Psoriasis activation of cells important in cardiovascular disease

Psoriasis is an immune mediated inflammatory disease which affects 2-3% of the world’s population. Over the last decade, psoriasis has been acknowledged as an independent risk factor for atherosclerosis. The precise mechanism or mechanisms of the heightened risk is widely speculated. Endothelial cells and macrophages are central players in the immunopathological development of both diseases. Interleukin-36 cytokines (IL-36) have been heavily implicated in psoriasis immunopathology. Significant upregulation of epidermal IL-36 is a recognised characteristic of psoriatic skin inflammation. IL-36 induces inflammatory responses in dendritic cells, fibroblasts and epithelial cells. While vascular alterations are a hallmark of psoriatic lesions and dermal endothelial cells are well known to play a critical role in dermal inflammation, the effects of IL-36 on endothelial cells have not been defined. We report that endothelial cells including dermal microvascular cells express a functionally active IL-36 receptor. Adhesion molecules VCAM-1 and ICAM-1 are upregulated following IL-36γ stimulation, and this is reversed in the presence of the endogenous IL-36 receptor antagonist. IL-36γ-stimulated endothelial cells secrete the proinflammatory chemokines IL-8, CCL2 and CCL20. Chemotaxis assays showed increased migration of T-cells following IL-36γ stimulation of endothelial cells. Both resident and infiltrating inflammatory myeloid cells contribute to the immunopathology of psoriasis by promoting the IL-23/IL-17 axis. We show that IL-36γ induces the production of psoriasis-associated cytokines from macrophages (IL-23, TNFα) and that this response is enhanced in macrophages from psoriasis patients. This effect is specific for IL-36γ and could not be mimicked by other IL-1 family cytokines such as IL-1α. Furthermore, IL-36γ stimulated macrophages potently activated endothelial cells as illustrated by ICAM-1(CD54) upregulation, and led to increased adherence of monocytes, effects that were markedly more pronounced for psoriatic macrophages. Interestingly, regardless of stimulus, monocytes isolated from psoriasis patients showed increased adherence to both the stimulated and unstimulated endothelium when compared to monocytes from healthy individuals. Collectively, these findings add to the growing evidence for IL-36γ having roles in psoriatic responses, by enhancing endothelium directed leukocyte infiltration into the skin and strengthening the IL-23/IL-17 pathway. Our findings also point to a cellular response which could potentially support cardiovascular comorbidities in psoriasis.University of Bradford and the Centre for Skin Science

Intestinal and enthesis innate immunity in early axial spondyloarthropathy

Axial SpA (axSpA), encompassing AS, is a multifactorial disease that localizes to sites of high spinal biomechanical stress. Much has been written on T cells and adaptive immunity in axSpA, which is understandable given the very strong HLA-B27 disease association. Extra-axial disease characteristically involves the anterior uveal tract, aortic root, lung apex and terminal ileum. Under recent classification, axSpA is classified as an intermediate between autoimmunity and autoinflammatory disease, with the latter term being synonymous with innate immune dysregulation. The purpose of this review is to evaluate the ‘danger signals’ from both the exogenous intestinal microbiotal adjuvants or pathogen-associated molecular patterns that access the circulation and endogenously derived damaged self-tissue or damage-associated molecular patterns derived from entheses and other sites of high biomechanical stress or damage that may serve as key drivers of axSpA onset, evolution, disease flares and eventual outcomes

IL-36γ has proinflammatory effects on human endothelial cells

Interleukin-36 cytokines are predominantly expressed by epithelial cells. Significant upregulation of epidermal IL-36 is now a recognised characteristic of psoriatic skin inflammation. IL-36 is known to induce inflammatory responses in dendritic cells, fibroblasts and epithelial cells. Although vascular alterations are a hallmark of psoriatic lesions and dermal endothelial cells are well known to play a critical role in skin inflammation, the effects of IL-36 on endothelial cells are unexplored. We here show that endothelial cells including dermal microvascular cells express a functionally active IL-36 receptor. Adhesion molecules VCAM-1 and ICAM-1 are upregulated by IL-36γ stimulation and this is reversed by the presence of the endogenous IL-36 receptor antagonist. IL-36γ stimulated endothelial cells secrete the proinflammatory chemokines IL-8, CCL2 and CCL20. Chemotaxis assays showed increased migration of T cells following IL-36γ stimulation of endothelial cells. These results suggest a role for IL-36γ in the dermal vascular compartment and it is likely to enhance psoriatic skin inflammation by activating endothelial cells and promoting leukocyte recruitment. This article is protected by copyright. All rights reserved

The Component Packaging Problem: A Vehicle for the Development of Multidisciplinary Design and Analysis Methodologies

This report summarizes academic research which has resulted in an increased appreciation for multidisciplinary efforts among our students, colleagues and administrators. It has also generated a number of research ideas that emerged from the interaction between disciplines. Overall, 17 undergraduate students and 16 graduate students benefited directly from the NASA grant: an additional 11 graduate students were impacted and participated without financial support from NASA. The work resulted in 16 theses (with 7 to be completed in the near future), 67 papers or reports mostly published in 8 journals and/or presented at various conferences (a total of 83 papers, presentations and reports published based on NASA inspired or supported work). In addition, the faculty and students presented related work at many meetings, and continuing work has been proposed to NSF, the Army, Industry and other state and federal institutions to continue efforts in the direction of multidisciplinary and recently multi-objective design and analysis. The specific problem addressed is component packing which was solved as a multi-objective problem using iterative genetic algorithms and decomposition. Further testing and refinement of the methodology developed is presently under investigation. Teaming issues research and classes resulted in the publication of a web site, (http://design.eng.clemson.edu/psych4991) which provides pointers and techniques to interested parties. Specific advantages of using iterative genetic algorithms, hurdles faced and resolved, and institutional difficulties associated with multi-discipline teaming are described in some detail

COVID-19 Vasculitis and vasculopathy-Distinct immunopathology emerging from the close juxtaposition of Type II Pneumocytes and Pulmonary Endothelial Cells

The SARS-CoV-2 virus ACE-2 receptor utilization for cellular entry and the defined ACE-2 receptor role in cardiovascular medicine hinted at dysregulated endothelial function or even direct viral endotheliitis as the key driver of severe COVID-19 vascular immunopathology including reports of vasculitis. In this article, we critically review COVID-19 immunopathology from the vasculitis perspective and highlight the non-infectious nature of vascular endothelial involvement in severe COVID-19. Whilst COVID-19 lung disease pathological changes included juxta-capillary and vascular macrophage and lymphocytic infiltration typical of vasculitis, we review the evidence reflecting that such “vasculitis” reflects an extension of pneumonic inflammatory pathology to encompass these thin-walled vessels. Definitive, extrapulmonary clinically discernible vasculitis including cutaneous and cardiac vasculitis also emerged- namely a dysregulated interferon expression or “COVID toes” and an ill-defined systemic Kawasaki-like disease. These two latter genuine vasculitis pathologies were not associated with severe COVID-19 pneumonia. This was distinct from cutaneous vasculitis in severe COVID-19 that demonstrated pauci-immune infiltrates and prominent immunothrombosis that appears to represent a novel immunothrombotic vasculitis mimic contributed to by RNAaemia or potentially diffuse pulmonary venous tree thrombosis with systemic embolization with small arteriolar territory occlusion, although the latter remains unproven. Herein, we also performed a systematic literature review of COVID-19 vasculitis and reports of post-SARS-CoV-2 vaccination related vasculitis with respect to the commonly classified pre-COVID vasculitis groupings. Across the vasculitis spectrum, we noted that Goodpasture’s syndrome was rarely linked to natural SARS-CoV-2 infection but not vaccines. Both the genuine vasculitis in the COVID-19 era and the proposed vasculitis mimic should advance the understanding of both pulmonary and systemic vascular immunopathology

Knowledge of public health informatics among Italian medical residents: design and preliminary validation of a questionnaire

Background: public health requires strong information skills and competencies, as it is information-intensive and information-driven. Public health informatics has been defined as the “systematic application of information, computer science, and technology to public health practice, research, and learning”. New information and communication technologies offer unprecedented opportunities, such as linking smart-phones and mobiles devices to web based tools for data collection, enabling and enhancing participatory epidemiology. However, being an emerging discipline, despite its potential and importance, public health informatics is often neglected and overlooked, being rarely offered as course. The present study was designed as a pilot study, with the aim of designing and validating a questionnaire on the knowledge of public health informatics among medical residents in public health in Italy.  Methods and Results: thirty-two Italian residents in public health volunteered to take part into the study. Mean age of the sample was 31.44±2.23 years, most responders were males (68.8%), from northern Italy (53.1%), at the third year of residency (34.4%) and currently doing practical training at the clinical management staff/hospital directorate (34.4%). Other places of training were the Prevention Department (21.9%), the Institute of Hygiene (18.8%), the local health units and the territory (12.5%), the occupational health service (6.3%) and the Regional Health Agency (3.1%). Cronbach’s alpha coefficient yielded a value of 0.909, demonstrating excellent psychometric properties of the instrument.  Conclusion: in conclusion, the developed questionnaire seems to be an appropriate and useful tool to detect gaps concerning knowledge, education and practices of public health informatics among residents in public health.&nbsp

The IL-23p19/EBI3 heterodimeric cytokine termed IL-39 remains a theoretical cytokine in man

Objective: The heterodimeric IL-12 family member cytokines including, IL-12, IL-23, IL-27, and IL-35 and have multiple roles in regulating innate and adaptive immunity with crucial functions in inflammatory disorders such as psoriasis. Chain pairing promiscuity is a feature of the IL-12 family. Recently, based on murine data, a new family member, IL-39, was proposed, consisting of IL23p19 (shared with IL-23) and EBI3 (shared with IL-27 and IL-35). IL-39 has subsequently been implicated in experimental murine lupus. Given the success of IL-23p19 therapeutic targeting in diseases including psoriasis, it is of great interest to confirm the presence of IL-39 in man. Human IL-39 is yet to be either detected or expressed, which has halted research in this area. Methods: Using a disulphide-linked human chimera protein composing of IL-23p19 and EBI3 human chains, we stimulated human leukocytes, and analysed cytokine secretion and STAT3 phosphorylation. Results and Conclusion: We report that this cytokine shows no activity in human cells. IL-39 chimera protein failed to induce either IL-6, IL-8, TNF, or IL-17A from leukocytes or STAT3 phosphorylation and thus, remains a ‘theoretical cytokine' in humans

The Impact of Intermittent Fasting (Ramadan Fasting) on Psoriatic Arthritis Disease Activity, Enthesitis, and Dactylitis: A Multicentre Study

Intermittent circadian fasting, namely Ramadan, is a common worldwide practice. Such fasting has a positive impact on psoriasis, but no data exist on its role in psoriatic arthritis (PsA)—a disease that is clearly linked to body mass index. We enrolled 37 patients (23 females and 14 males) with a mean age 43.32 ± 7.81 and they fasted for 17 h for one month in 2016. The baseline PsA characteristics were collected and 12 (32.4%) patients had peripheral arthritis, 13 (35.1%) had axial involvement, 24 (64.9%) had enthesitis, and 13 (35.1%) had dactylitis. Three patients (8.1%) were treated with methotrexate, 28 (75.7%) with TNF-α blockers, and 6 (16.2%) with IL-17 blockers. After a month of intermittent fasting, C-reactive protein (CRP) levels decreased from 14.08 ± 4.65 to 12.16 ± 4.46 (p < 0.0001), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) decreased from 2.83 ± 1.03 to 2.08 ± 0.67 (p = 0.0078), Psoriasis Area Severity Index (PASI) decreased from 7.46 ± 2.43 to 5.86 ± 2.37 (p < 0.0001), and Disease Activity index for PSoriatic Arthritis (DAPSA) decreased from 28.11 ± 4.51 to 25.76 ± 4.48 (p < 0.0001). Similarly, enthesitis improved after fasting, with Leeds Enthesitis Index (LEI) decreasing from 2.25 ± 1.11 to 1.71 ± 0.86 (p < 0.0001) and dactylitis severity score (DSS) decreasing from 9.92 ± 2.93 to 8.54 ± 2.79 (p = 0.0001). Fasting was found to be a predictor of a decrease in PsA disease activity scores (DAPSA, BASDAI, LEI, DSS) even after adjustment for weight loss. IL-17 therapy was found to be an independent predictor of decreases in LEI after fasting. These preliminary data may support the use of chronomedicine in the context of rheumatic diseases, namely PsA. Further studies are needed to support our findings