Causal association between air pollution and autoimmune diseases: a two-sample Mendelian randomization study.

Background: In recent years, an increasing number of observational studies have reported the impact of air pollution on autoimmune diseases (ADs). However, no Mendelian randomization (MR) studies have been conducted to investigate the causal relationships. To enhance our understanding of causality, we examined the causal relationships between particulate matter (PM) and nitrogen oxides (NOx) and ADs. Methods: We utilized genome-wide association study (GWAS) data on PM and NOx from the UK Biobank in European and East Asian populations. We also extracted integrated GWAS data from the Finnish consortium and the Japanese Biobank for two-sample MR analysis. We employed inverse variance weighted (IVW) analysis to assess the causal relationship between PM and NOx exposure and ADs. Additionally, we conducted supplementary analyses using four methods, including IVW (fixed effects), weighted median, weighted mode, and simple mode, to further investigate this relationship. Results: In the European population, the results of MR analysis suggested a statistically significant association between PM2.5 and psoriasis only (OR = 3.86; 95% CI: 1.89-7.88; PIVW < 0.00625), while a potential association exists between PM2.5-10 and vitiligo (OR = 7.42; 95% CI: 1.02-53.94; PIVW < 0.05), as well as between PM2.5 and systemic lupus erythematosus (OR = 68.17; 95% CI: 2.17-2.1e+03; PIVW < 0.05). In East Asian populations, no causal relationship was found between air pollutants and the risk of systemic lupus erythematosus and rheumatoid arthritis (PIVW > 0.025). There was no pleiotropy in the results. Conclusion: Our results suggest a causal association between PM2.5 and psoriasis in European populations. With the help of air pollution prevention and control, the harmful progression of psoriasis may be slowed.

ANKRD22 promotes resolution of psoriasiform skin inflammation by antagonizing NIK-mediated IL-23 production.

Inflammation resolution is an essential process for preventing the development of chronic inflammatory diseases. However, the mechanisms that regulate inflammation resolution in psoriasis are not well understood. Here, we report that ANKRD22 is an endogenous negative orchestrator of psoriasiform inflammation because ANKRD22-deficient mice are more susceptible to IMQ-induced psoriasiform inflammation. Mechanistically, ANKRD22 deficiency leads to excessive activation of the TNFRII-NIK-mediated noncanonical NF-κB signaling pathway, resulting in the hyperproduction of IL-23 in DCs. This is due to ANKRD22 being a negative feedback regulator for NIK because it physically binds to and assists in the degradation of accumulated NIK. Clinically, ANKRD22 is negatively associated with IL-23A expression and psoriasis severity. Of greater significance, subcutaneous administration of an AAV carrying ANKRD22-overexpression vector effectively hastens the resolution of psoriasiform skin inflammation. Our findings suggest ANKRD22, an endogenous supervisor of NIK, is responsible for inflammation resolution in psoriasis, and may be explored in the context of psoriasis therapy.

The Involvement of Cysteine-X-Cysteine Motif Chemokine Receptors in Skin Homeostasis and the Pathogenesis of Allergic Contact Dermatitis and Psoriasis.

Members of the C-X-C motif chemokine receptor (CXCR) superfamily play central roles in initiating the innate immune response in mammalian cells by orchestrating selective cell migration and immune cell activation. With its multilayered structure, the skin, which is the largest organ in the body, performs a crucial defense function, protecting the human body from harmful environmental threats and pathogens. CXCRs contribute to primary immunological defense; these receptors are differentially expressed by different types of skin cells and act as key players in initiating downstream innate immune responses. While the initiation of inflammatory responses by CXCRs is essential for pathogen elimination and tissue healing, overactivation of these receptors can enhance T-cell-mediated autoimmune responses, resulting in excessive inflammation and the development of several skin disorders, including psoriasis, atopic dermatitis, allergic contact dermatitis, vitiligo, autoimmune diseases, and skin cancers. In summary, CXCRs serve as critical links that connect innate immunity and adaptive immunity. In this article, we present the current knowledge about the functions of CXCRs in the homeostasis function of the skin and their contributions to the pathogenesis of allergic contact dermatitis and psoriasis. Furthermore, we will examine the research progress and efficacy of therapeutic approaches that target CXCRs.

Ash1L ameliorates psoriasis via limiting neuronal activity-dependent release of miR-let-7b.

BACKGROUND AND PURPOSE: Psoriasis is a common autoimmune skin disease that significantly diminishes patients' quality of life. Interactions between primary afferents of the somatosensory system and the cutaneous immune system mediate the pathogenesis of psoriasis. This study aims to elucidate the molecular mechanisms of how primary sensory neurons regulate psoriasis formation. EXPERIMENTAL APPROACH: Skin and total RNA were extracted from wild-type (WT) and ASH1-like histone lysine methyltransferase (Ash1l+/- ) mice in both naive and imiquimod (IMQ)-induced psoriasis models. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and fluorescence-activated cell sorting (FACS) were then performed. Microfluidic chamber coculture was used to investigate the interaction between somatosensory neurons and bone marrow dendritic cells (BMDCs) ex vivo. Whole-cell patch clamp recordings were used to evaluate neuronal excitability after Ash1L haploinsufficiency in primary sensory neurons. KEY RESULTS: The haploinsufficiency of ASH1L, a histone methyltransferase, in primary sensory neurons causes both neurite hyperinnervation and increased neuronal excitability, which promote miR-let-7b release from primary afferents in the skin in a neuronal activity-dependent manner. With a 'GUUGUGU' core sequence, miR-let-7b functions as an endogenous ligand of toll-like receptor 7 (TLR7) and stimulates the activation of dermal dendritic cells (DCs) and interleukin (IL)-23/IL-17 axis, ultimately exacerbating the symptoms of psoriasis. Thus, by limiting miR-let-7b release from primary afferents, ASH1L prevents dermal DC activation and ameliorates psoriasis. CONCLUSION AND IMPLICATIONS: Somatosensory neuron ASH1L modulates the cutaneous immune system by limiting neuronal activity-dependent release of miR-let-7b, which can directly activate dermal DCs via TLR7 and ultimately lead to aggravated psoriatic lesion.

Current practices for pediatric phototherapy: Findings from a cross-sectional study.

Phototherapy is broadly utilized for treatment of inflammatory skin conditions affecting pediatric patients. However, there are no specific guidelines or recommendations for implementing phototherapy in pediatric populations leading to variability in treatment procedures. Here, we present findings from a cross-sectional, survey-based study investigating the implementation of phototherapy in pediatric patients across the United States. A total of 39 sites from 19 different states identified via the National Psoriasis Foundation (NPF) Health Care Provider Directory responded. Common practices included a signed informed consent prior to performing phototherapy (86.4%, n = 32), no minimum age requirement for pediatric patients (91.8%, n = 34), the use of Fitzpatrick skin type to determine dosing protocol (100%, n = 37), and allowing parents to accompany their children into the lightbox (65%, n = 20). Our results provide insights into current common practices and themes for further study.

Pediatric psoriasis: Understanding pathological conditions and advances in treatment.

Psoriasis is a long-lasting skin disease that primarily affects the skin, nails, and joints and is characterized by inflammation. Genetic factors contribute to its development and environmental triggers can worsen symptoms. Pathologically, psoriasis is characterized by uncontrolled keratinocyte proliferation and abnormal differentiation, and histological features include acanthosis with inflammatory cell infiltration and neovascularization. Psoriasis often starts in childhood, with about one-third of cases beginning during this time. Its prevalence steadily increases from the ages of 1 to 18 years in a linear fashion. Young people with psoriasis often require treatment throughout their childhood and adolescence, and into adulthood. However, prolonged treatment may increase the risk of complications and adverse events, so it is important to adopt an effective treatment approach that minimizes this risk. In addition, psoriasis is often associated with various comorbidities that may place a great burden on the physical and mental health of the children beyond those due to psoriasis itself. To ensure good long-term health outcomes, individuals with psoriasis should undergo regular screening. Treatment should be provided not only for skin lesions, but also for any comorbidities; however, currently there is not enough evidence on the treatment of pediatric psoriasis and no globally agreed-on guidelines exist for treating psoriasis in children. This article describes the etiology, clinical symptoms, and disease burden of pediatric psoriasis, the pathological conditions and diagnosis of plaque psoriasis, psoriatic arthritis, and generalized pustular psoriasis, and the available treatments for these conditions in Japan.

Causal effects of time-varying body size on selected autoimmune disorders: a life course Mendelian randomisation study.

BACKGROUND: Based on Barker's hypothesis, some studies investigated the associations between birth weight and several disorders. Apart from issues with statistical power and well-known shortcomings of the observational study design, there are no studies accounting for changes in weight-related body size over the life course regarding rheumatoid arthritis, psoriasis, psoriatic arthritis and multiple sclerosis. METHODS: Using genetic information of up to 806 834 participants, this study investigated the associations between time-varying weight-related body size from birth to adulthood and the mentioned autoimmune diseases. Performing Mendelian randomisation (MR), the radial inverse-variance weighted approach was used iteratively in primary analyses. Robustness of the results was confirmed in several sensitivity analyses. Potential time-dependent mediation mechanisms were identified through network-clustering and assessed using multivariable MR. RESULTS: Genetically predicted birth weight (fetal effect) was positively associated with rheumatoid arthritis (OR 1.44; 95% CI 1.17 to 1.77; Padj =0.005) but not with psoriasis, psoriatic arthritis or multiple sclerosis. This association was found to be mediated by body mass index (BMI) in adulthood (OR 1.45; 95% CI 1.14 to 1.84; Padj =0.019) rather than childhood. The direct effect of birth weight attenuated (OR 1.19; 95% CI 0.88 to 1.62); Padj =1) after adjustment for time-varying BMI. CONCLUSION: Increased birth weight appears to be a risk factor for later manifestation of rheumatoid arthritis due to both fetal genetic components and high BMI persisting into adulthood. Approaches to prevent and minimise the risk of rheumatoid arthritis could include preventing obesity in adults with high birth weight.

Case of Exacerbation of Psoriasis Following COVID-19 Vaccination During Treatment with Brodalumab, Which Resulted in Secondary Failure.

A 43-year-old Japanese man who had suffered psoriasis vulgaris for eight years visited our hospital. His comorbidities were dyslipidemia, hyperuricemia, and obesity. He received phototherapy for six months, which did not result in improvement. Following treatment with brodalumab, his skin symptoms improved. However, seven months after brodalumab treatment, he received two doses of the mRNA-1273 COVID-19 vaccine, with a one-month interval between doses. One month following the second vaccination, his skin symptoms were exacerbated. He received additional NB-UVB therapy, but his skin symptoms did not improve. Nine months after the addition of NB-UVB therapy, treatment was switched to bimekizumab, and his skin became almost clear. Psoriasis is often associated with comorbidities like metabolic syndrome. Currently, additional COVID-19 vaccination is recommended for high-risk cases such as those with metabolic syndrome. Therefore, it is essential to remain vigilant regarding the potential exacerbation of psoriasis following COVID-19 vaccination even during treatment with highly effective biologic therapy.

Microbiota and IL-33/31 Axis Linkage: Implications and Therapeutic Perspectives in Atopic Dermatitis and Psoriasis.

Microbiome dysbiosis and cytokine alternations are key features of atopic dermatitis (AD) and psoriasis (PsO), two of the most prevalent and burdensome pruritic skin conditions worldwide. Interleukin (IL)-33 and IL-31 have been recognized to be major players who act synergistically in the pathogenesis and maintenance of different chronic inflammatory conditions and pruritic skin disorders, including AD and PsO, and their potential role as therapeutic targets is being thoroughly investigated. The bidirectional interplay between dysbiosis and immunological changes has been extensively studied, but there is still debate regarding which of these two factors is the actual causative culprit behind the aetiopathological process that ultimately leads to AD and PsO. We conducted a literature review on the Pubmed database assessing articles of immunology, dermatology, microbiology and allergology with the aim to strengthen the hypothesis that dysbiosis is at the origin of the IL-33/IL-31 dysregulation that contributes to the pathogenesis of AD and PsO. Finally, we discussed the therapeutic options currently in development for the treatment of these skin conditions targeting IL-31, IL-33 and/or the microbiome.

The Role of Sirtuins in the Pathogenesis of Psoriasis.

Psoriasis is the most common chronic inflammatory skin disease with a genetic basis. It is characterised by keratinocyte hyperproliferation, parakeratosis and inflammatory cell infiltration. Psoriasis negatively affects a patient's physical and emotional quality of life. Sirtuins (SIRTs; silent information regulators) are an evolutionarily conserved group of enzymes involved in the post-translational modification of proteins, including deacetylation, polyADP-ribosylation, demalonylation and lipoamidation. SIRTs are involved in a number of cellular pathways related to ageing, inflammation, oxidative stress, epigenetics, tumorigenesis, the cell cycle, DNA repair and cell proliferation, positioning them as an essential component in the pathogenesis of many diseases, including psoriasis. Activation of SIRT1 counteracts oxidative-stress-induced damage by inhibiting the mitogen-activated protein kinases (MAPK), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) pathways and may mitigate pathological events in psoriasis. There is a significant reduction in the expression of SIRT1, SIRT2, SIRT3, SIRT4 and SIRT5 and an increase in the expression of SIRT6 and SIRT7 in psoriasis. The aim of the review is to draw the attention of physicians and scientists to the importance of SIRTs in dermatology and to provide a basis and impetus for future discussions, research and pharmacological discoveries to modulate SIRT activity. In light of the analysis of the mode of action of SIRTs in psoriasis, SIRT1-SIRT5 agonists and SIRT6 and SIRT7 inhibitors may represent new therapeutic options for the treatment of psoriasis.

Pustular psoriasis: A distinct aetiopathogenic and clinical entity.

Pustular psoriasis is a distinct subset of psoriasis that presents with involvement of the skin in the form of sterile pustules along with systemic manifestations. Though it has been conventionally grouped under the umbrella of psoriasis, recent research has shed light on its pathogenetic mechanisms associated with the IL-36 pathway, which is distinct from conventional psoriasis. Pustular psoriasis in itself is a heterogeneous entity consisting of various subtypes, including generalised, localised, acute, and chronic forms. There is confusion regarding its current classification as entities like deficiency of IL-36 antagonist (DITRA) which are closely related to pustular psoriasis both in their pathogenetic mechanism and its clinical manifestations, are not included under pustular psoriasis. Entities like palmoplantar pustulosis, which presents with similar clinical features but is pathogenetically distinct from other forms of pustular psoriasis, are included under this condition. Management of pustular psoriasis depends upon its severity; while some of the localised variants can be managed with topical therapy alone, the generalised variants like Von Zumbusch disease and impetigo herpetiformis may need intensive care unit admission and tailor-made treatment protocols. The advent of newer biologics and better insight into the pathogenesis of pustular psoriasis has opened the way for newer therapies, including tumour necrosis factor-alpha inhibitors, interleukin-1 inhibitors, interleukin-17 inhibitors, and granulocyte monocyte apheresis. It continues to be an enigma whether pustular psoriasis is actually a variant of psoriasis or an entirely different disease entity, though we feel that it is an entirely different disease process.

Revisiting the interleukin 17 family of cytokines in psoriasis: pathogenesis and potential targets for innovative therapies.

Psoriasis is a common chronic inflammatory skin disease, associated with substantial comorbidity. TH17 lymphocytes, differentiating under the influence of dendritic cell-derived IL-23, and mediating their effects via IL-17A, are believed to be central effector cells in psoriasis. This concept is underlined by the unprecedented efficacy of therapeutics targeting this pathogenetic axis. In recent years, numerous observations made it necessary to revisit and refine this simple "linear" pathogenetic model. It became evident that IL-23 independent cells exist that produce IL-17A, that IL-17 homologues may exhibit synergistic biological effects, and that the blockade of IL-17A alone is clinically less effective compared to the inhibition of several IL-17 homologues. In this review, we will summarize the current knowledge around IL-17A and its five currently known homologues, namely IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25) and IL-17F, in relation to skin inflammation in general and psoriasis in particular. We will also re-visit the above-mentioned observations and integrate them into a more comprehensive pathogenetic model. This may help to appreciate current as well as developing anti-psoriatic therapies and to prioritize the selection of future drugs' mode(s) of action.

NAMPT and PARylation Are Involved in the Pathogenesis of Atopic Dermatitis.

Atopic dermatitis (AD) is a chronic inflammatory skin disease of very high prevalence, especially in childhood, with no specific treatment or cure. As its pathogenesis is complex, multifactorial and not fully understood, further research is needed to increase knowledge and develop new targeted therapies. We have recently demonstrated the critical role of NAD+ and poly (ADP-ribose) (PAR) metabolism in oxidative stress and skin inflammation. Specifically, we found that hyperactivation of PARP1 in response to DNA damage induced by reactive oxygen species, and fueled by NAMPT-derived NAD+, mediated inflammation through parthanatos cell death in zebrafish and human organotypic 3D skin models of psoriasis. Furthermore, the aberrant induction of NAMPT and PARP activity was observed in the lesional skin of psoriasis patients, supporting the role of these signaling pathways in psoriasis and pointing to NAMPT and PARP1 as potential novel therapeutic targets in treating skin inflammatory disorders. In the present work, we report, for the first time, altered NAD+ and PAR metabolism in the skin of AD patients and a strong correlation between NAMPT and PARP1 expression and the lesional status of AD. Furthermore, using a human 3D organotypic skin model of AD, we demonstrate that the pharmacological inhibition of NAMPT and PARP reduces pathology-associated biomarkers. These results help to understand the complexity of AD and reveal new potential treatments for AD patients.

Blue light and skin: what is the intriguing link?

Blue light has garnered attention because of its ability to penetrate more deeply into the skin layers, and induce cellular dysfunction and DNA damage. Photoageing, hyperpigmentation and melasma are some of the cutaneous changes that develop on exposure to blue light. To date, the therapeutic roles of blue light have been evaluated in dermatological conditions like psoriasis, eczema, acne vulgaris, actinic keratosis and cutaneous malignancies, among others. In this review, we have attempted to present an evidence-based compilation of the effects of blue light on the skin.

The Role of Adipokines in the Pathogenesis of Psoriasis.

Psoriasis is a chronic and immune-mediated skin condition characterized by pro-inflammatory cytokines and keratinocyte hyperproliferation. Dendritic cells, T lymphocytes, and keratinocytes represent the main cell subtypes involved in the pathogenesis of psoriasis, while the interleukin-23 (IL-23)/IL-17 pathway enhances the disease progression. Human adipose tissue is an endocrine organ, which secretes multiple proteins, known as adipokines, such as adiponectin, leptin, visfatin, or resistin. Current evidence highlights the immunomodulatory roles of adipokines, which may contribute to the progression or suppression of psoriasis. A better understanding of the complexity of psoriasis pathophysiology linked with adipokines could result in developing novel diagnostic or therapeutic strategies. This review aims to present the pathogenesis of psoriasis and the roles of adipokines in this process.

A Familial Novel Putative-Pathogenic Mutation Identified in Plaque-Psoriasis by a Multigene Panel Analysis.

Psoriasis is a chronic multifactorial skin disorder with an immune basis. It is characterized by patches of skin that are usually red, flaky and crusty, and that often release silvery scales. The patches appear predominantly on the elbows, knees, scalp and lower back, although they may also appear on other body areas and severity may be variable. The majority of patients (about 90%) present small patches known as "plaque psoriasis". The roles of environmental triggers such as stress, mechanical trauma and streptococcal infections are well described in psoriasis onset, but much effort is still needed to unravel the genetic component. The principal aim of this study was to use a next-generation sequencing technologies-based approach together with a 96 customized multigene panel in the attempt to determine if there are germline alterations that can explain the onset of the disease, and thus to find associations between genotypes and phenotypes. To this aim, we analyzed a family in which the mother showed mild psoriasis, and her 31-year-old daughter had suffered from psoriasis for several years, whereas an unaffected sister served as a negative control. We found variants already associated directly to psoriasis in the TRAF3IP2 gene, and interestingly we found a missense variant in the NAT9 gene. The use of multigene panels in such a complex pathology such as psoriasis can be of great help in identifying new susceptibility genes, and in being able to make early diagnoses especially in families with affected subjects.