CCL20 in psoriasis: A potential biomarker of disease severity, inflammation, and impaired vascular health.

BACKGROUND: Psoriasis is associated with increased cardiovascular risk that is not captured by traditional proinflammatory biomarkers. OBJECTIVE: To investigate the relationship between Psoriasis Area and Severity Index, circulating proinflammatory biomarkers, and vascular health in psoriasis. METHODS: In patients with psoriasis and in age and sex-matched controls, 273 proteins were analyzed with the Proseek Multiplex Cardiovascular disease reagents kit and Inflammatory reagents kit (Olink Bioscience), whereas vascular endothelial inflammation and health were measured via direct transcriptomic analysis of brachial vein endothelial cells. RESULTS: In psoriasis, chemokine ligand 20 (CCL20), interleukin (IL) 6, and IL-17A were the top 3 circulating proinflammatory cytokines. Vascular endothelial inflammation correlated with CCL20 (r = 0.55; P < .001) and less so with IL-6 (r = 0.36; P = .04) and IL-17A (r = 0.29; P = .12). After adjustment for potential confounders, the association between CCL20 and vascular endothelial inflammation remained significant (ß = 1.71; P = .02). In nested models, CCL20 added value (χ2 = 79.22; P < .001) to a model already incorporating the Psoriasis Area and Severity Index, Framingham risk, high-sensitivity C-reactive protein, Il-17A, and IL-6 (χ2 = 48.18; P < .001) in predicting vascular endothelial inflammation. LIMITATIONS: Our study was observational and did not allow for causal inference in the relationship between CCL20 and cardiovascular risk. CONCLUSION: We demonstrate that CCL20 expression has a strong association with vascular endothelial inflammation, reflects systemic inflammation, and may serve as a potential biomarker of impaired vascular health in psoriasis.

Serum IgE Predicts Difference of Population and Allergens in Allergic Diseases: Data from Weifang City, China.

BACKGROUND: Immunoglobulin E (IgE) is the most important promoter of allergic inflammation. However, there are few systematic studies on IgE in age range, genders, disease spectrum, and time regularity. AIM: To screen the common allergens, allergen spectrum, and IgE difference between type 2 inflammatory allergic diseases and other allergic diseases in Weifang, China. METHODS: A retrospective study was performed by estimating patients' clinical data suffering from allergic diseases (urticaria, pollinosis, allergic rhinitis, atopic dermatitis, and bronchial asthma) between May 2019 and April 2020 using an allergen detection kit of Macro-Union Pharmaceutical. RESULTS: 732 of the 1367 patients showed different antigen positive, and the positive rate was 53.5%. The most common allergens were dust mites, mixed fungi, Artemisia pollen, cat/dog dander, and cockroaches. There were 27.0% (369/1367) of the patients with single positive allergen-specific IgE (sIgE), 26.5% (363/1367) with multiple-positive IgE. The total immunoglobulin E (tIgE) levels varied with gender, age, and type of disease. There was a difference in the distribution of allergens between children and adults. A positive correlation between the serum-specific IgE and the corresponding local inhaled allergen density was observed. CONCLUSIONS: In this study, we found that type 2 inflammatory allergic diseases have higher serum IgE and a higher probability of inhaled sIgE positive. According to age, gender, and condition, serological IgE detection of allergens provides new insight into the early diagnosis and prevention of allergic diseases.

High-fat diet exacerbates imiquimod-induced psoriasis-like dermatitis in mice.

Psoriasis, a chronic inflammatory skin disease, is closely related to systemic metabolism. An elevated body mass index (BMI) is a risk factor for psoriasis; inflammasomes are activated by adipose tissue macrophages in obese subjects. We hypothesized that hyperlipidaemia is involved in the pathogenesis of psoriasis and examined the role of a high-fat diet (HFD) in the development of psoriasis in imiquimod (IMQ)-treated mice. The body weight and serum level of cholesterol were significantly higher in mice fed an HFD than in a regular diet (RD). HFD mice had higher psoriasis skin scores, and the number of neutrophils infiltrating into the lesional skin was elevated. IL-17A mRNA expression was significantly increased in the skin of IMQ-treated HFD mice; the expression of IL-22, IL-23 and TNF-α mRNA was not enhanced. Caspase-1 and IL-1ß were activated in the skin of IMQ-treated HFD mice, and their serum level of IL-17A, TNF-α and IL-1ß was significantly upregulated. Our findings strongly suggest that hyperlipidaemia is involved in the development and progression of psoriasis via systemic inflammation and inflammasome activation.

Chronic Psoriatic Skin Inflammation Leads to Increased Monocyte Adhesion and Aggregation.

Psoriasis patients exhibit an increased risk of death by cardiovascular disease (CVD) and have elevated levels of circulating intermediate (CD14(++)CD16(+)) monocytes. This elevation could represent evidence of monocyte dysfunction in psoriasis patients at risk for CVD, as increases in circulating CD14(++)CD16(+) monocytes are predictive of myocardial infarction and death. An elevation in the CD14(++)CD16(+) cell population has been previously reported in patients with psoriatic disease, which has been confirmed in the cohort of our human psoriasis patients. CD16 expression was induced in CD14(++)CD16(-) classical monocytes following plastic adhesion, which also elicited enhanced ß2 but not ß1 integrin surface expression, suggesting increased adhesive capacity. Indeed, we found that psoriasis patients have increased monocyte aggregation among circulating PBMCs, which is recapitulated in the KC-Tie2 murine model of psoriasis. Visualization of human monocyte aggregates using imaging cytometry revealed that classical (CD14(++)CD16(-)) monocytes are the predominant cell type participating in these aggregate pairs. Many of these pairs also included CD16(+) monocytes, which could account for apparent elevations of intermediate monocytes. Additionally, intermediate monocytes and monocyte aggregates were the predominant cell type to adhere to TNF-α- and IL-17A-stimulated dermal endothelium. Ingenuity Pathway Analysis demonstrated that monocyte aggregates have a distinct transcriptional profile from singlet monocytes and monocytes following plastic adhesion, suggesting that circulating monocyte responses to aggregation are not fully accounted for by homotypic adhesion, and that further factors influence their functionality.

The Preventive Effect of Coffee Compounds on Dermatitis and Epidermal Pigmentation after Ultraviolet Irradiation in Mice.

BACKGROUND: Ultraviolet (UV) irradiation is well known to promote inflammation and pigmentation of skin. UVB mainly affects dermatitis and pigmentation. Coffee contains a number of polyphenols, such as caffeic acid (CA) and chlorogenic acid (CGA) but their in vivo bioactivity for photobiology remains unclear. METHODS: C57BL/6j male mice were irradiated with UVB (1.0 kJ/m2/day) for 3 days. Five days after the final session of UVB irradiation, the dorsal skin, ear epidermis, and blood samples were analyzed to investigate the inflammatory factors, melanogenesis factors and related hormones. RESULTS: After the oral administration of CA (100 mg/day) or CGA (100 mg/day) for 8 days, only CA was found to inhibit dermatitis and pigmentation. The pathway by which CA inhibits dermatitis is related to the mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK)1/2/cAMP response element binding protein (CREB) pathway. Otherwise, the pathway by which CA inhibits pigmentation is related to the activation of the ß-endorphin-µ-opioid receptor and suppresses the cAMP-microphthalmia-associated transcription factor (MITF) pathway. CONCLUSION: It is suggested that the oral administration of CA prevented dermatitis and pigmentation after UVB irradiation in mice.

Histiocytoid autoimmunity-related neutrophilic dermatosis in a patient with rheumatoid arthritis.

Autoimmunity-associated neutrophilic dermatoses are a recently recognized manifestation of connective tissue diseases, in particular, lupus erythematosus. These entities are clinically and sometimes histopathologically distinct from classic neutrophilic dermatoses. We describe a case of an autoimmunity-related neutrophilic dermatosis in a patient with rheumatoid arthritis. In addition to this uncommon association, there was an absence of mature neutrophils and a population of immature histiocytoid granulocytes. This unusual case expands the concept of histiocytoid neutrophilic dermatoses to include those seen in association with autoimmune connective tissue diseases.

Impact of loss of NF-κB1, NF-κB2 or c-REL on SLE-like autoimmune disease and lymphadenopathy in Fas(lpr/lpr) mutant mice.

Defects in apoptosis can cause autoimmune disease. Loss-of-function mutations in the 'death receptor' FAS impair the deletion of autoreactive lymphocytes in the periphery, leading to progressive lymphadenopathy and systemic lupus erythematosus-like autoimmune disease in mice (Fas(lpr/lpr) (mice homozygous for the lymphoproliferation inducing spontaneous mutation)) and humans. The REL/nuclear factor-κB (NF-κB) transcription factors regulate a broad range of immune effector functions and are also implicated in various autoimmune diseases. We generated compound mutant mice to investigate the individual functions of the NF-κB family members NF-κB1, NF-κB2 and c-REL in the various autoimmune pathologies of Fas(lpr/lpr) mutant mice. We show that loss of each of these transcription factors resulted in amelioration of many classical features of autoimmune disease, including hypergammaglobulinaemia, anti-nuclear autoantibodies and autoantibodies against tissue-specific antigens. Remarkably, only c-REL deficiency substantially reduced immune complex-mediated glomerulonephritis and extended the lifespan of Fas(lpr/lpr) mice. Interestingly, compared with the Fas(lpr/lpr) animals, Fas(lpr/lpr)nfkb2(-/-) mice presented with a dramatic acceleration and augmentation of lymphadenopathy that was accompanied by severe lung pathology due to extensive lymphocytic infiltration. The Fas(lpr/lpr)nfkb1(-/-) mice exhibited the combined pathologies caused by defects in FAS-mediated apoptosis and premature ageing due to loss of NF-κB1. These findings demonstrate that different NF-κB family members exert distinct roles in the development of the diverse autoimmune and lymphoproliferative pathologies that arise in Fas(lpr/lpr) mice, and suggest that pharmacological targeting of c-REL should be considered as a strategy for therapeutic intervention in autoimmune diseases.

[Modern allergy diagnostic procedures and their clinical application]. / Moderne Allergiediagnostik und ihre klinische Anwendung.

Due to the increasing incidence of allergies, the importance of allergy diagnostic procedures is growing. In addition to a patient's history and prick, intracutaneous and patch testing, serological testing is an important diagnostic procedure. In recent years, tremendous advances have been made in the area of in vitro allergy tests. In particular, it is possible to predict severity and risk management of food allergies with component-based IgE diagnostic procedures. Even new allergy syndromes have been elucidated at the molecular level.

Phenobarbital-induced pellagra resulted in death.

Pellagra is caused by deficiency of niacin or its precursor tryptophan. While cutaneous lesions are the most prominent feature of the disease, gastrointestinal, neurological and psychiatric signs and symptoms are the other characteristics of the disease. In this case report, we present a 29-year-old female patient with discoloration of hands and feet diagnosed with pellagra.

Comparison of plasma vitamin A and E, copper and zinc levels in free-ranging and captive greater flamingos (Phoenicopterus roseus) and their relation to pododermatitis.

Pododermatitis is a worldwide problem in captive flamingos. Studies in domestic poultry showed that nutrition is a possible influencing factor for pododermatitis. Vitamin A and E, copper and zinc levels were analysed in two different diets (diet 1 = in-house mix and diet 2 = commercial diet) and in plasma of captive greater flamingos fed these diets and compared to those of free-ranging greater flamingos. Results were analysed with respect to type and severity of foot lesions of the individuals from the different groups. Juvenile and subadult/adult captive flamingos on diet 1 showed various types and severities of foot lesions, whereas no foot lesions were found at the time of blood sampling in juvenile captive flamingos on diet 2. Juvenile captive flamingos on diet 1 had significantly lower plasma zinc levels than juvenile captive flamingos on diet 2 and juvenile free-ranging flamingos; data were also lower than reference ranges for flamingos, poultry and cranes. There were no significant differences in plasma vitamin A, vitamin E, copper or zinc levels between animals with different types of foot lesions or with different severity scores. Shortly after the change to diet 2 (fed to juvenile captive flamingos that did not show any foot lesion), the flooring of the outdoor water pools was covered with fine granular sand. Because both factors (nutrition and flooring) were changed during the same evaluation period, it cannot be concluded which factor contributed in what extent to the reduction of foot lesions. While it is assumed that low plasma zinc levels identified in the group of juvenile captive flamingos on diet 1 were not directly responsible for foot lesions observed in these animals, they may have played a role in altering the skin integrity of the feet and predisposing them to pododermatitis.

Serum kallikrein-8 correlates with skin activity, but not psoriatic arthritis, in patients with psoriatic disease.

BACKGROUND: About 30% of cutaneous psoriasis (PsC) patients develop psoriatic arthritis (PsA) in the joint, which is under-recognized by dermatologists. Biomarkers for PsA are needed so that early referral to a rheumatologist is made. Kallikreins (KLKs) are secreted serine proteases implicated in skin desquamation and inflammation. This study examined KLK potential as serum biomarkers of PsA in cutaneous psoriasis patients. METHODS: KLKs were measured by ELISAs in synovial fluids of three PsA patients and three control early osteoarthritis (OA) patients, as well as in a cohort of 152 serum samples collected from age- and sex-matched PsC patients, with (n=76) or without PsA (n=76). KLK expression in psoriatic plaques was examined by immunohistochemistry. Univariate and multivariate logistic regression analyses were conducted to analyze the association between serum KLK levels and disease class (PsC, PsA). Serum KLKs that associated with PsA were correlated with clinical parameters of skin and joint activity. RESULTS: Among the seven KLKs tested, KLK6 and KLK8 were elevated in both PsA synovial fluids and psoriatic plaques, but only serum KLK8 levels were associated with psoriatic disease (odds ratio=2.56, p=0.03). Although significantly elevated in PsC and PsA sera compared to healthy controls, KLK8 did not discriminate PsA from PsC patients. KLK8 correlated positively with the psoriasis area and severity index (PASI) (r=0.43, p=0.001) independent of age, sex and psoriasis duration ( ß=1.153, p=0.0003) and exhibited no correlations with tender or swollen joint counts. CONCLUSIONS: Increased KLK8 serum level in PsA patients reflects disease activity in the skin but not in the joints. Serum KLK levels are not useful for screening psoriasis patients for PsA.

Frequency of symptomatic zinc deficiency in very low birth weight infants.

Current concepts on zinc requirements for premature infants rely on studies dating back more than 20 years. Given that nowadays more premature infants frequently survive we aimed to obtain recent frequency data on zinc deficiency in very low birth weight (VLBW) infants.226 VLBW infants born between July 2005 and December 2009 were retrospectively included in this study. Mean gestational age (GA) was 28.7 weeks (range 23+0 to 38+0) and mean birth weight 1120g (range 354-1495). All infants received zinc supplementation according to the ESPGHAN guidelines. 26 (11.5%) patients showed clinical signs for zinc deficiency of whom 15 had serum zinc concentrations < 50µg/dl, 9 between 50 and 70 µg/dl and 2 > 70 µg/dl. Infants presenting with dermatitis had significantly lower concentrations (mean 26.7 µg/dl, range 19-31) when compared to infants with diarrhoea or isolated peripheral oedema (35.3 µg/dl and 51.8 µg/dl respectively). Strongest independent risk factors were low GA, being small for GA and suffering from intestinal resection due to necrotizing enterocolitis. Frequency of zinc concentrations <50 µg/dl were calculated to be 6.6% in VLBW infants.Even though current guidelines for zinc supplementation were followed the frequency of zinc deficiency was found to be unexpectedly high in ELBW and SGA infants. Despite the retrospective nature of this single centre study, our data strongly suggest that recommendations on zinc supplementation in ELBW and SGA infants should be reviewed.

Hexavalent chromium: Regulation and health effects.

Despite the knowledge about heavy metals toxicity on humans, its use is widely spread mainly for industrial processes. Chromium is an element that belongs to this group and although it is present in our daily diet, it can also be harmful for humans, causing skin allergies and increasing the risk of lung cancer, among other health effects reported. In this review, we highlight its nutritional role, its toxicokinetic and toxicodynamic in humans, its regulation in the industry and the biomonitoring proposal of this element in blood and urine samples with the aim to control the level of exposure of the workers in military industry and also of the general population.

Neoplastic and inflammatory skin disorders and serum levels of polychlorinated biphenyls in a population living in a highly polluted area.

BACKGROUND: Although polychlorinated biphenyls (PCBs) have been classified as human carcinogens for their association with melanoma, few data are available for other skin lesions. OBJECTIVES: To investigate the prevalence of skin disorders in a highly PCB polluted area in northern Italy, with locally produced food as the main source of human contamination, and evaluate the association between skin lesions and PCB serum levels, taking account of possible confounders. MATERIALS & METHODS: Thirty-three PCB congeners were quantitatively assessed and a total of 189 subjects were equally divided into three groups using the tertiles of total PCB serum concentrations. All subjects underwent a clinical examination and were interviewed on their risk factors and history of skin diseases. RESULTS: No statistically significant difference was found in the prevalence of skin cancer, nevi, pigmentary disorders as well as inflammatory and infectious skin diseases among the three PCB exposure groups. It should be noted that the use of questionnaires to assess subjects' past sun exposure and photoprotection is intrinsically flawed due to random error. CONCLUSION: Our study does not support the hypothesis that chronic PCB exposure, through the ingestion of contaminated food, determines an increased risk of developing skin diseases.

Platelets: Underestimated Regulators of Autoinflammation in Psoriasis.

Platelets have long been known as mediators of hemostasis and, more recently, as mediators of thromboinflammation, although their physiopathological role has mostly been investigated in the context of disease of internal organs, such as liver and kidney, or systemic disorders. Of late, exciting recent data suggest that platelets may also play a role in inflammation at distal sites such as the skin: recent studies show that platelets, by engaging polymorphonuclear neutrophils (PMNs), contribute to local inflammation in the frequent skin disorder, psoriasis. In an experimental model, systemic depletion of platelets drastically attenuated skin inflammation by preventing PMN infiltration of the skin. A broader role of platelets in different types of skin inflammation is therefore likely, and in this paper, we specifically review recent advances in psoriasis. Special emphasis is given to the crosstalk with systemic platelet effects, which may be of interest in psoriasis-related cardiovascular comorbidities. Furthermore, we discuss the potential for platelet-centered interventions in the therapy for psoriasis.

Platelet P-selectin reflects a state of cutaneous inflammation: possible application to monitor treatment efficacy in psoriasis.

Haemostasis-maintaining platelets are also recognized as important modulators in the regulation of immune response. Activated platelets expressing P-selectin (CD62P) are involved in the extravasation of leucocytes. This study evaluated platelet P-selectin expression as a biomarker for cutaneous inflammation. P-selectin expression was assessed by flow cytometry in 147 successive patients suffering from an inflammatory or infectious skin condition at the day of admission for in-patient treatment as well as a day prior to demission. Forty-one patients admitted for allergy testing served as controls. A commercially available ELISA was used in 17 patients to determine soluble P-selectin in the plasma. In patients with psoriasis, the Psoriasis Area and Severity Index (PASI) was documented as a measure for disease severity. We observed a significant increase in platelet P-selectin expression in patients with inflammatory or infectious disorders, when compared to the control group (3,01% vs. 1,46%; P < 0.000001). Successful treatment resulted in a significant decrease in P-selectin expression to the level of the control group. In the case of psoriasis (n = 47), we found highly significant correlation between P-selectin and PASI (r = 0.51; P < 0.000001), as well as between the change in the PASI and the change in P-selectin expression (r = 0.4; P = 0.006). Platelet P-selectin expression as determined by flow cytometry correlated well with the results of soluble P-selectin, determined by ELISA (r = 0.63; P < 0.01). Thus, platelet P-selectin expression may be used as an efficacy biomarker to monitor treatment success in psoriasis. As platelet P-selectin correlates with soluble P-selectin in patient plasma, which can be measured by ELISA, the latter is feasible also for routine use.

Anti-IL5 decreases the number of eosinophils but not the severity of dermatitis in Sharpin-deficient mice.

Sharpin-deficient (Sharpin(cpdm)) mutant mice develop a chronic eosinophilic dermatitis. To determine the efficacy of eosinophil-depletion in chronic inflammation, Sharpin(cpdm) mice were treated with anti-IL5 antibodies. Mice treated with anti-IL5 had a 90% reduction of circulating eosinophils and a 50% decrease in cutaneous eosinophils after 10 days compared with sham-treated littermates. Reducing the number of eosinophils resulted in increased severity of alopecia and erythema and a significant increase in epidermal thickness. Skin homogenates from mice treated with anti-IL5 had decreased mRNA expression of arylsulfatase B (Arsb), diamine oxidase (amiloride-binding protein 1, also called histaminase; Abp1) and Il10, which are mediators that eosinophils may release to quench inflammation. Skin homogenates from mice treated with anti-IL5 also had decreased mRNA expression of Il4, Il5, Ccl11, kit ligand (Kitl) and Tgfa; and increased mRNA expression of Tgfb1, Mmp12 and tenascin C (Tnc). In order to further decrease the accumulation of eosinophils, Sharpin(cpdm) mice were crossed with IL5 null mice. Il5(-/-), Sharpin(cpdm)/Sharpin(cpdm) mice had a 98% reduction of circulating eosinophils and a 95% decrease in cutaneous eosinophils compared with IL5-sufficient Sharpin(cpdm) mice. The severity of the lesions was similar between IL5-sufficient and IL5-deficient mice. Double mutant mice had a significant decrease in Abp1, and a significant increase in Tgfb1, Mmp12 and Tnc mRNA compared with controls. These data indicate that eosinophils are not essential for the development of dermatitis in Sharpin(cpdm) mice and suggest that eosinophils have both pro-inflammatory and anti-inflammatory roles in the skin of these mice.

Platelets as versatile regulators of cutaneous inflammation.

It is generally accepted that the main roles of platelets are to maintain hemostasis and perform thrombosis at sites of injury. However, more recently it has become apparent that platelets also play prominent roles in immune and/or inflammatory processes. Platelets release various kinds and considerable amounts of secretory molecules such as chemokines, monoamines, and cytokine-like factors upon stimulation. They also express a wide variety of immune-related receptors, such as P-selectin and CD40L. Additionally, the hyperaggregability of platelets has been demonstrated in several inflammatory skin diseases. In the last decade, more specific and versatile roles for platelets in the pathophysiology of skin inflammation, such as in atopic dermatitis, have been disclosed, e.g. stimulating keratinocytes, leukocytes, endothelial cells, and other platelets; trafficking leukocytes to skin tissue; inhibiting monocytic apoptosis; inducing fibrosis; provoking itchiness; and regulating inflammation. New anti-platelet strategies directed against the platelet activation process may create new possibilities for the treatment of cutaneous inflammatory diseases such as atopic dermatitis.

Peripheral blood leukocyte subpopulation of dairy cows with digital dermatitis and effect of hoof trimming with antibiotic treatment.

In the present study, 30 cows were used to evaluate the changes in the peripheral blood leukocyte subpopulation of dairy cows with digital dermatitis (DD) following hoof trimming and antibiotic treatment. The cows were divided into two groups; 18 cows (DD group) had DD on both hind feet, and 12 cows (control group) had four feet with no clinical abnormalities. The DD group was further divided into two groups based on the treatment; the antibiotic group (8 cows) was treated with only 2% lincomycin liquid spray once daily for 3 days, and the trimmed group (10 cows) received trimming of hooves as well as treatment with 2% lincomycin liquid spray. The plasma cortisol concentration was significantly higher in both DD groups before treatment than in the control group, and it decreased significantly after hoof trimming in the trimmed group. The number of CD3(+), CD4(+), WC1(+) and CD21(+) cells in both DD groups before treatment was significantly lower than that of the control group. The number of CD3(+), CD4(+), WC1(+) and CD21(+) cells in the trimmed group increased after treatment. These results indicated that cows with DD suffer from stress and reduced number of T and B cells. Treatment of DD with both hoof trimming and 2% lincomycin liquid spray was effective for reducing the stress and bringing the immune cell number back to the normal range.