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Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (15 June 2023) | Viewed by 27355

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Dr. Ralf J. Ludwig

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Guest Editor

Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany
Interests: pemphigus and pemphigoid diseases; complex model systems of human inflammatory skin diseases
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Takashi Hashimoto

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Co-Guest Editor

Department of Dermatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
Interests: autoimmune bullous diseases; pemphigus; bullous Pemphigoid; hereditary skin diseases; ichthyosis; epidermolysis bullosa hereditaria; autoimmune diseases; collagen diseases; keratinizing skin diseases
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Prof. Dr. Robert Gniadecki

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Co-Guest Editor

Division of Dermatology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
Interests: cutaneous lymphoma; psoriasis; genomics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are delighted to host a Special Issue on “Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases” at Biomolecules. Chronic, non-communicable inflammatory skin diseases, such as psoriasis, atopic dermatitis, vitiligo, pemphigus, and many more, affect up to 20% of the population. Over recent years, we have observed an unparalleled increase in the understanding of disease pathogenies. This, however, has not been implemented into clinical practice to its’ full potential. Thus, there is still a high, and so far unmet medical need for the development of effective, safe and personalized treatments for patients suffering from chronic, non-communicable inflammatory skin diseases. To facilitate clinical translation based on pathomechanistic insights, we here will publish reviews that summarize the state-of-the-art on disease pathogenesis and current drug developments in the field. We will also consider highly innovative original articles and short communications.

Articles covering the following chronic, non-communicable inflammatory skin diseases are especially welcome: Atopic dermatitis, psoriasis, prurigo nodularis, lichen planus, hidradenitis suppurativa, alopecia areata, vitiligo, chronic urticaria, pemphigus diseases, pemphigoid diseases, dermatitis herpetiformis, epidermolysis bullosa acquisita, dermatomyositis, systemic sclerosis, morphea, cutaneous lupus, and autoinflammatory diseases.

Please note that publication charges apply. Please feel free to contact any of the guest editors or the Editorial Office should you have any questions. We are looking forward to your submissions.

Dr. Ralf J. Ludwig
Prof. Dr. Takashi Hashimoto
Prof. Dr. Robert Gniadecki
Guest Editors

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. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

skin
inflammation
autoimmunity
drug discovery
pathogenesis

Related Special Issue

Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases II in Biomolecules

Published Papers (10 papers)

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Research

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17 pages, 1144 KiB

Open AccessArticle

Inheritance-Specific Dysregulation of Th1- and Th17-Associated Cytokines in Alopecia Areata

by Monica M. Van Acker, Rebekah R. Schwartz, Kelly Andrews, Kristina Seiffert-Sinha and Animesh A. Sinha

Biomolecules 2023, 13(9), 1285; https://doi.org/10.3390/biom13091285 - 23 Aug 2023

Cited by 1 | Viewed by 1247

Abstract

Autoimmune diseases tend to cluster in families, suggesting genetic predisposition to autoimmunity associated with familial background. We have previously reported similarities in gene expression patterns and PTPN22 polymorphisms between alopecia areata (AA) patients and their healthy relatives, but not unrelated healthy controls. However, the spectrum of disease promoting (or preventing) pathways that may be activated in blood relatives of AA patients remains to be defined. Here, we investigated the extent to which cytokines associated with the Th1 and Th17 pathway are differentially expressed in the blood of patients with AA and its clinical subtypes in comparison to both healthy relatives as well as unrelated healthy controls. A comprehensive set of Th1- and Th17-related cytokines were evaluated by ELISA. We found a significant elevation of the Th17 inducer IL-23, the Th17 product IL-17A, the Th1 hallmark cytokine IFNγ, and TNFα, a Th1 cytokine with relevance to the Th17 pathway in AA patients, regardless of disease subtype, compared to healthy individuals. On further examination, we found that healthy family members grouped together with patients in terms of elevated Th1- and Th17-pathway cytokines in an inheritance-specific manner, distinct from unrelated controls. The elevation of Th17-associated cytokines in healthy controls related to AA patients indicates that Th1 and Th17 dysregulation in AA may be genetically based. Of note, one unrelated control displayed elevated levels of IL-17A and IL-23 similar to those detected in patients. One year after initial blood draw, areas of beard hair loss consistent with the diagnosis of AA were reported by this individual, indicating that the elevation in Th17-related cytokines may have predictive value. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

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12 pages, 2753 KiB

Open AccessArticle

Combining 16S Sequencing and qPCR Quantification Reveals Staphylococcus aureus Driven Bacterial Overgrowth in the Skin of Severe Atopic Dermatitis Patients

by Amedeo De Tomassi, Anna Reiter, Matthias Reiger, Luise Rauer, Robin Rohayem, CK-CARE Study Group, Claudia Traidl-Hoffmann, Avidan U. Neumann and Claudia Hülpüsch

Biomolecules 2023, 13(7), 1030; https://doi.org/10.3390/biom13071030 - 23 Jun 2023

Cited by 1 | Viewed by 1808

Abstract

Atopic dermatitis (AD) is an inflammatory skin disease with a microbiome dysbiosis towards a high relative abundance of Staphylococcus aureus. However, information is missing on the actual bacterial load on AD skin, which may affect the cell number driven release of pathogenic factors. Here, we combined the relative abundance results obtained by next-generation sequencing (NGS, 16S V1-V3) with bacterial quantification by targeted qPCR (total bacterial load = 16S, S. aureus = nuc gene). Skin swabs were sampled cross-sectionally (n = 135 AD patients; n = 20 healthy) and longitudinally (n = 6 AD patients; n = 6 healthy). NGS and qPCR yielded highly inter-correlated S. aureus relative abundances and S. aureus cell numbers. Additionally, intra-individual differences between body sides, skin status, and consecutive timepoints were also observed. Interestingly, a significantly higher total bacterial load, in addition to higher S. aureus relative abundance and cell numbers, was observed in AD patients in both lesional and non-lesional skin, as compared to healthy controls. Moreover, in the lesional skin of AD patients, higher S. aureus cell numbers significantly correlated with the higher total bacterial load. Furthermore, significantly more severe AD patients presented with higher S. aureus cell number and total bacterial load compared to patients with mild or moderate AD. Our results indicate that severe AD patients exhibit S. aureus driven increased bacterial skin colonization. Overall, bacterial quantification gives important insights in addition to microbiome composition by sequencing. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

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17 pages, 893 KiB

Open AccessArticle

Pruritus Is Associated with an Increased Risk for the Diagnosis of Autoimmune Skin Blistering Diseases: A Propensity-Matched Global Study

by Ulrike Raap, Maren M. Limberg, Khalaf Kridin and Ralf J. Ludwig

Biomolecules 2023, 13(3), 485; https://doi.org/10.3390/biom13030485 - 06 Mar 2023

Viewed by 1673

Abstract

Autoimmune bullous skin diseases (AIBDs), such as bullous pemphigoid (BP) and pemphigus, are characterized and caused by autoantibodies targeting structural proteins. In BP, clinical experience and recent systematic evaluation identified pruritus to be common and an important cause of impaired quality of life. Furthermore, chronic pruritus may be the sole clinical symptom of BP. In pemphigus, a retrospective study recently documented a high prevalence of pruritus. The temporal relation between pruritus and BP/pemphigus are, however, unknown. Likewise, the presence of pruritus in AIBDs other than BP and pemphigus is unknown. To address this, we performed propensity-matched retrospective cohort studies using TriNetX, providing real-world patient data to (i) assess the risk to develop AIBDs following the diagnosis of pruritus and (ii) vice versa. We assessed this in eight AIBDs: BP, mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita, dermatitis herpetiformis, lichen planus pemphigoides (LPP), pemphigus vulgaris, pemphigus foliaceous, and paraneoplastic pemphigus (PNP). For all AIBDs, pruritus was associated with an increased risk for the subsequent diagnosis of each of the eight investigated AIBDs in 1,717,744 cases (pruritus) compared with 1,717,744 controls. The observed hazard ratios ranged from 4.2 (CI 3.2–5.5; p < 0.0001) in MMP to 28.7 (CI 3.9–211.3; p < 0.0001) in LPP. Results were confirmed in two subgroup analyses. When restricting the observation time to 6 months after pruritus onset, most HRs noticeably increased, e.g., from 6.9 (CI 6.2–7.9; p < 0.0001) to 23.3 (CI 17.0–31.8; p < 0.0001) in BP. Moreover, pruritus frequently developed following the diagnosis of any of the eight AIBDs, except for PNP. Thus, all AIBDs should be considered as differential diagnosis in patients with chronic pruritus. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

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21 pages, 7706 KiB

Open AccessArticle

NOD2 Agonism Counter-Regulates Human Type 2 T Cell Functions in Peripheral Blood Mononuclear Cell Cultures: Implications for Atopic Dermatitis

by Vladimir-Andrey Gimenez-Rivera, Harshita Patel, Franck P. Dupuy, Zoulfia Allakhverdi, Charlie Bouchard, Joaquín Madrenas, Robert Bissonnette, Ciriaco A. Piccirillo and Carolyn Jack

Biomolecules 2023, 13(2), 369; https://doi.org/10.3390/biom13020369 - 15 Feb 2023

Cited by 2 | Viewed by 1871

Abstract

Atopic dermatitis (AD) is known as a skin disease; however, T cell immunopathology found in blood is associated with its severity. Skin Staphylococcus aureus (S. aureus) and associated host–pathogen dynamics are important to chronic T helper 2 (Th2)-dominated inflammation in AD, yet they remain poorly understood. This study sought to investigate the effects of S. aureus-derived molecules and skin alarmins on human peripheral blood mononuclear cells, specifically testing Th2-type cells, cytokines, and chemokines known to be associated with AD. We first show that six significantly elevated Th2-related chemokine biomarkers distinguish blood from adult AD patients compared to healthy controls ex vivo; in addition, TARC/CCL17, LDH, and PDGF-AA/AB correlated significantly with disease severity. We then demonstrate that these robust AD-associated biomarkers, as well as associated type 2 T cell functions, are readily reproduced from healthy blood mononuclear cells exposed to the alarmin TSLP and the S. aureus superantigen SEB in a human in vitro model, including IL-13, IL-5, and TARC secretion as well as OX-40-expressing activated memory T cells. We further show that the agonism of nucleotide-binding oligomerization domain-containing protein (NOD)2 inhibits this IL-13 secretion and memory Th2 and Tc2 cell functional activation while inducing significantly increased pSTAT3 and IL-6, both critical for Th17 cell responses. These findings identify NOD2 as a potential regulator of type 2 immune responses in humans and highlight its role as an endogenous inhibitor of pathogenic IL-13 that may open avenues for its therapeutic targeting in AD. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

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13 pages, 704 KiB

Open AccessReview

Eosinophils, Basophils, and Neutrophils in Bullous Pemphigoid

by Maren M. Limberg, Tobias Weihrauch, Natalie Gray, Nancy Ernst, Karin Hartmann and Ulrike Raap

Biomolecules 2023, 13(7), 1019; https://doi.org/10.3390/biom13071019 - 21 Jun 2023

Cited by 2 | Viewed by 1716

Abstract

Bullous pemphigoid (BP) is an autoimmune blistering skin disease, of which the incidence has increased in recent years. BP is characterized by circulating IgG and IgE autoantibodies against the hemidesmosomal proteins BP180 and BP230. Although autoantibodies trigger inflammatory cascades that lead to blister formation, effector cells and cell-mediated autoimmunity must also be considered as important factors in the pathogenesis of BP. The aim of this review is to outline the current knowledge on the role of eosinophils, basophils, and neutrophils in BP. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

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12 pages, 285 KiB

Open AccessReview

Classification and Antigen Molecules of Autoimmune Bullous Diseases

by Takashi Hashimoto, Hua Qian, Norito Ishii, Takekuni Nakama, Chiharu Tateishi, Daisuke Tsuruta and Xiaoguang Li

Biomolecules 2023, 13(4), 703; https://doi.org/10.3390/biom13040703 - 20 Apr 2023

Cited by 1 | Viewed by 1485

Abstract

Autoimmune bullous diseases (AIBDs), which are a group of tissue-specific autoimmune diseases of the skin, present with various blistering lesions on the skin and mucous membranes, and show autoantibodies of IgG, IgA and IgM against epidermal cell surfaces and basement membrane zone. To date, AIBDs have been classified into a number of distinct subtypes by clinical and histopathological findings, and immunological characteristics. In addition, various biochemical and molecular biological studies have identified various novel autoantigens in AIBDs, which has resulted in proposals of new subtypes of AIBDs. In this article, we summarized various distinct AIBDs, and proposed the latest and most comprehensive classification of AIBDs with their autoantigen molecules. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

14 pages, 1452 KiB

Open AccessEditor’s ChoiceReview

Granzyme B in Autoimmune Skin Disease

by Anna Gleave and David J. Granville

Biomolecules 2023, 13(2), 388; https://doi.org/10.3390/biom13020388 - 18 Feb 2023

Cited by 4 | Viewed by 2797

Abstract

Autoimmune diseases often present with cutaneous symptoms that contribute to dysfunction, disfigurement, and in many cases, reduced quality-of-life. Unfortunately, treatment options for many autoimmune skin diseases are limited. Local and systemic corticosteroids remain the current standard-of-care but are associated with significant adverse effects. Hence, there is an unmet need for novel therapies that block molecular drivers of disease in a local and/or targeted manner. Granzyme B (GzmB) is a serine protease with known cytotoxic activity and emerging extracellular functions, including the cleavage of cell–cell junctions, basement membranes, cell receptors, and other structural proteins. While minimal to absent in healthy skin, GzmB is markedly elevated in alopecia areata, interface dermatitis, pemphigoid disease, psoriasis, systemic sclerosis, and vitiligo. This review will discuss the role of GzmB in immunity, blistering, apoptosis, and barrier dysfunction in the context of autoimmune skin disease. GzmB plays a causal role in the development of pemphigoid disease and carries diagnostic and prognostic significance in cutaneous lupus erythematosus, vitiligo, and alopecia areata. Taken together, these data support GzmB as a promising therapeutic target for autoimmune skin diseases impacted by impaired barrier function, inflammation, and/or blistering. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

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12 pages, 296 KiB

Open AccessReview

Anti-Laminin 332-Type Mucous Membrane Pemphigoid

by Luhuai Shi, Xiaoguang Li and Hua Qian

Biomolecules 2022, 12(10), 1461; https://doi.org/10.3390/biom12101461 - 12 Oct 2022

Cited by 7 | Viewed by 1529

Abstract

Anti-laminin (LM) 332-type mucous membrane pemphigoid (MMP) is a rare autoimmune bullous disease and was originally discovered as anti-epiligrin cicatricial pemphigoid. Anti-LM332-type MMP has clinical manifestations similar to those of other types of MMP and can only be distinguished through the detection of circulating autoantibodies against LM332. Our group and others have established a number of immunological methods with varying sensitivity and specificity for detection of anti-LM332 autoantibodies; however, none of the established methods has been widely used for clinical diagnosis. There is currently no unified standard treatment, and it is very difficult to completely cure anti-LM332-type MMP. In addition, an increasing body of evidence suggests that there may be a strong correlation between anti-LM332-type MMP and tumors. In this article, we review the current progression of diagnosis and treatment of anti-LM332-type MMP, as well as the possible correlation between anti-LM332-type MMP and tumors. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

16 pages, 1196 KiB

Open AccessEditor’s ChoiceReview

Heat Shock Protein 90 (Hsp90) and Hsp70 as Potential Therapeutic Targets in Autoimmune Skin Diseases

by Stefan Tukaj and Krzysztof Sitko

Biomolecules 2022, 12(8), 1153; https://doi.org/10.3390/biom12081153 - 20 Aug 2022

Cited by 11 | Viewed by 3560

Abstract

Over a hundred different autoimmune diseases have been described to date, which can affect every organ in the body, including the largest one, the skin. In fact, up to one-fifth of the world’s population suffers from chronic, noninfectious inflammatory skin diseases, the development of which is significantly influenced by an autoimmune response. One of the hallmarks of autoimmune diseases is the loss of immune tolerance, which leads to the formation of autoreactive lymphocytes or autoantibodies and, consequently, to chronic inflammation and tissue damage. The treatment of autoimmune skin diseases mainly focuses on immunosuppression (using, e.g., corticosteroids) but almost never leads to the development of permanent mechanisms of immune tolerance. In addition, current therapies and their long-term administration may cause serious adverse effects. Hence, safer and more effective therapies that bring sustained balance between pro- and anti-inflammatory responses are still desired. Both intra- and extracellular heat shock proteins (Hsps), specifically well-characterized inducible Hsp90 and Hsp70 chaperones, have been highlighted as therapeutic targets for autoimmune diseases. This review presents preclinical data on the involvement of Hsp90 and Hsp70 in modulating the immune response, specifically in the context of the treatment of selected autoimmune skin diseases with emphasis on autoimmune bullous skin diseases and psoriasis. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

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Other

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66 pages, 1737 KiB

Open AccessSystematic Review

Dupilumab in Inflammatory Skin Diseases: A Systematic Review

by Henning Olbrich, Christian D. Sadik, Ralf J. Ludwig, Diamant Thaçi and Katharina Boch

Biomolecules 2023, 13(4), 634; https://doi.org/10.3390/biom13040634 - 31 Mar 2023

Cited by 10 | Viewed by 8501

Abstract

Dupilumab was first approved for the treatment of atopic dermatitis (AD) and blocks the signaling of interleukin (IL)-4 and -13. Several other chronic skin conditions share mechanistic overlaps with AD in their pathophysiology, i.e., are linked to type 2 inflammation. Most recently, dupilumab was approved by the U.S. Food and Drug Administration for prurigo nodularis (PN). Given its relatively good safety profile, effective off-label use of dupilumab has been reported for a multitude of dermatologic diseases and several clinical trials for dermatologic skin conditions are currently ongoing. We conducted a systematic review of applications of dupilumab in dermatology other than AD and PN by searching the databases PubMed/Medline, Scopus, Web of Science and Cochrane Library as well as the clinical trial registry ClinicalTrials.gov. We found several reports for effective treatment of bullous autoimmune diseases, eczema, prurigo, alopecia areata, chronic spontaneous urticaria, Netherton syndrome and a variety of other chronic inflammatory skin diseases. Full article

(This article belongs to the Special Issue Pathogenesis and Drug Development for Non-communicable Inflammatory Skin Diseases)

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