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Background The effectiveness of biologics for psoriasis shows heterogeneity among patients. With pharmacogenetic markers, it might be possible to predict treatment response. Objectives We aimed to test the association between genetic markers and the response to biologics in psoriasis (etanercept, adalimumab, ustekinumab) in a prospective cohort. Methods We investigated the copy number variation in the LCE3B and LCE3C genes, and eight single-nucleotide polymorphisms ( SNPs) in HLA-C*06, CD84, IL12B, IL23R, TRAF3 IP2, ERAP1, IFIH1 and TNFAIP3. The decrease in Psoriasis Area and Severity Index ( PASI) was calculated as ∆ PASI (absolute PASI decrease compared with baseline) and PASI 75 (proportion of patients with ≥ 75% improvement vs. baseline). Associations between genetic variants and treatment outcome were assessed using multivariable linear regression analysis (∆ PASI corrected for baseline PASI, primary analysis) and Pearson's χ2-test or Fisher's exact test ( PASI 75, secondary analysis). Results We included 348 treatment episodes in 234 patients. Patients heterozygous ( GA) for the SNP in CD84 (rs6427528) had a better ∆ PASI response to etanercept after 3 months ( P = 0·025) than the homozygous reference group ( GG). In addition, patients heterozygous ( CT) for the IL12B variant showed a better response (∆ PASI) to ustekinumab ( P = 0·017) than the reference group ( CC). Patients homozygous ( GG) for the SNP in TNFAIP3 showed a worse response (∆ PASI) to ustekinumab ( P = 0·031) than the reference group ( TT). The associations with ustekinumab resulting from the primary analysis were not confirmed in the secondary ( PASI 75) analysis. Conclusions We demonstrated a strong association between etanercept use in psoriasis and variations in CD84, a gene that was previously found to be a predictor of response to etanercept in rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

A letter to the editor on a research study on Autoinflammatory Disorders (AID) characterized by an unprovoked innate immune response, resulting in recurrent or ongoing systemic inflammation and fever, is presented.

Background Deletion of the late cornified envelope ( LCE) proteins LCE3B and LCE3C is a strong and widely replicated psoriasis risk factor. It is amenable to biological analysis because it precludes the expression of two epidermis-specific proteins, rather than being a single-nucleotide polymorphism of uncertain significance. The biology of the 18-member LCE family of highly homologous proteins has remained largely unexplored so far. Objectives To analyse LCE3 expression at the protein level in human epithelia, as a starting point for functional analyses of these proteins in health and disease. Methods We generated the first pan- LCE3 monoclonal antibody and provide a detailed analysis of its specificity towards individual LCE members. LCE2 and LCE3 expression in human tissues and in reconstructed human skin models was studied using immunohistochemical analyses and quantitative polymerase chain reaction. Results Our study reveals that LCE2 and LCE3 proteins are differentially expressed in human epidermis, and colocalize only in the upper stratum granulosum layer. Using an in vitro reconstructed human skin model that mimics epidermal morphogenesis, we found that LCE3 proteins are expressed at an early time point during epidermal differentiation in the suprabasal layers, while LCE2 proteins are found only in the uppermost granular layer and stratum corneum. Conclusions Based on the localization of LCE2 and LCE3 in human epidermis we conclude that members of the LCE protein family are likely to have distinct functions in epidermal biology. This finding may contribute to understanding why LCE3B/C deletion increases psoriasis risk. [ABSTRACT FROM AUTHOR]

Background Schnitzler's syndrome (SchS) is an autoinflammatory disease characterized by a chronic urticarial rash, a monoclonal component and signs of systemic inflammation. Interleukin ( IL)-1β is pivotal in the pathophysiology. Objectives Here we investigated the cellular source of proinflammatory mediators in the skin of patients with SchS. Methods Skin biopsies of lesional and nonlesional skin from eight patients with SchS and healthy controls, and patients with cryopyrin-associated periodic syndrome ( CAPS), delayed-pressure urticaria ( DPU) and cold-contact urticaria ( CCU) were studied. We studied in vivo IL-1β, IL-17 and antimicrobial protein ( AMP) expression in resident skin cells and infiltrating cells. In addition we investigated the in vitro effect of IL-1β, IL-17 and polyinosinic-polycytidylic acid (poly: IC) stimulation on cultured epidermal keratinocytes. Results Remarkably, we found IL-1β-positive dermal mast cells in both lesional and nonlesional skin of patients with SchS, but not in healthy control skin and CCU, and fewer in CAPS. IL-17-positive neutrophils were observed only in lesional SchS and DPU skin. In lesional SchS epidermis, mRNA and protein expression levels of AMPs were strongly increased compared with nonlesional skin and that of healthy controls. When exposed to IL-1β, poly: IC or IL-17, patient and control primary human keratinocytes produced AMPs in similar amounts. Conclusions Dermal mast cells of patients with SchS produce IL-1β. This presumably leads to activation of keratinocytes and neutrophil influx, and further amplification of inflammation by IL-17 (from neutrophils and mast cells) and epidermal AMP production leading to chronic histamine-independent neutrophilic urticarial dermatosis. [ABSTRACT FROM AUTHOR]

Background Psychosocial stress can be a risk factor for the maintenance and exacerbation of chronic inflammatory diseases, such as psoriasis and rheumatoid arthritis ( RA). Objectives To gain insight into the specificity of the psychophysiological stress response during chronic inflammation, we assessed autonomic and neuroendocrine responses to stress in different chronic inflammatory diseases. Methods Thirty patients with psoriasis (nine women, mean age 58·5 years ± 12·4), 34 patients with RA (16 women, mean age 60·8 years ± 9·2) and 25 healthy controls (16 women, mean age 55·6 years ± 8·7) underwent a standardized psychosocial stress task ( Trier Social Stress Test). Salivary levels of α-amylase and cortisol and self-reported tension levels were measured before and after the stress test. Results The cortisol response to stress was heightened in patients with psoriasis compared with patients with RA and healthy controls, whereas there were no differences in the autonomic and self-reported measures. Conclusions The altered neuroendocrine stress response in patients with psoriasis suggests that stressful events might have different physiological consequences for specific patient groups with chronic inflammatory conditions, possibly adversely affecting disease status. [ABSTRACT FROM AUTHOR]

Background The use of recently introduced biologics targeting specific immune mechanisms has identified crucial steps in the pathogenesis of psoriasis. Studying the dynamics of changes of these target mechanisms in sequential skin biopsies during treatment with biologics may reveal potential biomarkers. Correlation between clinical parameters and the expression of specific genes during treatments may identify markers indicative of treatment response. Objectives This observational open-label study aimed to provide an overview of important cell biological changes in lesional skin during treatment with adalimumab, and their relationship to clinical improvement. Methods Ten patients with moderate-to-severe plaque psoriasis were included and treated with adalimumab for 16 weeks. At baseline, and after 10 days and 16 weeks of treatment clinical scores were assessed and biopsies were taken to examine gene expression at the mRNA and protein level. Results The expression of marker genes for innate immunity, and epidermal differentiation and proliferation was rapidly restored to normal levels, whereas genes of the adaptive immune system showed a delayed decrease. The static and dynamic course of CD1a+ Langerhans cells and Ki67+ nuclei showed a significant strong correlation to the Psoriasis Area and Severity Index score. No correlation between interleukin-17 expression and clinical scores was found. Conclusions The innate immune system is affected during adalimumab treatment well before the changes in the adaptive immune system become apparent. We may speculate that the addition of a treatment with an early effect on adaptive immunity to adalimumab may result in superior effectiveness compared with monotherapies. [ABSTRACT FROM AUTHOR]

Background Recent studies have emphasized the importance of heritable and acquired skin barrier abnormalities in common inflammatory diseases such as psoriasis and atopic dermatitis (AD). To date, no comprehensive studies on the effect of experimental barrier disruption on cornified envelope protein expression have been performed. Objectives To analyse the effect of experimental skin barrier disruption on the expression of cornified envelope structural proteins and keratinocyte differentiation-regulating proteins. Methods We examined mRNA (day 1, 3 and 7) and protein (day 1, 2, 4 and 9) expression levels of structural proteins and regulatory molecules after sodium dodecyl sulphate (SDS) application on normal skin, and tape stripping of uninvolved epidermis of patients with psoriasis and AD and healthy controls. Results Upon tape stripping, several structural molecules were significantly downregulated (at the mRNA level as well as the protein level), including LCE5A, LCE2B, FLG, FLG2 and LOR, whereas others were upregulated: IVL, SPRR1, SPRR2, HRNR and most notably LCE3A. The epidermal crosslinking enzymes TGM1, TGM3 and TGM5 were all upregulated, whereas proteases involved in the desquamation process (CTSV, KLK5 and KLK7) were downregulated or unaffected. Most results were similar in SDS-instigated irritant contact dermatitis. There was no significant difference in response between normal epidermis and nonlesional skin of patients with psoriasis and AD. Conclusions Skin barrier disruption induces a temporary barrier repair response composed of increased expression of several cornification-related proteins, and decreased expression of some structural and desquamation-related proteins. [ABSTRACT FROM AUTHOR]

Tenascin-X is a large extracellular matrix glycoprotein that is widely distributed within connective tissues and is associated with an autosomal recessive type of Ehlers-Danlos syndrome (EDS). Tenascin-X represents the first EDS susceptibility gene that does not code for a fibrillar collagen or collagen-processing enzyme. We describe a paediatric case of tenascin-X deficiency and review the literature. [ABSTRACT FROM AUTHOR]

Psychological stressors might contribute to the severity of chronic inflammatory diseases such as psoriasis by dysregulating hypothalamic-pituitary-adrenal (HPA) axis activity. To evaluate the role of cortisol, a key component of the HPA axis, in reaction to psychological stress in patients with psoriasis. Serum cortisol, clinical indicators of disease severity (Psoriasis Area and Severity Index) and self-report measures of daily stressors were measured monthly for 6 months in 62 patients with psoriasis. In addition to the previous findings in this sample showing that peak levels of daily stressors predicted an increase in disease severity a month later, the peak levels of daily stressors were also significantly associated with a lower cortisol level. Moreover, patients who persistently experienced higher levels of daily stressors had lower mean cortisol levels than patients who experienced lower levels of daily stressors. Results suggest that daily stressors influence disease outcome in patients with psoriasis by affecting cortisol levels at moments of high stress. Furthermore, patients with persistently high levels of stressors seem to have a specific psychophysiological profile of lowered cortisol levels and may be particularly vulnerable to the influence of stressors on their psoriasis. [ABSTRACT FROM AUTHOR]

Background Microarray studies on the epidermal transcriptome in psoriasis and atopic dermatitis (AD) have revealed genes with disease-specific expression in keratinocytes of lesional epidermis. These genes are possible candidates for disease-specific pathogenetic changes, but could also provide a tool for molecular diagnostics of inflammatory skin conditions in general. Objectives To analyse if gene expression signatures as found in purified epidermal cells from AD are also present in other eczematous conditions such as allergic and irritant contact dermatitis. Methods We used real-time quantitative polymerase chain reaction, immunohistochemistry and bioinformatics to investigate gene expression in different forms of eczema. Normal epidermis and psoriatic epidermis were analysed for comparison. Results Carbonic anhydrase II was highly induced in epidermis from all forms of eczema but not in psoriasis. Remarkably, the presumed neuron-specific Nel-like protein 2 showed a strong induction only in AD epidermis. Interleukin-1F9, elafin, β-defensin-2 and vanin-3 were strongly induced in psoriasis, but not in any type of eczema. High levels of the chemokines CCL17 and CXCL10 were predominantly found in epidermis of allergic contact dermatitis. The chemokine CXCL8 was highly expressed in psoriasis, AD and allergic contact dermatitis, but not in irritant contact dermatitis. Cluster analysis or multinomial logistic regression indicated that expression levels of a set of seven genes are a strong predictor of the type of inflammatory response. Conclusions These observations contribute to molecular diagnostic criteria for inflammatory skin conditions. [ABSTRACT FROM AUTHOR]

Background The antiprotease activity of cystatin M/E regulates skin barrier formation, as it inhibits the activity of cathepsin V, cathepsin L and legumain, thereby controlling the processing of transglutaminase 3. Misregulation of this pathway by unrestrained protease activity, as seen in cystatin M/E-deficient mice, leads to abnormal stratum corneum and hair follicle formation, and severe disturbance of skin barrier function. Objectives Our major aim was to make a quantitative analysis of the expression of all players of this pathway in the epidermis of patients with inflammatory skin diseases. A second aim was to determine if reconstructed human skin could be used as an in vitro model system to investigate this pathway. Methods Autopsy material from normal human tissues, biopsies from normal skin of healthy volunteers, and lesional skin from patients with atopic dermatitis and psoriasis were used to study the expression of the above-mentioned molecules at the mRNA level by quantitative real-time polymerase chain reaction. Localization of the protein was performed by immunofluorescence microscopy, and expression was quantitated by image analysis. Results In skin, cystatin M/E is expressed at relatively higher levels than its target proteases, when compared with other tissues, which emphasizes its prominent role in cutaneous biology. We found decreased expression of cystatin M/E and cathepsin V in lesional atopic dermatitis and psoriasis epidermis at the mRNA level as well as the protein level. Cathepsin L and transglutaminase 3 were increased at the transcriptional level; however, this was not reflected by higher protein levels. Interestingly, the expression of all these molecules in reconstructed skin was qualitatively and quantitatively similar to the in vivo situation. Conclusions Disturbance of the cystatin M/E – cathepsin pathway could contribute to the dysregulated skin barrier function observed in inflammatory dermatoses. Human reconstructed skin appears to be a valuable model to study this novel biochemical pathway in vitro. [ABSTRACT FROM AUTHOR]

Background There is increasing evidence that stressors contribute to the severity of chronic inflammatory diseases such as psoriasis. However, much less is known about possible individual differences between patients in their stress reactivity, particularly the role of cognitive and behavioural factors, such as the role of worrying or scratching behaviour, in reaction to itch. Objectives To investigate the direct and moderating role of individual stress reactivity factors, particularly of cognitive and behavioural patterns of worrying and scratching, on the relationship between daily stressors and changes in disease severity [Psoriasis Area and Severity Index (PASI)] and itch in patients with psoriasis. Methods Patients were followed for 6 months through monthly clinical and self-reported measures of daily stressors, itch, disease severity and individual reactivity factors. Data from 62 patients were suitable for analysis. Results Cognitive and behavioural patterns of worrying and scratching were both independently related to an increase 4 weeks later in disease severity (PASI) and itch, at moments when patients experienced a high level of daily stressors. At these moments, stressors also interacted with vulnerability factors, showing that patients with more daily stress and high worrying and scratching had particularly worsened disease severity and itch. Conclusions Patients with high levels of worrying and scratching are most vulnerable to the impact of stressors on their psoriasis, particularly at highly stressful periods. [ABSTRACT FROM AUTHOR]

Background Cystatins are natural and specific inhibitors of endogenous mammalian lysosomal cysteine proteinases and exogenous microbial cysteine proteinases. Cystatins were shown to provide regulatory and protective functions against uncontrolled proteolysis in several disease processes. Recently we reported that cystatin M/E, which is a novel member of the cystatin gene family, has an unusually restricted expression pattern that is limited to skin. Although cystatin M/E possesses two distinct biochemical properties (it is a proteinase inhibitor and a substrate for transglutaminase) its physiological function is unknown. Disturbance of the balance between proteinases and their inhibitors can lead to irreversible damage as in chronic inflammatory reactions and tumour invasion. Objectives To examine the expression pattern of cystatin M/E in inflammatory conditions and neoplastic skin disorders in order to obtain possible clues on its function. Furthermore, we wished to determine whether cystatin M/E expression could discriminate between various types of neoplasia. Methods Biopsy material of normal skin, atopic dermatitis and psoriatic lesional skin, healing excisional wounds in healthy volunteers, and several types of epidermal neoplasia (keratoacanthoma, actinic keratosis, basal cell carcinoma and squamous cell carcinoma) were used in this study. For comparison we studied the expression of cystatin M/E in squamous neoplasias from noncutaneous origin. Affinity-purified polyclonal antibodies against cystatin M/E were used for immunohistochemical detection. Results Cystatin M/E is constitutively expressed in the stratum granulosum of normal skin, sebaceous glands, eccrine sweat glands and the infundibular epithelium of hair follicles. Expression in atopic dermatitis and psoriasis was found to extend to several layers of the stratum spinosum. In wound healing, cystatin M/E was not found in the edge of migrating keratinocytes, but it was strongly expressed in the... [ABSTRACT FROM AUTHOR]

Impetigo herpetiformis (IH) is a rare pustular dermatosis with unknown aetiology, typically occurring during pregnancy. Based upon a similar clinical and histological presentation, i.e. spongiform accumulation of polymorphonuclear leucocytes in the stratum corneum, several authors consider IH as a variant of generalized pustular psoriasis (GPP), while others state that IH is a separate entity. Skin-derived antileucoproteinase (SKALP) is a strong and specific inhibitor of human leucocyte elastase (HLE) and proteinase 3, two neutral proteinases that have been implicated in leucocyte migration and tissue destruction. Previously, we reported decreased SKALP activity in pustular forms of psoriasis compared with plaque psoriasis. In this study we present a case study of a patient with IH, where SKALP activity was measured using biochemical and immunochemical techniques. Epidermal scales and sera were collected during the course of the disease. Comparison was made with three patients with GPP and six patients with plaque psoriasis. Initially, anti-HLE activity in epidermal scales of the patient with IH was comparable with values in patients with GPP, i.e. decreased compared with plaque psoriasis. During the course of the disease, anti-elastase activity dropped to undetectable levels, concomitant with the appearance of free elastase activity. This finding suggests a total saturation of epidermal anti-HLE activity. Low levels of SKALP. presumably complexed with HLE, could be measured immunochemically in scale extracts. Serum levels of total SKAEP correlated with the disease activity. We suggest that a reduced amount of epidermal SKAEP contributes to an imbalance between elastase and its inhibitor, resulting in the formation of epidermal pustules. This mechanism of pustule formation could apply both to GPP and IH, suggesting a final common pathway in the pathogenic mechanisms of IH and GPP. [ABSTRACT FROM AUTHOR]

Allergic and irritant contact dermatitis are similar clinically, histologically and on immunohistochemistry. In the present investigation, we assessed whether study of the recruitment of cycling epidermal cells, and the expression of keratin 16 and involucrin, are of use in differentiating between the response to contact allergens and the response to the irritant detergent sodium lauryl sulphate. Both allergic and irritant challenges induced epidermal proliferation, and the expression of keratin 16 and involucrin, but the dynamics were different. Two and 3 days after challenge, a highly significant difference between the allergic and irritant reactions was observed with respect to involucrin expression assessed by MON-150 staining. [ABSTRACT FROM AUTHOR]

Application of sodium dodecyl sulphate (SDS) on the skin of healthy volunteers was used as a model for acute chemical injury. The time course of the response with respect to cell proliferation was studied using ornithine decarboxylase (ODC) activity. Erythema, polymorphonuclear leucocyte (PMN) infiltration, and the induction of epidermal antiproteinase activity (SKALP/elafin) were used as markers for the inflammatory response. ODC induction was similar to that in other models of acute skin injury, such as tape-stripping and ultraviolet light radiation. The amount of PMN infiltration correlated with erythema, but not with ODC induction. In contrast with findings in the tape-stripping model, no induction of SKAIP/elafin activity was found after SDS application. We conclude that cell proliferation as measured by ODC induction is a common feature in the various models for skin injury. Both the kinetics and the intensity of the inflammatory response, and the induction of epidermal antiproteinase activity, appear to vary, depending on the specific model. [ABSTRACT FROM AUTHOR]

The distribution of three (recently discovered) extracellular matrix components (tenascin, biglycan and decorin) was studied in normal adult human skin and in a number in monogenic disorders of keratinization, using immunohistology. The expression of tenascin, which is sparsely distributed in normal human dermis, was found to he grossly increased in epidermolytic hyper keratoses and in Darier's disease. Tenascin expression in three types of ichthyosis (X-linked recessive ichthyosis, autosomal dominant ichthyosis vulgaris, non-erythrodermic lamellar ichthyosis) was similar to that of normal skin. The presence of biglycan and decorin did not show a marked variation between the different disorders studied, suggesting that their expression is subject to regulatory mechanisms distinct from those of tenascin. The increased expression of tenascin in two disorders of keratinization with a hyper proliferative phenotype, lends further support to the hypothesis that dermal tenascin expression is increased as a result of epidermal hyperproliferation. [ABSTRACT FROM AUTHOR]

Tenascin (hexabrachion, cytotactin) is an extracellular matrix glycoprotein whose expression Is strongly Increased in hyperproliferative skin diseases, as shown by immunohistochemistry with polyclonal sera. In this study we describe a new monoclonal antibody (T2H5) against human tenascin. The specificity of T2H5 was validated by sequential immunoprecipitation of tenascin with polyclonal sera. T2H5 was used to analyse the presence of tenascin in basal cell carcinoma. Using Western blotting, at least two forms of tenascin were found, with approximate molecular weights of 210 and 300 kDa. In cultured human skin fibroblasts only the high molecular weight form was found. [ABSTRACT FROM AUTHOR]

The expression of tenascin, a recently discovered extracellular matrix glycoprotein, was studied by immunohistochemistry in normal human skin and in a number of skin diseases with epidermal hyperproliferation such as psoriasis, basal cell carcinoma. Bowen's disease and solar keratosis. Tenascin expression in the upper dermis of normal skin was found to vary from almost absent to patchy along the basal membrane. Staining was continuous and intense around blood vessels, hair follicles and eccrine sweat ducts. In basal cell carcinoma a marked expression of tenascin was found in the tumour stroma, especially adjacent to the basal membrane surrounding the tumour cell nests. In Bowen's disease and solar keratosis, tenascin expression was found in the dermis next to the keratinocytes, in psoriasis the dermal papillae of clinically involved skin were intensely stained and a continuous band of tenascin was present in the upper dermis along the basal membrane. The distribution of tenascin differed from other known extracellular matrix components. [ABSTRACT FROM AUTHOR]

Elastase inhibiting activity (EIA) was demonstrated in the epidermis from lesions and in psoriatic scale, whereas normal epidermis did not contain significant EIA. Two new elastase inhibitors were partially purified and characterized using psoriatic scale as a source. The two species (approximate molecular weights 10 and 20 kDa) were shown to be stable, and high-affinity inhibitors of human leucocyte elastase (Ki < 10-10 M). No activity against human cathepsin G could be demonstrated. Cultured human keratinocytes were shown to contain EIA activity similar to that found in psoriatic scale. EIA could also be demonstrated in human epidermis following the induction of an experimental inflammatory response by sellotape-stripping. We propose the acronym SKALP (skin-derived antileucoprotease) as a name for these new proteinase inhibitors. [ABSTRACT FROM AUTHOR]

We report an investigation of peripheral blood polymorphonuclear leukocytes (PMN) from untreated patients with mild, quiescent psoriasis. Four aspects of the ‘metabolic burst’ were measured to illustrate phagocytosis-related events. These were: myeloperoxidase activity, hydrogen peroxide release, superoxide production and luminol-amplified chemiluminescence. Our study does not support the concept of an intrinsic abnormality of the PMN in psoriasis, but provides additional evidence for disease activity-dependent changes in phagocytic behaviour. Possible interactions with certain humoral factors, the so-called opsonins, are discussed. [ABSTRACT FROM AUTHOR]

Background. After the injection of rabbit anti-mouse glomerular basement membrane (GBM) antibody into normal C57BL/6J mice severe albuminuria develops, which reaches a peak at 24 h. This early albuminuria is dependent on polymorphonuclear granulocytes (PMN) and is completely absent in the congenic beige mutant strain (C57BL/6J, bg/bg), which is genetically deficient in leukocytic neutral proteinase activity. We now studied the development of anti-GBM nephritis in beige mice during the later heterologous phase. Methods. In untreated beige mice we assessed the albuminuria and glomerular lesions on days 1–5 after i.v. injection of anti-GBM antibody. Secondly, effector mechanisms involved in the later days of the heterologous phase were studied by substitution of whole anti-GBM antibodies by F(ab′)2 fragments, by leukocyte depletion (total body irradiation), scavenging of reactive oxygen metabolites (dimethylsulfoxide treatment), and complement depletion (cobra venom factor treatment). Results. In the later part of the heterologous phase (days 2–5), when there is still no sign of autologous antibody formation, i.v. injection of anti-GBM anti-bodies in beige mice induces nephritis with gradually increasing albuminuria, that reaches levels similar to those in non-deficient, congenic controls by day 3. This late albuminuria did not occur after injection of F(ab′)2 fragments of the antibody, could be prevented by leukocyte depletion, and was greatly reduced by treatment with dimethylsulfoxide, a scavenger of hydroxyl radicals. The late albuminuria was not influenced by complement depletion with cobra venom factor. Histologic and immunohistologic studies gave no indication for a role of glomerular macrophages or lymphocytes. Conclusions. The heterologous phase in murine anti-GBM nephritis is a biphasic process, with sequential involvement of different and independent mediating systems: both phases are PMN-dependent, but only the early albuminuria depends on leukocytic neutral proteinase activity, whereas the albuminuria and the glomerular damage at later days are effected by reactive oxygen metabolites, most probably originating from PMN accumulating in the glomerulus. [ABSTRACT FROM PUBLISHER]

The article focuses on the significance of microbiome in psoriasis. Topics discussed include the expansion of microbiome field, the relationship between diseases, the DNA sequencing technologies, microbial gene sequencing, genetic risk factors of psoriasis, and the effect of gut microbiome on human physiology.

Two new elastase inhibitors (SKALP, skin-derived antileucoproteases) were recently described in the lesional skin in psoriasis. The present study investigated the distribution of SKALP activity in the marginal zone of spreading psoriatic plaques. In a 4-mm zone immediately adjacent to the erythematosquamous plaques, SKALP activity was slightly increased compared to distant uninvolved skin. Within the lesion the anti-elastase activity was pronounced, but was significantly higher in the central zone of the plaque compared to the periphery. The appearance of SKALP in the psoriatic lesion appears to be a late event compared to endothelial involvement, intraepidermal accumulation of PMNs, epidermal proliferation and abnormal keratinization. This observation lends further support for the hypothesis that the induction of anti-elastase activity is associated with the off-switch of cutaneous inflammation. [ABSTRACT FROM AUTHOR]

Background Recent genome-wide association studies have identified several genetic risk factors for psoriasis, but data on their association with age at onset are lacking. Objectives To compare the association between known risk alleles and psoriasis in well-defined cohorts with paediatric- and adult-onset psoriasis. Methods Based on previous studies we selected seven genes and loci associated with psoriasis. Patients with paediatric-onset (< 18 years) and adult-onset psoriasis (≥ 18 years) and controls were genotyped. Genotype frequencies were compared between controls ( n = 450) and all cases ( n = 217), and between controls and cases stratified for confirmed age at onset (paediatric onset n = 80, adult onset n = 85). Results Paediatric-onset psoriasis showed a significant association with single nucleotide polymorphisms in the ERAP1 ( P = 0·042) and IL23R loci ( P = 0·042), LCE3C_LCE3B-del ( P = 0·003) and HLA-C*06 ( P = 1·72 × 10−19) when compared with the control group. A significant association of these four genes was also demonstrated when all psoriasis cases were compared with controls. In adult-onset psoriasis a significant association was found for HLA-C*06 ( P = 5·11 × 10−6) and for LCE3C_LCE3B-del ( P = 0·042). No associations were found for the IFIH1, IL12B and TRAF3IP2 loci. Conclusions Notwithstanding the small cohort sizes, we demonstrated an association with established and recently discovered genetic risk factors in paediatric-onset psoriasis including genes involved in epidermal barrier function and adaptive immunity. Our data suggest that heritable factors may play a more important role in paediatric-onset psoriasis than in adult-onset psoriasis. [ABSTRACT FROM AUTHOR]