopathic arthritis (SJIA), clearly indicating that it may not be effective in the treatment of these diseases. In conclusion, ml-SOM offers a novel approach for transcriptome-guided drug repositioning that could be particularly useful for biologics drugs.