Le rôle primordial des cellules de la peau dans la réponse immunitaire est désormais bien établi. Cependant, pourraient-elles également être responsables de l'activation du système immunitaire observée dans le psoriasis, une maladie inflammatoire chronique de la peau? Cette étude vise à comprendre la capacité des kératinocytes psoriasiques à activer in vitro les leucocytes. Le profil de sécrétion de lymphocytes sains co-cultivés avec des kératinocytes (sains ou psoriasiques) a été évalué pour 22 analytes. Les taux élevés de diverses cytokines dans les cultures avec kératinocytes psoriasiques démontrent leur capacité à induire une sécrétion de médiateurs pro-inflammatoires. Les cytokines surexprimées suggèrent également un potentiel d'activation des neutrophiles. L'altération in vitro de plusieurs fonctions des neutrophiles (survie, adhérence cellulaire et production d'anion superoxyde) par les kératinocytes a permis de confirmer ce potentiel. En conclusion, cette étude présente le kératinocyte psoriasique comme étant un instigateur probable de l'inflammation dans la pathogenèse de cette maladie.

Inflammatory myeloid dendritic cells (DCs) are critical in the pathogenesis and maintenance of psoriasis vulgaris, a chronic inflammatory skin disease of unknown etiology. New ways to define these cells, and their precursors, may allow us to better understand their role in inflammation. Immunohistochemistry was performed on frozen tissue sections of normal and psoriasis biopsies to examine the dermal expression of potential markers of inflammatory DCs, namely CLEC9A, CD103, SlanDC, and TREM-1. The allostimulatory capacity of DC subsets (of SlanDC+ and CD1c+) was compared in a mixed leukocyte assay (MLR). Potential precursors of inflammatory DCs were FACS-sorted for transcriptomic profiling and functional assays. CLEC9A, CD103, and SlanDC did not prove useful in uniquely identifying myeloid dendritic cells in normal skin, and inflammatory dendritic cells in inflammation. TREM-1 was highly upregulated in psoriasis lesional skin as compared to non-lesional, and its activation may be critical in the maintenance of inflammation. Contrary to published findings, CD1c+ DCs possessed a higher allo-stimulatory capacity than SlanDCs, and induced greater IL-17 in T cells. TREM-1 may provide a novel therapeutic target for psoriasis treatment. The six circulating monocyte and dendritic cell populations in human peripheral blood were obtained via FACS sorting, and their genomic profiles will be examined. By comparing the genomic profiles of the six circulating monocyte and dendritic cell populations in human blood, and examining their allo- and autostimulatory capacities in a peptidoglycan (PGN) stimulated in vitro model of inflammation, the source of these inflammatory dendritic cells can be identified, and provide future targets of therapy for this psoriasis.

Tableau d’honneur de la Faculté des études supérieures et postdoctorales, 2010-2011 / La méthode d'auto-assemblage permet la production de substituts cutanés sans matériel exogène. L'objectif principal de notre travail a été de modifier cette méthode originale afin de produire un nouveau modèle de substituts cutanés pathologiques fabriqués à partir de cellules psoriasiques. Dans un premier temps, des substituts sains ont été cultivés en présence et en absence de sérum de veau foetal dans le but d'optimiser les conditions de culture. Puis, des analyses histologiques, immunohistochimiques, de perméabilité et des propriétés physico-chimiques ont été réalisées. Les résultats obtenus ont permis de conclure que le retrait du sérum à partir de la culture à l'interface air-liquide ne cause aucun problème majeur au niveau de la différenciation épidermique, de la jonction dermo-épidermique, du derme et de la perméabilité des substituts. De plus, des analyses par spectroscopic infrarouge à transformée de Fourier ont permis d'observer que le retrait du sérum améliore même l'organisation lipidique pour trois des cinq populations cellulaires testées. Parallèlement à cette étude, des substituts psoriasiques ont été produits à partir de cellules psoriasiques dans le but de vérifier si ces derniers allaient permettre la conservation de ce phénotype en culture. Des analyses histologiques et immunohistochimiques ont été effectuées et ont permis d'observer que le phénotype psoriasique (hyperprolifération et différenciation anormale des kératinocytes) est en partie conservé dans les substituts pathologiques. De plus, lors d'un traitement à l'acide rétinoïque, ceux-ci réagissent de façon similaire à ce qui est observé dans les peaux psoriasiques in vivo. Finalement, des substituts produits à partir de cellules non lésionnelles ont été reconstruits pour vérifier s'il existait une différence entre les cellules lésionnelles et non lésionnelles d'un même patient. Les résultats ont permis d'observer que les cellules non lésionnelles ne sont pas totalement «normales» et qu'elles conservent en partie les caractéristiques du psoriasis. En conclusion, ce nouveau modèle de substituts cutanés pathologiques pourrait devenir un puissant outil dermopharmaceutique permettant de tester de nouveaux traitements pour vaincre le psoriasis.

No description available.

No description available.

Although early studies on HCR provided valuable information for its characterization, the functions of HCR remain unclear. / In addition, we also isolated HCR partners in keratinocyte using a yeast two-hybrid screening. Two novel HCR partners, keratin 17 and nm23-H2, were identified. Since the expression of keratin 17 in epidermis has been recognized as a hallmark of psoriatic plaques, our findings support HCR as a candidate gene for psoriasis susceptibility. We speculate that nm23-H2 is involved in endocytosis together with HCR because nm23 also participated in endocytotic pathways. / In this study, we attempted to relate the function of HCR gene to its role in the pathogenesis of psoriasis. We first examined the subcellular localization of HCR. From a series of co-localization experiments, we eventually localized HCR in early endosomes because almost completely overlapped with active Rab4 which regulates vesicle traffic from early endosomes to perinuclear recycling endosomes and to the plasma membrane indicating that HCR may regulate sorting of internalized cargo from early endosomes to the recycling endosomes or back to the cytoplasm. / Psoriasis is a common chronic skin disorder affecting approximately 1-2% of the Caucasian population. A genetic basis for psoriasis susceptibility has been determined, however, the genetic influence of psoriasis is complex. Several genetic linkage studies have been identified. PSORS1 at 6p21.3 which has been narrowed down to a few hundred kilobase intervals around the HLA-C is the most consistently observed susceptibility locus for psoriasis in both linkage analyses and genome wide scans. HCR is a candidate gene lying within the HLA region which was previously named PG8 for 'putative gene 8' and is now more commonly called HCR for 'alpha-helix coiled-coil rod homolog'. The HCR gene is highly polymorphic. SNP association analysis showed that one SNP haplotype, named HCR*WWCC (corresponding to SNPs at nucleotides 307, 325, 1723, 2327, and involving amino acids 103, 109, 575 and 776, respectively), was associated with psoriasis. Early studies showed that the protein was confined to basal keratinocytes in healthy and non-lesional skin, whereas, it was expressed above the tips of basal and suprabasal dermal papillae in psoriatic lesional skin. / Li, Chunman. / "November 2005." / Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0810. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (leaves 137-149). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese. / School code: 1307.

Le PAF (Platelet-Activating Factor) est un médiateur reconnu pour son implication dans plusieurs effets physiologiques et pathologiques, particulièrement les états inflammatoires. À l'instar du PAF, les lymphocytes T Th17 sont aussi reconnus comme exerçant un rôle majeur dans la physiopathologie des maladies auto-immunes. L'objectif de ce projet est de déterminer s'il existe un lien entre ces deux composants. En fait, nous avons émis l'hypothèse que le PAF pourrait provoquer une production de cytokines spécifiques par les cellules présentatrices d'antigène qui elles, interagissant avec les lymphocytes T, pourraient mener ultimement à une différentiation en Th17. En effet, les cellules T ne peuvent interagir directement avec le PAF puisqu'elles n'expriment pas de récepteur pour celui-ci à leur surface. Les cellules T Th17 expriment un facteur de transcription spécifique RORr, nécessitent absolument la sous-unité IL-23p19 pour leur expansion et produisent IL-17. Nous avons donc, dans un premier temps, regardé la capacité d'un type de cellules présentatrices d'antigène, les cellules de Langerhans à produire IL-23p19 en réponse au PAF. Ensuite, nous avons mis en contact ces cellules de Langerhans pré-stimulées au PAF avec des lymphocytes T activés pendant 5 jours pour vérifier l'expression de RORII et la production d'IL-17 dans ces lymphocytes T, plus précisément les lymphocytes T CD4 + . Cette étude nous a permis de mettre en évidence que certains éléments impliqués dans les processus inflammatoires sont possiblement inséparables et interagissent probablement les uns avec les autres pour mener aux séquelles multiples de l'inflammation.

Introduktion: Psoriasis är en hudsjukdom som drabbar en till fyra procent av världens befolkning. Symptomen av psoriasis visar sig på huden vilket är ett stort och synligt organ hos människan. En frisk och välmående hud är viktigt för människans fysiska- och psykiska välmående. Syfte: Att beskriva människors upplevelser av att leva med psoriasis. Metod: Litteraturstudien genomfördes enligt Graneheim och Lundmans metod för kvalitativ innehållsanalys med manifest ansats. Resultat: Litteraturstudien visade att människor med psoriasis kan ha upplevelser av att bli sedd och behandlad som annorlunda och upplevelser av att känna sig hindrad av en förändrad kropp. Resultatet visade även att det fanns känslor av att inte få den hjälp och det stöd som behövs samt att en personlig livssyn kan användas för att finna kraft i vardagen. Slutsats: Ökad kunskap om vad det finns för upplevelser hos personer som lever med psoriasis kan ge vårdpersonal större förståelse för de behov som individerna uttrycker. Att lyssna till dessa individers uttryckta behov och vara uppmärksam på behov av stöttning både fysiskt och psykiskt skulle bidra till en bättre omvårdnad här hela människan tas i beaktande. Att ta vara på varje individs egna resurser och förmågor skulle kunna användas som medel för stöttning till att finna kraft i vardagen.

Background: The p63 gene is a member of the p53 transcription factor family and can produce six different proteins using two promoters and differential splicing. Expression of p63 is required for proper formation of epithelial tissues. Studies on the transcriptional control of specific genes involved in cell survival, proliferation, differentiation and adhesion have revealed the contributions of p63 to the continuously renewing stratified epithelium. In this thesis, the aim was to improve our understanding of the roles of p63 in epithelial homeostasis by investigating expression of p63 in normal and benign hyper-proliferative epithelia and exploring the influence of p63 deregulation on cancer progression. Materials and methods: Using quantitative real time RT-PCR and immunohistochemistry, we first examined the expression of different p63 isoforms in patients diagnosed with psoriasis - a benign hyper-proliferative and inflammatory skin disease. Afterwards, we investigated responses of p63 in psoriatic epidermis upon Narrowband-UVB (NB-UVB) phototherapy. At the same time, we studied the potential impact of p63 in carcinogenesis by searching for p63 transcriptional targets in a cell line derived from squamous cell carcinoma of the head and neck (SCCHN) - the sixth most common cancer worldwide with over-expression of the ∆Np63α protein as a common feature. p63 gene silencing and microarray were used to identify p63 regulated genes. Real time RT-PCR, western blot, immunohistochemistry, chromatin immunoprecipitation, transient transfection and reporter assays were performed to confirm specific genes as direct p63 targets. Results: Significant down-regulation of p63 mRNA levels was found in psoriatic lesions compared to patients’ own clinically normal skin. Moreover, a trend of decreased TAp63 mRNA levels was seen in patients’ normal skin compared to age- and sex-matched healthy controls. Following NB-UVB phototherapy, an effective first line therapy for psoriasis, expression of p63 was not significantly affected. However, significant changes in p53, FABP5, miR-21 and miR-125b were found. Surprisingly, location and expression levels of p63 proteins detected by immunohistochemistry were similar under all skin conditions. A direct transcriptional regulation of TRAF4 by p63 was seen in the SCCHN cell line and we further found that the localization of the TRAF4 protein was associated with histological differentiation of SCCHN cells. However, unlike its over-expression in SCCHN, similar TRAF4 mRNA expression levels were seen in psoriatic lesions as compared to healthy controls. Besides TRAF4, a total of 127 genes were identified as potentially p63 regulated in the SCCHN cell line and strikingly, about 20% of these genes are involved in cell adhesion or migration. Conclusions: Dysregulation of p63 isoforms in psoriatic epidermis, especially decreased TAp63 expression, and their resistance to NB-UVB phototherapy implicated a contribution of p63 to the psoriasis phenotype. Transcriptional regulation of genes involved in multiple biological pathways indicated that over-expression of p63 in SCCHN might account for altered cell differentiation, adhesion and migration, thus contributing to SCCHN. In conclusion, our studies have found additional mechanisms through which p63 guarded homeostasis of the established epithelium. Deregulation of p63 might play a role in distinct pathological conditions by participating in diverse cellular pathways under different microenvironments.

La psoriasis es una enfermedad cutánea crónica que ha sido relacionada con el síndrome metabólico. El objetivo de este trabajo fue evaluar en pacientes con psoriasis la presencia de alteraciones en parámetros antropométricos y marcadores séricos relacionados con el síndrome metabólico, y su modificación tras un tratamiento con ultravioleta B de banda estrecha. Comparamos a 50 pacientes con psoriasis con 50 controles emparejados por sus características antropométricas (edad, sexo e índice de masa corporal) en un estudio transversal. Posteriormente, evaluamos los parámetros en estudio en los pacientes antes y después de una pauta de UVB de banda estrecha (UVB-BE). Los pacientes fueron reclutados en el Servicio de Dermatología del Hospital Parc Taulí de forma prospectiva excluyendo los meses de mayor irradiancia solar. Los controles fueron emparejados con cada paciente según sus características. Se excluyeron los pacientes con artritis psoriásica y los pacientes y controles con una lista de enfermedades inflamatorias crónicas. La evaluación consistió en un panel de determinaciones antropométricas y analíticas que se obtuvo al inicio de la inclusión y en los pacientes una vez completado el tratamiento. Estas determinaciones incluyeron un perfil glucémico, lipídico, inflamatorio, del metabolismo fosfocálcico, y de un conjunto de adipocitoquinas. La población mostró una media de sobrepeso. En igualdad de índice de masa corporal, los pacientes con psoriasis presentaron una mayor contenido de grasa corporal medido mediante bioimpedancia, que se correlacionó con la circunferencia de la cintura, y concentraciones séricas más elevadas de colesterol LDL, leptina, lipocalina-2, proteína ligadora de retinoides-4, receptor soluble del TNF, y apo-B. La vitamina D fue baja (<20 ng/ml) tanto en los pacientes como en los controles, y en los pacientes aumentó al final del tratamiento, sin que hubiera correlación entre dicho aumento y la mejoría del PASI. El PASI al inicio mostró una correlación con las concentraciones basales de las lipocalinas RBP-4 y lipocalina-2, así como con la PCR de alta sensibilidad. Al final del tratamiento con fototerapia, los pacientes experimentaron un descenso de la IL-6 y la ferritina en correlación con la dosis total acumulada de UVB-BE. El análisis de componentes principales permitió evidenciar un componente protector del desarrollo de síndrome metabólico en los controles sin psoriasis, que no estaba presente en los pacientes. Los pacientes presentaron frente a los controles un posicionamiento diferente en el mapa de componentes principales de la omentina, la lipocalina-2, la resistina y la RBP-4. En conclusión, identificamos en los pacientes con psoriasis sin artropatía un perfil metabólico y antropométrico distinto al de los controles. La insuficiencia de vitamina D fue habitual en ambos, y el aumento de síntesis de la misma con la fototerapia no mostró correlación con la mejoría del PASI. Nuestros resultados contribuyen a clarificar la función de ciertas adipocitoquinas en la génesis de las alteraciones inflamatorias y metabólicas presentes en la psoriasis. / Psoriasis is a chronic cutaneous disease that has been linked with metabolic syndrome. The present study aimed to evaluate the presence of alterations in anthropometric and serum parameters related to metabolic syndrome in psoriatic patients, along with their changes after treatment with narrow-band UVB. Fifty psoriatic patients were compared with 50 gender, age and body mass index-matched controls in a cross-sectional study. Additionally we evaluated the study parameters in the patients before and after a course of narrow-band UVB phototherapy. Patients were prospectively recruited in the Department of Dermatology of Hospital Parc Taulí excluding the months of high solar irradiance. Controls were matched with patients according to their characteristics. Patients with psoriatic arthritis and patients and controls with a list of inflammatory diseases were excluded. The evaluation consisted of a panel of anthropometric and laboratory determinations, that were obtained at the moment of inclusion, and in the patients after completion of phototherapy. These determinations included a glycaemic, inflammatory and lipid profile, vitamins and adipocytokines. The study population showed overweight. With a comparable body mass index, psoriatic patients had a higher fat content as determined by electric bioimpedance, which was correlated with waist circumference. They also had higher serum concentrations of LDL-cholesterol, apo-B, leptin, lipocalin-2, retinoid binding protein-4 (RBP-4), and soluble receptor of TNF. Vitamin D levels were low (<20 ng/ml) in patients and controls, and it markedly increased after phototherapy in patients, without correlation with PASI (Psoriasis Area and Severity Index) improvement. Initial PASI correlated with basal high sensitivity C-reactive protein, lipocalin-2 and RBP-4. At the completion of phototherapy, the patients showed a decrease in their IL-6 and ferritin levels, in correlation with total cumulative UVB dose. In healthy controls, principal components analysis yielded a protective component against metabolic syndrome, which was not present in the patients. Patients showed a different positioning of omentin, lipocalin-2, resistin and RBP-4 in principal components’ map when compared to healthy controls. In conclusion, we identified in psoriatic patients without arthrtitis a different metabolic and anthropometric profile when compared to healthy gender, age and body mass index-matched controls. Vitamin D insufficiency was common in both study groups, and increase in its synthesis after phototherapy did not correlate with psoriasis improvement. Our results add new data that clarify the role of certain adipocytokines in the genesis of inflammatory and metabolic disturbances in psoriatic disease.