Cells In Psoriatic Skin Research Articles

The interplay between epidermal barrier distribution, microbiota composition, and immune infiltrate defines and stratifies psoriasis patients and is associated with disease severity

Psoriasis is a chronic inflammatory autoimmune skin disease characterized by keratinocyte hyperproliferation, primarily driven by the IL-23/IL-17 axis. In addition to immune response, various skin components, including the epidermal barrier and the skin microbiota, have been individually implicated in the disease pathogenesis. Here, we aimed to investigate the interplay between epidermal tight junctions, Staphylococcus aureus enterotoxin B (SEB), and CD4 T cell-mediated immune responses. By immunofluorescence analyses of skin biopsies, we observed that claudin-1 distribution was significantly altered in psoriatic patients, which correlated with the localization of Staphylococcus aureus and SEB across skin layers and with disease severity. Furthermore, functional CD4 TCRvβ17 cells were associated with SEB presence in patients skin and positively correlated with psoriasis severity. Notably, in patients with SEB detected in the dermis, CD4 TCRvβ17 IL-17 cells were linked to barrier abnormalities.Unsupervised analysis stratified psoriasis patients into three groups based on SEB presence and location, supporting the previous findings. The patient group with SEB in the dermis exhibited improved responses to biological therapy, including reductions in PASI score, claudin-1 fragmentation, S. aureus and SEB presence, and CD4 TCRvβ17 cell percentages. Our findings emphasize the complex interplay between epidermal barrier distribution, SEB localization, and functional CD4 TCRvβ17 cells in psoriatic skin, highlighting their potential in patient stratification in association with the severity of the disease.

Enhanced NAMPT-Mediated NAD Salvage Pathway Contributes to Psoriasis Pathogenesis by Amplifying Epithelial Auto-Inflammatory Circuits.

Dysregulated cross-talk between immune cells and epithelial compartments is responsible for the onset and amplification of pathogenic auto-inflammatory circuits occurring in psoriasis. NAMPT-mediated NAD salvage pathway has been recently described as an immunometabolic route having inflammatory function in several disorders, including arthritis and inflammatory bowel diseases. To date, the role of NAD salvage pathway has not been explored in the skin of patients affected by psoriasis. Here, we show that NAD content is enhanced in lesional skin of psoriatic patients and is associated to high NAMPT transcriptional levels. The latter are drastically reduced in psoriatic skin following treatment with the anti-IL-17A biologics secukinumab. We provide evidence that NAMPT-mediated NAD+ metabolism fuels the immune responses executed by resident skin cells in psoriatic skin. In particular, intracellular NAMPT, strongly induced by Th1/Th17-cytokines, acts on keratinocytes by inducing hyper-proliferation and impairing their terminal differentiation. Furthermore, NAMPT-mediated NAD+ boosting synergizes with psoriasis-related cytokines in the upregulation of inflammatory chemokines important for neutrophil and Th1/Th17 cell recruitment. In addition, extracellular NAMPT, abundantly released by keratinocytes and dermal fibroblasts, acts in a paracrine manner on endothelial cells by inducing their proliferation and migration, as well as the expression of ICAM-1 membrane molecule and chemokines important for leukocyte recruitment into inflamed skin. In conclusion, our results showed that NAMPT-mediated NAD salvage pathway contributes to psoriasis pathogenic processes by amplifying epithelial auto-inflammatory responses in psoriasis.

082 CD8+ IL-23R+ PD-1+ T cells in psoriatic skin possibly play a role in maintaining inflammation and disease recurrence

082 CD8+ IL-23R+ PD-1+ T cells in psoriatic skin possibly play a role in maintaining inflammation and disease recurrence

154 MDR1-expressing T cells accumulate in the resolved skin of psoriatic plaque after treatment with topical corticosteroid but not with anti-IL-17A mAb

Topical corticosteroid is a widely used for treatment of psoriasis. However, its long-term use may bring about resistance to the treatment. We have previously shown that multiple drug resistance 1 (MDR1)-expressing T cells infiltrate in the skin lesions of psoriasis, especially at the skin treated with a corticosteroid. Corticosteroids are a substrate of MDR1, and possible association of MDR1+ T cells and corticosteroid resistance has been documented in some diseases. Since MDR1+ T cells in psoriatic skin include a large number of IL-17A and IL-22-producing cells, they can be associated with corticosteroid resistance. In this study, we sought to clarify whether the blockade of IL-17A by Secukinumab affects MDR1 expression. We analyzed stocked T cells expanded by IL-2 and anti-CD3/CD28 mAb-coated microbeads from biopsy specimens taken from the skin of 7 patients treated with topical corticosteroid and from the skin of 6 patients treated with Secukinumab. The function of MDR1 was investigated by Rh123 efflux assay. Rh123low cells expressed ABCB1 gene, while Rh123hi cells did not. In addition, verapamil, a specific inhibitor of MDR1 depressed the efflux of Rh123 at 94.0±2.3 percent, and thus, we considered Rh123low cells as MDR1+ cells. In vitro treatment of a corticosteroid significantly increased the frequency of MDR1+ cells (P=0.02). The frequency of MDR1+ T cells was significantly higher in the corticosteroid-treated skin than in Secukinumab-treated patients’ skin (P=0.01). Notably, this difference was more apparent in CD4+ T cells than in CD8+ T cells. Our results suggest that, unlike corticosteroid-treated skin, MDR1+ T cells do not accumulate in the skin of Secukinumab-treated patients. While anti-IL-17A mAb more strongly improves psoriasis than do topical corticosteroids, it renders remaining skin T cells susceptible to corticosteroid treatment.

The Significance of IL-36 Hyperactivation and IL-36R Targeting in Psoriasis.

Psoriasis is an immune-mediated inflammatory skin disease that involves mainly T helper (Th)17, Th1 and Th22 lymphocytes, which cause hyper-proliferation of the epidermis with aberrant differentiation of keratinocytes, and local production of chemokines and cytokines. These fuel a self-amplifying loop where these products act on T cells to perpetuate cutaneous inflammatory processes. Among the various inflammatory mediators involved, interleukin (IL)-36 cytokines are important for the recruitment and activation of neutrophils and Th17 cells in psoriatic skin. In particular, IL-36s induce chemokines and cytokines interfere with differentiation/cornification programs in the epidermis, as well as promote pathological angiogenesis and endothelial cell activation. IL-36 cytokines belong to the IL-1 family, and comprise IL-36α, IL-36β, and IL-36γ agonists as well as IL-36 receptor antagonist and IL-38 antagonists. IL-36 cytokines are up-regulated in psoriatic epidermis, and their expression is strongly induced by TNF-α and IL-17. Contrarily, IL-38 antagonist is downregulated, and its impaired expression may be relevant to the dysregulated inflammatory processes induced by IL-36. Here, we discuss on the pathogenic mechanisms leading to the altered balance of IL-36 agonists/antagonists and the significance of this dysregulation in psoriasis. Collection of the information will provide a theoretical basis for the development of novel therapeutic strategies based on IL-36 agonist/antagonist manipulation in psoriasis.

Role of Angiogenic Growth Factors in Psoriasis: A Review.

Psoriasis is a chronic disease of inflammatory nature. It involves autoimmune mechanism and the systemic diseased state is created by the interaction of immune system, autoantigens and variety of environmental triggers. It is a complex skin disease which involves participation of numerous factors, making it multifactorial in nature. The main characteristics include proliferation of keratinocytes, increase in dermal vascularity and infiltrated immune cells. Among all factors, vascular alterations present a significant feature of the disease and angiogenesis seems to have an important role in giving rise to psoriasis phenotype. In the early phases of psoriasis there occurs sprouting of new blood vessels which disappear with disease clearance. Psoriatic lesions show highly altered vascular network in the form of numerous enlarged, tortuous and hyperpermeable cutaneous blood vessels. Secretion of various pro-angiogenic growth factors promote the expansion of vascular network in psoriatic skin cells. In addition to pro-angiogenic growth factors, pro-inflammatory cytokines also contribute to this process by activating endothelial cells and exerting pro-angiogenic action as well. Angiogenesis, in psoriasis display a close association of vascular endothelium activation, angiogenesis, inflammation and lesional skin, as is demonstrated by in vivo models. The present review discusses angiogenesis as the central process in the evolution of psoriasis and summarizes various angiogenic mediators and their respective roles in the development of psoriasis. Anti-angiogenic therapies targeting vasoproliferation may represent a valid approach for the development of anti-psoriatic drugs and further development in this field can pave way to new fields of treatment. Such therapies could be at par to those directly targeting inflammation.

The Quest for Psoriasis Autoantigens: Genetics Meets Immunology in the Melanocyte

The Quest for Psoriasis Autoantigens: Genetics Meets Immunology in the Melanocyte

Modular deconvolution of tissue transcriptomes: pitfalls and solutions

BackgroundMaking hypothesis-led interrogations of whole-genome transcriptomic datasets is a challenge. Transcriptional modules define specific biological processes, but multiple modules have now been published with overlapping annotations. In this study we aimed to generate and validate the modular discrimination index (MDI) score, ranking the accuracy and resolution of any cell type specific module to assess cellular enrichment in tissues from transcriptional datasets. MethodsWe made use of publicly available transcriptomic datasets of purified immune cell types to compare the expression of modules annotated to reflect the expression of different immune cells. MDI scores were derived from the relative expression of each module in its annotated cell type, relative to all other cells. Independent datasets from human tissue and blood samples were then used to validate the MDI score in relation to the relative enrichment of different modules' gene expression. FindingsWe found that 26 T-cell modules varied both in their composition and in their gene expression in a tuberculin skin test, a prototypical T cell driven cell inflammatory process. To address this heterogeneity, we assessed the accuracy of cell-type modules, by calculating MDI scores for all published T cell, B cell, natural killer cell and neutrophil modules. MDI scores strongly predicted each module's ability to show histologically proven cellular enrichment in a variety of independent tissue samples: T cells in psoriatic skin, B cells in lung fibrosis, and neutrophils in erythema nodosum leprosum skin lesions. In addition, MDI scores were also validated in relation to changes in cell frequency in blood: modules with the greatest MDI score were most predictive of each module's association with cell numbers for both high frequency cells (neutrophils r2=0·545, p=0·01) and low frequency cells (B cells r2=0·865, p=0·01) in blood. Finally, we showed that modules with the highest MDI score elicited the T cell enrichment seen in the tuberculin skin test, whereas this was most often not detected by low MDI scoring modules. InterpretationThis study shows that MDI scoring provides a robust and reproducible assessment of a transcriptional module's accuracy and resolution, and should be determined before using modular deconvolution of tissue samples. The MDI scoring framework can be extended and applied across a range of disciplines for which annotated modules could be used to interrogate transcriptional datasets. FundingWellcome Trust.

Interferon-γ/CCR5 expression in invariant natural killer T cells and CCL5 expression in capillary veins of dermal papillae correlate with development of psoriasis vulgaris

There have been extensive studies regarding which types of T lymphocytes are involved in psoriasis vulgaris (PV). However, it has remained unclear which types of T lymphocytes might directly contribute to psoriasiform epidermal and vascular hyperplasia. To understand the role of T-cell receptor (TCR)Vα24+ invariant natural killer (iNK)T cells in the development of PV. Seventeen patients were enrolled in this study. Using biopsy samples of PV plaques, TCRVα24(+) iNKT cells were investigated regarding their cytokine production to understand their roles in development of disease. The number of interferon (IFN)-γ+ iNKT cells correlated with the length of the psoriasiform hyperplasia rete ridge and the Psoriasis Area and Severity Index. IFN-γ+ iNKT cells in psoriatic skin exhibited higher C-C chemokine receptor (CCR)5 expression, and the amount of C-C chemokine ligand (CCL)5, a ligand for CCR5, was increased in capillary veins of psoriasis plaques. CCR5+ iNKT-cell numbers significantly correlated with the number of capillary vein endothelial cells expressing CCL5 in PV. Furthermore, the number of CCL5+ capillary veins correlated with the maximum rete ridge length. IFN-γ/CCR5 expression in iNKT cells and CCL5 expression in vessels of dermal papillae correlate with the development of psoriasiform hyperplasia and microabscess. We propose that these iNKT cells may become useful targets for development of novel therapeutic approaches to PV.

Interleukin 20 protein locates to distinct mononuclear cells in psoriatic skin

We previously demonstrated that mRNA for the pro-inflammatory cytokine interleukin 20 (IL-20) is expressed in suprapapillary keratinocytes of lesional psoriatic skin (LS). Here, we describe the distribution of IL-20 protein and the identity of the IL-20-positive cells in LS. We found that the main part of IL-20 immunoreactivity is present in mononuclear cells of the dermal papillae, and that the IL-20-positive cells located in the papillae were langerin+, CD1a+, CD4+ and CD303+. These cells might be immature dendritic cell. In situ hybridization for IL-20 mRNA on non-LS, ex vivo stimulated with IL-1β revealed a colocalization between IL-20 mRNA and the keratinocyte marker CK14. No IL-20 mRNA was detected in the dermal mononuclear cells. Our results suggest that IL-20 is produced by keratinocytes, released into the epidermis and then possibly taken up by papillary mononuclear cells. Our study supports that IL-20 is involved in the pathogenesis of psoriasis.

Notch signaling may be involved in the abnormal differentiation of epidermal keratinocytes in psoriasis.

Localization of each keratin isoform differs among epidermal layers. Proliferating basal cells synthesize keratin 14 (K14) and suprabasal cells express keratin 10 (K10) in normal skin. Notch signaling is essential for keratinocyte differentiation. Notch1 is expressed in all epidermal layers, Notch2 in the basal cell layer and Notch3 in basal cell and spinous cell layers in normal epidermis. It has been poorly elucidated how localization and expression levels of Notch molecules are related to epidermal molecular markers K10 and K14 in psoriatic skin with abnormal differentiation of epidermal tissue. This study aimed to investigate the relationship between abnormal differentiation of epidermal cells in psoriatic skin and expression of Notch molecules. We investigated keratins (K14 and K10) and Notches (1, 2, 3 and 4) using immunohistochemistry in psoriatic skin (n=30) and normal skin (n=10). In normal skin, K14 and K10 were discretely observed in the basal cell layer and suprabasal layer, respectively. In psoriatic skin, K14 was expressed in the pan epidermal layer while it and K10 were co-expressed in some middle suprabasal layer cells. Notch1, 2, 3, and 4 localized in all epidermal layers in normal skin. In psoriatic skin, Notch1, 2, and 4 mainly localized in suprabasilar layers and Notch3 is lacalized in pan epidermal, suprabasilar, and basilar layers. Protein and mRNA of Notch1, 2, and 3 isoforms decreased in psoriatic epidermis compared with normal epidermis. These data suggest that decrements in these Notch molecules might cause aberrant expression of K10 and K14 leading to anomalous differentiation of the epidermis in psoriatic lesions.

The Role of Angiogenesis in the Pathogenesis of Psoriasis: Mechanisms and Clinical Implications

Psoriasis is a complex multisystemic skin disease characterized by the recurrent apparition of erythematous plaques often covered by silvery scales. In recent years, the importance attributed to angiogenesis in psoriasis by the scientific community has grown significantly. The vascular network found within these lesions is highly altered, especially in the papillary dermis which is infiltrated by a large number of tortuous and dilated capillaries. Also, endothelial cells composing these vessels are activated and express many adhesion molecules promoting leukocyte recruitment (ICAM-1, VCAM-1, Thy-1, E- and P-selectin). Thus, this pathological angiogenesis is not a mere consequence of the disease, but a key component promoting leukocyte accumulation, inflammation and therefore, skin lesions. This review presents the current understanding and the clinical implications of angiogenesis in psoriasis. Psoriatic skin cells, particularly keratinocytes, promote the expansion of the vascular network through the secretion of pro-angiogenic factors such as VEGF and angiopoietins. Moreover, pro-inflammatory cytokines such as TNF-α, which exert pro-angiogenic action as well as activation of endothelial cells, also contribute to this process. It was demonstrated by in vivo models that angiogenesis, activation of vascular endothelium, inflammation and skin lesions are all closely related in psoriasis. Indeed, angiogenesis promoted by VEGF-secreting keratinocytes leads to local inflammation and skin lesions mimicking psoriasis. From a clinical perspective, most psoriatic treatments have direct, or at least indirect, anti-angiogenic impact, suggesting that their clinical efficacy might be partly explained by these properties. Altogether, these findings identify angiogenesis and the activation of endothelial cells as novel pharmacological targets against psoriasis.

Reduction of inflammatory slan (6‐sulfo LacNAc) dendritic cells in psoriatic skin of patients treated with etanercept

Dermal dendritic cells (DCs) play a central role in the immunopathology of psoriasis. We previously identified slanDCs as pro-inflammatory TNF-α, IL-23- and IL-12-producing DCs in human blood and as prominent inflammatory dermal TNF-αsecreting and CD11c-positive DC subset in psoriasis. Here, we ask for the effects of TNF-α-inhibition on inflammatory slanDCs in skin and blood of 10 patients with psoriasis during 24weeks of treatment with etanercept. Treatment with etanercept reduced the frequency of dermal slanDCs but did not induce apoptosis as determined by lack of increased active caspase-3-expression. In parallel, we found increased frequencies of slanDCs in blood which expressed lower levels of HLA-DR. Stimulating slanDCs isolated from the blood of healthy donors in vitro induced a strong production of IL-1β, IL-6, IL-23 and IL-12p70. This capacity was efficiently reduced in the presence of etanercept, thereby indicating that TNF-α is an autocrine stimulus for maturation and pro-inflammatory cytokine production of slanDCs. In vivo, we noticed that treatment with etanercept did reduce the number of dermal slanDCs in parallel to the overall expression of TNF-α and IL-23p19. However, successful treatment did not down-regulated the percentage of dermal slanDCs that stained positive for TNF-α and IL-23p19 indicating that remaining slanDCs kept their pro-inflammatory capacity. This study provides novel insights into the immune regulatory properties of etanercept at the level of inflammatory slanDCs in vivo in skin and blood as well as in vitro.

CXCL16 and CXCR6 Are Upregulated in Psoriasis and Mediate Cutaneous Recruitment of Human CD8+ T Cells

Psoriatic skin lesions are characterized by an inflammatory infiltrate, consisting of dendritic cells, monocytes, and both CD4(+) and CD8(+) T lymphocytes. Although the chemokines involved in the migration of CD4(+) T cells into psoriatic skin are well characterized, those regulating CD8(+) T-cell recruitment are less understood. We found that the percentages of peripheral blood CD8(+) T cells expressing CXCR6 were higher in psoriatic patients than in healthy or atopic individuals. In addition, CXCR6 expression in psoriatic patients was more abundant in the CD8(+) than in the CD4(+) T-cell compartment. CXCR6 mRNA expression was also stronger in skin CD8(+) T cells than in the corresponding blood-derived counterparts. Immunofluorescence analysis revealed profound upregulation of the CXCR6 ligand CXCL16 by monocytes, keratinocytes, and dendritic cells in psoriatic skin compared with healthy or atopic dermatitis skin. In line with this, CXCR6(+) CD8(+) T cells also were most prevalent in psoriatic skin. Furthermore, CXCL16 induced Ca(2+) influx and chemotactic migration of psoriatic skin-derived CD8(+) T cells in vitro. Most importantly, CXCL16 potently recruited human CD8(+) T cells to human skin grafts previously transplanted onto SCID mice in vivo. These investigations indicate that CXCL16-CXCR6 interactions mediate homing of CD8(+) T cells into human skin, and thereby contribute to psoriasis pathogenesis.

Combination Biologic Treatment of Refractory Psoriasis and Psoriatic Arthritis

To the Editor: The pathophysiology of psoriasis and psoriatic arthritis (PsA) is dependent on a multistep process that leads to chronic or recurrent inflammation1,2,3. Blockade of cytokines, receptors, and coreceptors represents one approach to treating these diseases, but a significant number of patients have a recurrent course or a persistent disease process. A persistent process appears to suggest that blockade of individual inflammatory mediators is not enough to control the disease. On the other hand, among the patients who do respond to disease-modifying antirheumatic drugs (DMARD), the doses needed to control the disease sometimes are too high and may lead to severe adverse reactions. A different or complementary approach to conventional therapy is to use combination therapy that simultaneously targets different pathogenic mechanisms of the disease pathophysiology. The rationale of using a combination of biologic agents is based upon the complex pathogenic mechanisms involved in the disease process, in which Th1 and Th17 cells play major roles. It has been shown that keratinocytes and dendritic cells in psoriatic skin overproduce interleukin 23 (IL-23), which is one of the cytokines that regulates the Th17 cells, and IL-22 induces keratinocyte proliferation. In addition, clinical data show that tumor necrosis factor-α (TNF-α) inhibitors reduce epidermal hyperplasia as well as synovitis/enthesitis by decreasing Th1 and Th17 cell responses1. The literature on combination biologic therapy for patients with autoimmune diseases is sparse, probably because the majority of cases are well controlled with 1 biologic agent alone or in combination with classic DMARD, and safety issues and adverse events are major concerns. We describe a patient with psoriasis and PsA refractory to standard treatment with DMARD alone or in combination with biological therapy. The patient responded to the combination of 2 biologic agents given concomitantly. A 38-year-old white … Address correspondence to Dr. Espinoza; E-mail: lespin1{at}lsuhsc.edu

Sun exposure rapidly reduces plasmacytoid dendritic cells and inflammatory dermal dendritic cells in psoriatic skin

Interferon (IFN)-α-producing plasmacytoid dendritic cells (pDCs), inflammatory CD11c+CD1c- myeloid dendritic cells (mDCs) and macrophages have been found to contribute to the pathogenesis of psoriasis. Heliotherapy is a well-established treatment modality of this disease, although the details of how the effects are mediated are unknown. To test the hypothesis that exposure to natural sun affects pathogenic DC subsets in lesional skin. Skin biopsies were obtained from lesional and nonlesional skin in 10 patients with moderate to severe psoriasis subjected to controlled sun exposure on Gran Canaria. Biopsies were obtained at baseline, day 2 and day 16 and examined by immunohistochemistry. Sixteen days of heliotherapy had excellent clinical effect on patients with psoriasis, with significant reductions in Psoriasis Area and Severity Index (PASI) scores. In lesional skin pDC numbers and expression of MxA, a surrogate marker for IFN-α, were rapidly reduced. Inflammatory CD11c+CD1c- mDCs were significantly reduced whereas resident dermal CD11c+CD1c+ mDCs were unaffected. Expression levels of the maturation marker DC-LAMP (CD208) on mDCs were significantly reduced after sun exposure, as were the numbers of lesional dermal macrophages. A decrease of dermal DC subsets and macrophages was already observed after 1 day of sun exposure. An additional finding was that DC-SIGN (CD209) is primarily expressed on CD163+ macrophages and not DCs. The clinical improvement in psoriasis following sun exposure is associated with rapid changes in dermal DC populations and macrophages in lesional skin, preceding the clinical effect. These findings support the concept that these DC subsets are involved in the pathogenesis of psoriasis and suggest that sun-induced clinical benefit may partly be explained by its effect on dermal DCs.

Identification of a Novel Proinflammatory Human Skin-Homing Vγ9Vδ2 T Cell Subset with a Potential Role in Psoriasis

γδ T cells mediate rapid tissue responses in murine skin and participate in cutaneous immune regulation including protection against cancer. The role of human γδ cells in cutaneous homeostasis and pathology is characterized poorly. In this study, we show in vivo evidence that human blood contains a distinct subset of proinflammatory cutaneous lymphocyte Ag and CCR6-positive Vγ9Vδ2 T cells, which is rapidly recruited into perturbed human skin. Vγ9Vδ2 T cells produced an array of proinflammatory mediators including IL-17A and activated keratinocytes in a TNF-α- and IFN-γ-dependent manner. Examination of the common inflammatory skin disease psoriasis revealed a striking reduction of circulating Vγ9Vδ2 T cells in psoriasis patients compared with healthy controls and atopic dermatitis patients. Decreased numbers of circulating Vγ9Vδ2 T cells normalized after successful treatment with psoriasis-targeted therapy. Taken together with the increased presence of Vγ9Vδ2 T cells in psoriatic skin, these data indicate redistribution of Vγ9Vδ2 T cells from the blood to the skin compartment in psoriasis. In summary, we report a novel human proinflammatory γδ T cell involved in skin immune surveillance with immediate response characteristics and with potential clinical relevance in inflammatory skin disease.

Increased expression of CD208 (DC‐LAMP) in epidermal keratinocytes of psoriatic lesions

Psoriasis is a chronic inflammatory skin disease characterized by epidermal hyperproliferation and infiltration of inflammatory leukocytes. The aim of this study was to clarify the role of innate immunity involving dendritic cells (DC) and keratinocytes in psoriasis. We immunohistochemically examined the expression of DC markers such as CD1a, CD83, CD207 (Langerin), CD208 (DC-LAMP) and CD209 (DC-SIGN) in psoriatic skin and gamma-interferon (IFN-gamma)/12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated keratinocytes in vitro. CD208 was strongly expressed in basal and suprabasal layer keratinocytes in addition to DC in the perivascular lesions of the psoriatic dermis. Furthermore, the enhanced expression of CD208 in the perinuclear lesions of IFN-gamma-/TPA-stimulated keratinocytes was observed in vitro. Because a defect of the granular layer in psoriatic lesions has been recognized, increased expression of lysosome-related CD208 in the basal and suprabasal keratinocytes of psoriatic lesions might represent aberrant epidermal differentiation. Additionally, these CD208-positive keratinocytes possessing putative antigen-processing activity might play a key role as antigen-presenting cells in psoriatic skin.

Persistent Expression of CD26/DPPIV After Treatment with Infliximab in Psoriasis Despite Clinical Improvement

Sir, Tumour necrosis factor α (TNF-α) is a proven adequate target for treatment of psoriasis. The chimeric TNF-α antibody infliximab binds to the transmembrane receptors and induces a neutralizing effect on soluble TNF by reversed signalling, ultimately causing a reduction in lesional T cells and, indirectly, increased programmed cell death of keratinocytes (1). CD26/dipeptidylpeptidase IV (DPPIV) is a multifunctional glycoprotein known to be present and upregulated on the surface of keratinocytes and T cells in psoriatic skin compared with the skin of healthy volunteers (2). The expression of CD26/DPPIV on peripheral blood T-lymphocytes of untreated psoriatic patients, however, was found to be substantially reduced, in particular on the CD8+CD26bright subset (3). Furthermore, TNF-α has been reported to influence CD26/DPPIV expression (4, 5). In vitro cell cultures have shown that anti-TNF-α can upregulate the expression of CD26/DPPIV on human-activated lymphocytes (6). CD26/DPPIV expression may have a crucial role and might function as a marker correlating with disease activity in the pathogenesis of psoriasis. The objective of this study was therefore to determine whether antiTNF-α therapy with infliximab modulates CD26/DPPIV expression on keratinocytes and T cells.

The cells in psoriatic skin

The cells in psoriatic skin