Mechanisms Of Psoriasis Research Articles

Psoriasis and neurodermatitis: comparing psychopathology, quality of life and coping mechanisms

Background: Both psoriasis and neurodermatitis patients report psychological distress and impaired quality of life, but how they cope with it is area of interest. The objective of this study was to study and compare psychopathology, quality of life and coping mechanism in psoriasis and neurodermatitis patients.Methods: 30 cases each of psoriasis and neurodermatitis were assessed at dermatology out-patient department of a tertiary care hospital by using Symptom check list -90-Revised (SCL-90-R), dermatological life quality index (DLQI) and Brief cope scale (BCS).Results: All Patients with neurodermatitis perceived it as a problem and in psoriasis it was 90%.The quality of life (QOL) was affected in both more in neurodermatitis as compared with psoriasis. Neurodermatitis showed significant psychopathology on SCL-90-Rin parameters of interpersonal sensitivity and Psychoticism. Depression, Anxiety, Somatisation, Obsessive-compulsiveness were seen in both groups. Self-blame, religion, positive-reframing were used commonly as coping mechanisms in neurodermatitis while in psoriasis there was acceptance, active coping, planning, and self-distraction, use of emotional and instrumental support, positive-reframing.Conclusions: Quality of life is significantly lower in neurodermatitis. Psychopathologies were significantly high in neurodermatitis. Maladaptive coping styles were used in both groups.

Expression of pro-angiogenic genes in mesenchymal stem cells derived from dermis of patients with psoriasis.

Recent experimental studies revealed that angiogenesis and lymphangiogenesis are closely related to psoriasis. Our microarray analysis suggested that the pro-angiogenic genes platelet endothelial cell adhesion molecule-1 (PECAM1), facio-genital dysplasia-5 (FGD5), prostaglandin-endoperoxide synthase-1 (PTGS1), melanoma cell adhesion molecule (MCAM), vasohibin-2 (VASH2), and stabilin-1 (STAB1) are differentially expressed in dermal mesenchymal stem cells in psoriasis. The aim of this study was to investigate the mRNA and protein expression of PECAM1, FGD5, PTGS1, MCAM, VASH2, and STAB1 for angiogenesis and the possible mechanisms in psoriasis. We studied 12 patients with plaque psoriasis and 14 healthy controls matched for age and sex. Dermal mesenchymal stem cells were expanded, passaged, and identified by cellular morphology, immunophenotyping, and multipotential differentiation. The mRNA and protein expression of the above-mentioned six genes were confirmed by quantitative real-time reverse transcription-polymerase chain reaction and Western blotting. The significantly decreased expression of PECAM1, PTGS1, FGD5, and MCAM at both mRNA and protein level (except VASH2 and STAB1) were demonstrated in mesenchymal stem cells from psoriatic skin lesions compared with non-lesional from healthy controls. We provide the first report that pro-angiogenic genes PECAM1, PTGS1, FGD5, and MCAM rather than VASH2 and STAB1 may be play a vital role in pathological dermal angiogenesis disorders of psoriasis. Therefore, anti-angiogenesis is attractive and offers future potential for application in patients with psoriasis.

Update on psoriasis immunopathogenesis and targeted immunotherapy.

Over recent years, significant progress has been made in characterisation of the underlying pathogenic mechanisms in psoriasis, a common cutaneous disease that is associated with major systemic co-morbidity and reduced life expectancy. Basic science discoveries have informed the design of novel therapeutic approaches, many of which are now under evaluation in late-stage clinical trials. Here we describe the complex interplay between immune cell types and cytokine networks that acts within self-perpetuating feedback loops to drive cutaneous inflammation in psoriasis. Genetic studies have been pivotal in the construction of the disease model and more recently have uncovered a distinct aetiology for rare, pustular variants of psoriasis. The translation of mechanistic insights into potential advancements in clinical care will also be described, including several treatments that target the interleukin-23 (IL-23)/T17 immune axis.

Levels of autophagy in psoriatic keratinocytes and its pathological role

Autophagy is a general phenomenon in eukaryotic cells, and it has turned out that dysregulated autophagy contributes to the development of many diseases. Researches have indicated that down-regulation of autophagy is closely related to abnormal cell proliferation, differentiation and inflammation. It has been found that abnormal cell proliferation, differentiation and immune regulation exist in skin lesions of psoriasis. These findings suggest a link between the pathogenesis of psoriasis and dysregulated autophagy in keratinocytes, and recent studies have shown that abnormal keratinocyte autophagy may be involved in the pathological mechanism in psoriasis. This review presents recent advances in studies on the relationship of autophagy with cell proliferation, differentiation and inflammation, pathological state of psoriatic keratinocytes, autophagy in normal keratinocytes and psoriatic keratinocytes. Key words: Psoriasis; Autophagy; Keratinocytes; Pathology

Expression of apoptosis regulating proteins p53 and bcl-2 in psoriasis.

Dysfunctional apoptosis has an important role in the development of several skin diseases. Psoriatic keratinocytes possess an enhanced ability to resist apoptosis, which might be one of the key pathogenetic mechanisms in psoriasis. P53 and bcl-2 are two proteins which control apoptosis. Several studies have evaluated the expression of these two proteins in the psoriatic skin, but the results are controversial. Fifty-eight cases of psoriatic skin biopsies were studied, and the grade of p53 and bcl-2 immunostaining was correlated with the histopathological indices of severity. Bcl-2 expression in the epidermis strongly correlated with the expression in the basal cells and lymphocytes (P--0.001 and 0.035). There was no correlation with epidermal hyperplasia or with p53 expression in the three compartments. Bcl-2 expression in the basal layer correlated with the p53 expression in the epidermis (P--0.027), basal layer (P--0.015) and the lymphocytes (P--0.034). There was a strong correlation among the p53 expression in all the compartments. There was also a weak correlation of the p53 expression in the epidermis with the epidermal hyperplasia (P--0.042). Bcl-2 does not appear to play an important role in the apoptotic process in psoriasis. In contrast, it is likely that p53 has a far more important role to play. Mutation analysis of the p53 protein is necessary to evaluate if the protein has mutated or if it is of the wild type.

Five regulatory genes detected by matching signatures of eQTL and GWAS in psoriasis

BackgroundPsoriasis is a common immune-mediated inflammatory skin disease with strong genetic dispositions. Although more than 40 susceptibility loci have been revealed mostly through psoriasis genome wide association studies, genetic variants with small effect remain to be identified. ObjectiveIn order to explore the susceptibility genes with potential regulatory function, we queried jointly two psoriasis genome wide association cohorts and an expression dataset. MethodsWe integrated conventional genome-wide association evidences in 2326 Han Chinese and 2719 Caucasian populations, and the signature of expression quantitative trait loci (eQTL) in lymphoblastoid B cells, with application of Bayesian algorithm. ResultsFive genes with implied regulatory effect were revealed to be associated significantly with the risk of psoriasis, with one novel signal in FAM20B gene which is significantly expressed (P=3.24×10−5). Besides, seven single nucleotide polymorphisms were identified to be involved in the mechanism of psoriasis through eQTL effect. ConclusionsWe identified FAM20B as a risk regulatory gene in the etiology of psoriasis at first time. This study shed a spotlight on the immune regulatory mechanism in psoriasis.

Four Polymorphisms ofVEGF(+405C>G, −460T>C, −2578C>A, and −1154G>A) in Susceptibility to Psoriasis: A Meta-Analysis

The contribution of genetic polymorphisms in the vascular endothelial growth factor (VEGF) gene to psoriasis risk is a controversial topic. The aim of this meta-analysis was to investigate large-scale evidence to determine the degree to which four common VEGF polymorphisms (+405C>G [dbSNP: rs2010963], -460T>C [dbSNP: rs833061], -2578C>A [dbSNP: rs699947], and -1154G>A [dbSNP: rs1570360]) are associated with susceptibility to psoriasis. A literature search of PubMed, Embase, Web of Science, Chinese National Knowledge Infrastructure, and Chinese Biomedical Literature Database was conducted to identify all eligible studies published before September 15, 2013. The principal outcome measure for evaluating the strength of the association was crude odds ratios (ORs) along with their corresponding 95% confidence intervals (95% CIs). Two thousand five hundred thirty-one patients and 2670 controls from nine case-control studies detailing a possible association between the VEGF genotypes and psoriasis risk were selected. Our meta-analysis provides evidence that two independent alleles +405G and -460C may be a protective factor for psoriasis in Asians, whereas the -1154A allele had a slight but statistically significant preventive effect on the development of psoriasis in Caucasians. The -2578C>A polymorphism, however, did not correlate with any significant difference between patients and healthy controls, even when the groups were stratified by ethnicity. Results from the meta-analysis do support the hypothesis that single-nucleotide polymorphism markers at +405C>G, -460C>T, and -1154G>A of the VEGF gene may serve as biological markers of psoriasis. Future studies should investigate interactions among multiple genotypes and environmental exposures to identify the role of proangiogenic markers in psoriasis and to delineate the underlying mechanisms of psoriasis.

Epigenetic mechanisms in psoriasis

Psoriasis is a chronic,recurrent inflammatory skin disorder with complex pathogenesis,in which inheritance may play a most important role.Recently,a series of studies have demonstrated that epigenetic mechanisms are involved in the pathogenesis of psoriasis.Epigenetics refers to stable and inheritable changes in gene expression without any changes in DNA sequence,and its mechanisms include DNA methylation,histone modification and regulation by noncoding RNA such as RNA interference.Understanding the epigenetic mechanisms in psoriasis is of great importance for the clarification of pathogenesis and for the development of effective therapeutic modality.The authors summarize recent findings in epigenetic mechanisms in psoriasis,in the hope of providing clues and directions for future research in this field. Key words: Psoriasis ; Epigenesis, genetic ; Methylation

Molecular mechanisms in psoriasis: historical perspective and current pathogenesis

Molecular mechanisms in psoriasis: historical perspective and current pathogenesis

A Pathogenetic Approach to Autoimmune Skin Disease Therapy: Psoriasis and Biological Drugs, Unresolved Issues, and Future Directions

Psoriasis is a chronic inflammatory disease with a complex pathophysiology and a multigenic background. Autoimmunity and genetic hallmarks couple to confer the disease, which is characterized by chronic plaques (85-90% of all cases) and/or psoriasis arthritis (PsA), and involve the peripheral and sacro-iliac joints, nails, and skeleton. Dissecting the ethiopathogenetic mechanisms of psoriasis and PsA is a major basic research challenge. One important question is whether a single inflammatory mediator can be responsible for the interactive network that forms between immune cells and cytokines in this disease. Despite much progress, no research has yet been able to define a single model to explain the multifaceted pathogenesis of psoriasis and PsA. It is known that both the innate and adaptive immune systems are involved, antigen presenting cells and T lymphocytes play a prominent role, and that the deregulation of the T helper (Th)- 1/Th-2/Th-17/Th-23 axis is directly implicated in disease pathogenesis. Pharmacological therapy for psoriasis has evolved with the development of human knowledge of the disease pathophysiology. Thus, the first "ethiopathogenetic" drugs (e.g., methotrexate, cyclosporin, and alefacept) inhibited T-cell activation directly or targeted co-accessory molecules implicated in T-cell activation. When the mechanism underlying psoriatic inflammation was accepted as a cytokine network disorder, more specific biologics were studied in murine models and were later used clinically. Tumor necrosis factor was the first successful target of cytokine inhibition therapy for psoriasis and PsA (e.g., infliximab, adalimumab, and etanercept). With the recently discovered role for Th-17 in autoimmunity, drugs targeting interleukin-23 (ustekinumab) have become accepted for the pharmacological treatment of psoriasis. The expansion of pharmacological treatment options for psoriasis is not complete. As the knowledge of pathogenetic mechanisms increases, it may be possible to design therapeutic approaches that selectively target the ethiopathogenetic cells or cytokines while sparing the others. In this way, using a more targeted drug therapy may preserve the integrity of the immune system. Thus, one great struggle in treating this complex disease is the challenge to synthesize the "perfect" drug.

Serum Levels of IL-17 and IL-22 Are Reduced by Etanercept, but not by Acitretin, in Patients with Psoriasis: a Randomized-Controlled Trial

There are no controlled trials comparing etanercept and acitretin efficacy and therapeutic mechanisms in psoriasis. In the present study, 30 patients were given etanercept 50 mg twice weekly and 30 patients acitretin 0.4 mg/kg per day, both for 12 weeks. Before and after treatment, psoriasis area and severity index was calculated, and serum levels of interleukin (IL)-17, IL-22, and IL-23 were investigated. After treatment, psoriasis area and severity index was significantly lower for both groups. However, etanercept-treated patients showed lower psoriasis area and severity index than acitretin-treated ones. Psoriasis patients showed higher IL-17 and IL-22 levels than controls, while no IL-23 was found in any serum. Furthermore, a correlation between IL-17 levels and psoriasis severity was found. Only etanercept was able to reduce IL-17 and IL-22 levels. Our findings suggest that etanercept is more effective than acitretin in the treatment of psoriasis and that it is able to affect Th17 system.

Targeting the IL-12/IL-23 cytokine family in the treatment of psoriatic disease

Both IL-12 and IL-23 have important roles in psoriasis, a complex Th1- and Th17-mediated auto-immune disease. Although they share the subunit p40, they have different immunologic profiles. Targeting these two cytokines, particularly the common subunit, has been studied recently in the treatment of this sometimes severe disease. This article reviews mechanisms of psoriasis and some studies supporting the substantial efficacy, as well as safety, of this new class of drugs, including Phase I, II and III trials.

Under‐expression of VHL and over‐expression of HDAC‐1, HIF‐1α, LL‐37, and IAP‐2 in affected skin biopsies of patients with psoriasis

A feature of psoriasis is the rapid proliferation of keratinocytes, during which apoptosis is blocked and angiogenesis starts. It is known that tumor hypoxic cells produce histone deacetylase-1 (HDAC-1), which up-regulates hypoxia-inducible factor-1alpha (HIF-1alpha) and down-regulates von Hippel-Lindau (VHL) protein by up-regulating vascular endothelial growth factor (VEGF) expression. It has been reported recently that the porcine peptide PR39 (homologous to human LL-37) has angiogenic and antiapoptotic activity. Thus, LL-37, induced by insulin-like growth factor-1 (IGF-1), could help in the production of VEGF. PR39 also induces the expression of inhibitor of apoptosis protein-2 (IAP-2), which blocks apoptosis. The purpose of this work was to analyze whether these genes and their proteins are expressed in psoriatic biopsies. Using semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) messenger RNA (mRNA) expression and immunohistochemical staining, we studied VHL, IAP-2, and related genes in skin biopsies from psoriatic patients and healthy subjects. An over-expression of the mRNA for HDAC-1, HIF-1alpha, LL-37, and IGF-1 in psoriatic skin, in comparison with skin from healthy subjects, was found. The antiangiogenic VHL mRNA and protein were under-expressed in psoriatic skin and highly expressed in healthy skin. The antiapoptotic IAP-2 was over-expressed in dermal endothelial cells from psoriatic skin. The pro-apoptotic Bax, Fas, and FasL mRNAs were expressed. These findings suggest that there could be an association of HDAC-1, HIF-1alpha, LL-37, VHL, and IAP-2 with angiogenic and apoptotic mechanisms in psoriasis.

Latest developments in the mechanisms of psoriasis and pemphigus

Latest developments in the mechanisms of psoriasis and pemphigus

Inverse Regulation of the Nuclear Factor-κB Binding to the p53 and Interleukin-8 κB Response Elements in Lesional Psoriatic Skin

Nuclear factor-kappaB (NF-kappaB) is an inducible nuclear transcription factor regulating a range of cellular processes. An imbalance of the DNA binding activity of NF-kappaB may, therefore, be part of the pathophysiological mechanisms in psoriasis. The purpose of this study was to determine the NF-kappaB DNA binding activity in psoriatic skin using three different kappaB sites and to determine how DNA binding activity was modulated by the anti-psoriatic drug calcipotriol. By electrophoretic mobility shift assay, we demonstrated that the NF-kappaB DNA binding to the p53 kappaB site was decreased, whereas the NF-kappaB DNA binding to the interleukin-8 (IL-8) kappaB site was increased in lesional psoriatic skin compared with non-lesional psoriatic skin. No regulation was seen on the NF-kappaB DNA binding to the major histocompatibility complex class I kappaB site. These changes were paralleled by a similar decrease in p53 expression and an increase in IL-8 expression in involved psoriatic skin compared with uninvolved skin as determined by quantitative RT-PCR. The alteration in NF-kappaB DNA binding activity was neither accompanied by any change in the expression of the inhibitor kappaB (IkappaB) kinases, IKKalpha, IKKbeta, and IKKgamma nor in the expression of the NF-kappaB inhibitor proteins, IkappaBalpha and IkappaBbeta. Immunofluorescence analysis revealed that p65 was sequestered in the cytoplasm of keratinocytes, whereas p50 exhibited a cytoplasmic as well as a nuclear localization. Interestingly, this distribution of p50 and p65 was similar in lesional and non-lesional psoriatic skin. Topical application of calcipotriol to lesional psoriatic skin for 4 d resulted in increased NF-kappaB binding to the p53 kappaB site and decreased NF-kappaB binding to the IL-8 kappaB site. Taken together, our data demonstrate that the NF-kappaB DNA binding activity is regulated in a specific manner in psoriatic skin depending on the kappaB sites investigated, and that topical treatment of psoriatic skin normalizes the abnormal NF-kappaB binding activity seen in lesional psoriatic skin.

Common clinical features and disease mechanisms of psoriasis and psoriatic arthritis.

Psoriasis and psoriatic arthritis are chronic inflammatory diseases that significantly affect patients' quality of life. Not only do these diseases impact patients' physical well-being, but also detrimentally affect their life socially and psychologically. There are many different patterns of skin and joint involvement. Understanding the pathogenesis of these diseases has evolved greatly in the past few decades. It is now understood that psoriasis and psoriatic arthritis are T cell mediated disorders. A number of proinflammatory cytokines have been suggested as playing a role in the disease mechanism, such as tumor necrosis factor-alpha and interferon-gamma. Other important factors proposed in the pathogenesis of these diseases include the role of genetics and environmental factors. New immunomodulating therapies, which are being developed as our understanding of the involvement of innate and adaptive immunity advances, will provide patients with safer, more effective, long-term, management options.

Immunopathogenic mechanisms in psoriasis.

Psoriasis is a common autoimmune skin disease characterized by T cell-mediated hyperproliferation of keratinocytes. The disease has a strong but complex genetic background with a concordance of approximately 60% in monozygotic twins, and recent linkage and high resolution association studies indicate that HLA-Cw*0602 is itself a major susceptibility allele for psoriasis. Patients carrying this allele have been shown to have different clinical features and earlier age of disease onset, and patients homozygous for this allele have about 2.5 times higher disease risk than heterozygotes. Published data indicate that CD8+ T cells may play a major effector role in psoriasis. Epidermal infiltration of predominantly oligoclonal CD8+ T cells, and probably also of CD4+ T cells in the dermis, is a striking feature of chronic psoriasis lesions, indicating that these cells are responding to specific antigens. We argue that CD4+ T cells are essential for initiating and maintaining the pathogenic process of psoriasis but that cross-primed CD8+ T cells are the main effector cells responding to antigens in the HLA-Cw*0602 binding pocket of keratinocytes. It is further proposed that CD8+ T cells are involved in the control of the Th1 polarization, which is observed in psoriasis lesions, through a complex interplay between CD4+, CD8+ T cells and cross-presenting dendritic cells. It is also suggested that spontaneous remissions or fluctuations in disease activity may be determined by a balance within the lesions between effector and suppressor CD4+ and CD8+ T cells.

Alteration and Significance of Heparin-Binding Epidermal-Growth-Factor-Like Growth Factor in Psoriatic Epidermis

Background: Heparin-binding epidermal-growth-factor-like growth factor (HB-EGF) has proved to be a mitogen of keratinocytes, which may be involved in the pathogenesis of inflammatory diseases, but its mechanism in psoriasis remains unknown. Objective: To investigate the alteration of HB-EGF in the epidermis of active psoriasis vulgaris. Methods: The expression of HB-EGF in normal skin tissues, uninvolved tissues and psoriatic lesions was detected by in situ hybridization and immunohistochemistry. Results: HB-EGF mRNA and protein were located in the basal layer of normal epidermis (10/10, 100.00%), with nearly no expression in the suprabasal layers (1/10, 10.00%); the expression of HB-EGF was located not only in the basal layer (21/21, 100.00%), but was also seen as focal overexpression in the suprabasal layers of uninvolved epidermis (20/21, 95.24%) and the marginal part of psoriatic lesions (18/21, 85.71%), while nearly no expression of HB-EGF was found in the central part of psoriatic lesions (1/21, 4.76%). Conclusion: HB-EGF may play an important role in the early pathogenesis of psoriasis.

Trends and developments in the pharmacological treatment of psoriasis.

In the history of psoriasis pharmacotherapy , the milestone developments have largely occurred by chance. Serendipitous observations in single patients have led to the discovery of such important treatments as methotrexate (1), deltanoids (active form of vitamin D and its analogues) (2), cyclosporin (3) and, most recently, tumour necrosis factor alpha (TNF-a) inhibitors (4). While these observations have been of therapeutic importance, they have also had a major impact on current views on the pathogenesis of this skin disease. From the initial model, where the hyperproliferation of epidermal keratinocytes was considered to be a central event, the current understanding places the immune system at the hub of the pathogenic series of events. Vigorous research and constantly increasing insight into the mechanisms of psoriasis have led to the identi® cation of a number of potential targets for therapeutic intervention. For the ® rst time, the rational, mechanism-based development of new anti-psoriatic therapeutic has become a reality. The purpose of this article is to present a systematic review of emerging drug therapies for psoriasis that, although in the early stage of development today, may enter the clinical practice of tomorrow. The current, established treatments are not mentioned; readers are referred to recently published excellent reviews on this subject (5 ± 8). The compounds included in this review have been selected from a screening of the Medline records; where references are not cited the information has been obtained from IDdb (Investigationa l Drugs Database, Current Drugs Ltd., http://www.iddb3.com/) and PharmaProjects (PJP Publications Ltd.# 2002, http://www.pharmaprojects.co.uk). IMMUNOSUPPRESSIVE AND ANTIINFLAMMATORY DRUGS The autoimmune cutaneous reaction is believed to play a causative role in the development of skin lesions in psoriasis (9). Most of the compounds under current development for psoriasis belong to different classes of immunosuppressives and anti-in ammatory drugs. The central cell in the current pathogenic model is the memory (CD45RO ) T-lymphocyte mediating the type 1 immune response. A type 1 immune response is mediated by TH1 and TC1 lymphocytes secreting a speci® c cytokine pro® le (IFN-g, TNF-a, IL-12). The recently reviewed immunopathogenesis of psoriasis (9, 10) will be mentioned only to the extent necessary for an understanding of the mechanism of action of the drugs included here. The memory T-lymphocytes secrete three major cytokines, IL-2, TNF-a and IFN-g. IL-2 acts at the early stages of T-cell activation and clone expansion, while TNF-a and IFN-g have a twofold role: to drive and stabilize the type I immune reaction (11) and by direct action on keratinocytes to stimulate their growth leading to epidermal hyperproliferation (12). The latter aspect is believed to be an aberrant regenerative response of the epidermal stem cells (12, 13).

Disease mechanisms in psoriasis and psoriatic arthritis.

Any hypothesis that tries to explain disease mechanisms in psoriasis and psoriatic arthritis (PsA) must take into account the containment of the inflammatory process to three specific sites: the skin, synovium, and enthesis. This article reviews the recent literature that advances our understanding of disease mechanisms at these specific sites. Additional progress will be achieved by research that focuses on common pathogenic pathways at these sites, in particular when searching for foreign candidates or auto-antigens triggering the T-cell-mediated immune response.