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Molecular Genetics and Pathogenesis of Atopic Dermatitis and Psoriasis

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Immunology".

Deadline for manuscript submissions: closed (30 January 2023) | Viewed by 17612

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Special Issue Editor

Dr. Shigaku Ikeda

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Guest Editor

Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan
Interests: Keratinizing and bullous disorders (including psoriasis); Hair disorders; Medical mycology; Atopic dermatitis; molecular genetics; regenerative medicine

Special Issue Information

Dear Colleagues,

Psoriasis (PSO) and atopic dermatitis (AD) are common skin diseases by which patients’ QOL has been severely affected. Despite recent progress in the development of novel therapeutics, there have not been perfect therapeutic guidelines to cover all patients. This has is due to the variability and diversity of both diseases, as PSO and AD are multifactorial diseases. In this Special Issue, I would like to summarize genetics, immunology, environmental factors, and co-morbidities on both diseases. I hope that this Special Issue will bring insight into diversity in pathophysiology, and the innovation of novel therapeutic modalities of PSO and AD.

Dr. Shigaku Ikeda
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

Psoriasis
Atopic dermatitis
GWAS
Molecular Immunology
Environmental factors
Co-morbidities

Published Papers (6 papers)

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Research

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15 pages, 2841 KiB

Open AccessArticle

Experimental and Clinical Evidence Suggests That Treatment with Betacellulin Can Alleviate Th2-Type Cytokine-Mediated Impairment of Skin Barrier Function

by Ge Peng, Saya Tsukamoto, Yoshie Umehara, Ryoma Kishi, Mitsutoshi Tominaga, Kenji Takamori, Ko Okumura, Hideoki Ogawa, Shigaku Ikeda and François Niyonsaba

Int. J. Mol. Sci. 2022, 23(19), 11520; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911520 - 29 Sep 2022

Cited by 1 | Viewed by 1399

Abstract

Betacellulin (BTC) is a peptide ligand that belongs to the epidermal growth factor family, the members of which have been implicated in skin morphogenesis, homeostasis, repair, and angiogenesis; however, the role of BTC in the regulation of the skin barrier remains unknown. To examine the role of BTC in skin barrier function, we analyzed atopic dermatitis (AD) transcriptomic data from Gene Expression Omnibus (GEO) datasets, performed BTC immunohistochemistry using human skin tissues, and evaluated the effects of BTC on primary human keratinocytes by real-time PCR, Western blotting, and assay of the transepidermal electrical resistance (TER), a functional parameter to monitor the tight junction barrier. We found that the gene expression of BTC was downregulated in skin lesions from patients with AD, and this downregulated expression recovered following biological treatments. Consistently, the BTC protein levels were downregulated in the lesional skin of AD patients compared with the normal skin of healthy participants, suggesting that the BTC levels in skin might be a biomarker for the diagnosis and therapy of AD. Furthermore, in human keratinocytes, BTC knockdown reduced the levels of skin-derived antimicrobial peptides and skin barrier-related genes, whereas BTC addition enhanced their levels. Importantly, in human skin equivalents, BTC restored the increased tight junction permeability induced by Th2 cytokine IL-4/IL-13 treatment. In addition, specific inhibitors of epidermal growth factor receptor (EGFR) and protein kinase C (PKC) abolished the BTC-mediated improvement in skin barrier-related proteins in keratinocyte monolayers. Collectively, our findings suggest that treatment with BTC might improve the Th2-type cytokine-mediated impairment of skin barrier function through the EGFR/PKC axis and that BTC might be a novel potential biomarker and therapeutic target for the treatment of skin conditions characterized by the overproduction of Th2 cytokines and dysfunctional skin barriers, such as AD. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Atopic Dermatitis and Psoriasis)

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19 pages, 3433 KiB

Open AccessArticle

The Protective Role of pVHL in Imiquimod-Induced Psoriasis-like Skin Inflammation

by Isaí Martínez-Torres, Araceli Tepale-Segura, Octavio Castro-Escamilla, Juan Carlos Cancino-Diaz, Sandra Rodríguez-Martínez, Sonia Mayra Perez-Tapia, Laura C. Bonifaz and Mario Eugenio Cancino-Diaz

Int. J. Mol. Sci. 2022, 23(9), 5226; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23095226 - 07 May 2022

Cited by 4 | Viewed by 2169

Abstract

Psoriasis is a chronic inflammatory disease distinguished by an excessive proliferation and abnormal differentiation of keratinocytes. Immune cells, such as T lymphocytes and neutrophils, and inflammatory cytokines, such as Tumor Necrosis Factor-α (TNF-α) and interleukin 17 (IL-17), are essential for maintaining psoriatic lesions. Additionally, a hypoxic milieu present in the skin promotes the expression of transcriptional factor hypoxia-inducible factor-1 alpha (HIF-1α). This protein regulates the expression of angiogenic and glycolytic factors, such as vascular endothelial grown factor and lactate dehydrogenase (LDH), both relevant in chronic inflammation. The von Hippel–Lindau protein (pVHL) is a negative regulator of HIF-1α. Previously, we found that pVHL was almost absent in the lesions of psoriasis patients; therefore, we investigated the impact of rescue pVHL expression in lesional skin. We used the imiquimod-induced psoriasis-like mouse model as an adenoviral vector that allowed us to express pVHL in the skin. Our data show that, in lesional skin, pVHL expression was reduced, whereas HIF-1α was increased. Remarkably, the retrieval of pVHL prevented psoriatic lesions, diminishing erythema, scale, and epidermal and vascular thickness. Furthermore, pVHL expression was capable of reducing HIF-1α, LDH, TNF-α and immune cell infiltration (mainly IL-17⁺ neutrophils). In conclusion, our results demonstrate that pVHL has a protective role to play in the pathophysiology of psoriasis. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Atopic Dermatitis and Psoriasis)

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10 pages, 14589 KiB

Open AccessArticle

Blood-Based Immune Profiling Combined with Machine Learning Discriminates Psoriatic Arthritis from Psoriasis Patients

by Michelle L. M. Mulder, Xuehui He, Juul M. P. A. van den Reek, Paulo C. M. Urbano, Charlotte Kaffa, Xinhui Wang, Bram van Cranenbroek, Esther van Rijssen, Frank H. J. van den Hoogen, Irma Joosten, Wynand Alkema, Elke M. G. J. de Jong, Ruben L. Smeets, Mark H. Wenink and Hans J. P. M. Koenen

Int. J. Mol. Sci. 2021, 22(20), 10990; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222010990 - 12 Oct 2021

Cited by 6 | Viewed by 2342

Abstract

Psoriasis (Pso) is a chronic inflammatory skin disease, and up to 30% of Pso patients develop psoriatic arthritis (PsA), which can lead to irreversible joint damage. Early detection of PsA in Pso patients is crucial for timely treatment but difficult for dermatologists to implement. We, therefore, aimed to find disease-specific immune profiles, discriminating Pso from PsA patients, possibly facilitating the correct identification of Pso patients in need of referral to a rheumatology clinic. The phenotypes of peripheral blood immune cells of consecutive Pso and PsA patients were analyzed, and disease-specific immune profiles were identified via a machine learning approach. This approach resulted in a random forest classification model capable of distinguishing PsA from Pso (mean AUC = 0.95). Key PsA-classifying cell subsets selected included increased proportions of differentiated CD4+CD196+CD183-CD194+ and CD4+CD196-CD183-CD194+ T-cells and reduced proportions of CD196+ and CD197+ monocytes, memory CD4+ and CD8+ T-cell subsets and CD4+ regulatory T-cells. Within PsA, joint scores showed an association with memory CD8+CD45RA-CD197- effector T-cells and CD197+ monocytes. To conclude, through the integration of in-depth flow cytometry and machine learning, we identified an immune cell profile discriminating PsA from Pso. This immune profile may aid in timely diagnosing PsA in Pso. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Atopic Dermatitis and Psoriasis)

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Review

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14 pages, 1919 KiB

Open AccessReview

How Do Classical Subtypes Correspond to Endotypes in Atopic Dermatitis?

by Tsuyoshi Suzuki, Shumpei Kondo, Yasuaki Ogura, Masaki Otsuka and Yoshiki Tokura

Int. J. Mol. Sci. 2024, 25(1), 265; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25010265 - 23 Dec 2023

Viewed by 828

Abstract

Since atopic dermatitis (AD) is a heterogeneous condition, the subtyping of AD is a crucial issue. The classical subtypes of AD are represented by extrinsic and intrinsic subtypes, European–American and Asian subtypes, and adult and pediatric subtypes. While the subtyping of AD was historically conducted based on the phenotype, recent findings on the mechanisms of AD have revealed the importance of the endotype, which can characterize individual patients more accurately. Considering the current development of AD therapies, AD endotyping is a prerequisite for a personalized therapeutic choice. Endotypes of AD can be stratified from different viewpoints, including cytokine expression patterns, allergen properties, epidermal barrier conditions, ceramide variation, the involvement of innate immunity, and serum biomarkers. Among them, the cytokine-based endotype seems to be the most useful one and is categorized into type 2 cytokine (IL-4, IL-13 and IL-31)-high, type 1 cytokine (IFN-γ)-high, and/or type 3 cytokine (IL-22 and IL-17)-high, or mixed subtypes. Recently proposed biomarker endotyping aims at individualized treatment options, although the daily clinical use of endotypes is a future issue. To better understand the endotypes for clinicians, attempts to adjust each of the classical subtypes to endotypes are required. This review will discuss the correspondence of the classical subtypes to the various endotypes that have recently been proposed. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Atopic Dermatitis and Psoriasis)

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20 pages, 900 KiB

Open AccessReview

Psoriasis and Cardiometabolic Diseases: Shared Genetic and Molecular Pathways

by Stefano Piaserico, Gloria Orlando and Francesco Messina

Int. J. Mol. Sci. 2022, 23(16), 9063; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23169063 - 13 Aug 2022

Cited by 15 | Viewed by 4623

Abstract

A convincing deal of evidence supports the fact that severe psoriasis is associated with cardiovascular diseases. However, the precise underlying mechanisms linking psoriasis and cardiovascular diseases are not well defined. Psoriasis shares common pathophysiologic mechanisms with atherosclerosis and cardiovascular (CV) risk factors. In particular, polymorphism in the IL-23R and IL-23 genes, as well as other genes involved in lipid and fatty-acid metabolism, renin–angiotensin system and endothelial function, have been described in patients with psoriasis and with cardiovascular risk factors. Moreover, systemic inflammation in patients with psoriasis, including elevated serum proinflammatory cytokines (e.g., TNF-α, IL-17, and IL-23) may contribute to an increased risk of atherosclerosis, hypertension, alteration of serum lipid composition, and insulin resistance. The nonlinear and intricate interplay among various factors, impacting the molecular pathways in different cell types, probably contributes to the development of psoriasis and cardiovascular disease (CVD). Future research should, therefore, aim to fully unravel shared and differential molecular pathways underpinning the association between psoriasis and CVD. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Atopic Dermatitis and Psoriasis)

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14 pages, 663 KiB

Open AccessReview

Current Concepts of Psoriasis Immunopathogenesis

by Marijana Vičić, Marija Kaštelan, Ines Brajac, Vlatka Sotošek and Larisa Prpić Massari

Int. J. Mol. Sci. 2021, 22(21), 11574; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222111574 - 26 Oct 2021

Cited by 52 | Viewed by 5371

Abstract

Psoriasis is a recurrent, chronic, immune-mediated, systemic inflammatory disease of the skin, joints, and other organic systems. After atopic dermatitis, chronic stationary psoriasis is the most common inflammatory skin disease, affecting an average of 2–4% of the world’s population. The disease carries a significant burden due to its numerous comorbidities and the major impact on patients’ social and emotional aspects of life. According to current knowledge, psoriasis is a multifactorial disease that occurs in genetically predisposed individuals under various environmental factors, which trigger an immune response disorder with a series of complex inflammatory cascades. The disease is initiated and maintained by mutual interaction of the innate and adaptive immune cells, primarily dendritic cells, T lymphocytes, and keratinocytes, whose leading role alternates at different stages of the disease, consisting mainly in the IL-23/Th17 pathway. Inflammatory events result in consequent epidermal and dermal changes and evolution of the characteristic psoriatic phenotype, respectively. This paper aims to present a comprehensive overview of current knowledge on psoriasis genetic and environmental etiological factors, immunopathogenesis, and the leading cellular and cytokine participants in the inflammatory pathways of this disease. Full article

(This article belongs to the Special Issue Molecular Genetics and Pathogenesis of Atopic Dermatitis and Psoriasis)

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