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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 (31 July 2023) | Viewed by 30724

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Special Issue Editors

Prof. Dr. Annamaria Offidani

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Guest Editor

Dermatological Unit, Department of Clinical and Molecular Sciences, Polytechnic University of the Marche Region, Ancona, Italy
Interests: skin immune-mediated skin diseases; psoriasis; suppurative hidradenitis; chronic urticaria; atopic dermatitis; adnexal diseases; melanoma and non-melanoma skin cancer; scleroderma
Special Issues, Collections and Topics in MDPI journals

Dr. Federico Diotallevi

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Co-Guest Editor

Dermatology Unit, Polytechnic Marche University, Ancona, Italy
Interests: psoriasis; clinical dermatology; pediatric dermatology; skin inflammation; melanoma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The skin is the largest organ in the body, where a multitude of cell types interact, which perform plastic and dynamic cellular communication in order to maintain various vital processes such as inflammation, immune responses including tolerance induction and disease prevention, wound healing, and angiogenesis. Of paramount importance are the immunological functions of the skin that protect against harmful exposure from external and internal environments. However, in some skin diseases this complex mechanism of cellular interactions is altered and knowledge of the molecules pivotal to these alterations is of fundamental importance for the creation of appropriate drugs. The aim of this Special Issue is to analyze inflammatory and autoimmune skin diseases and focus on the molecular targets of the most recent pharmacological treatments.

Prof. Dr. Annamaria Offidani
Dr. Federico Diotallevi
Guest Editors

Manuscript Submission Information

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Keywords

skin diseases
skin immunology
skin autoimmunity
skin inflammation
inflammatory cytokines
biological therapies
immunotherapy
target therapies

Published Papers (13 papers)

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Editorial

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4 pages, 188 KiB

Open AccessEditorial

Skin, Autoimmunity and Inflammation: A Comprehensive Exploration through Scientific Research

by Federico Diotallevi and Annamaria Offidani

Int. J. Mol. Sci. 2023, 24(21), 15857; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms242115857 - 01 Nov 2023

Viewed by 627

Abstract

Human skin, as the body’s largest organ, orchestrates a multifaceted interplay of cellular interactions that regulate essential physiological processes, including inflammation, immune responses, wound healing, and angiogenesis [...] Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

Research

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18 pages, 2910 KiB

Open AccessArticle

PTB Regulates the Metabolic Pathways and Cell Function of Keloid Fibroblasts through Alternative Splicing of PKM

by Rong Huang, Rong Han, Yucheng Yan, Jifan Yang, Guoxuan Dong, Miao Wang, Zhiguo Su, Hu Jiao and Jincai Fan

Int. J. Mol. Sci. 2023, 24(6), 5162; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24065162 - 08 Mar 2023

Viewed by 1259

Abstract

Keloids, benign fibroproliferative cutaneous lesions, are characterized by abnormal growth and reprogramming of the metabolism of keloid fibroblasts (KFb). However, the underlying mechanisms of this kind of metabolic abnormality have not been identified. Our study aimed to investigate the molecules involved in aerobic glycolysis and its exact regulatory mechanisms in KFb. We discovered that polypyrimidine tract binding (PTB) was significantly upregulated in keloid tissues. siRNA silencing of PTB decreased the mRNA levels and protein expression levels of key glycolytic enzymes and corrected the dysregulation of glucose uptake and lactate production. In addition, mechanistic studies demonstrated that PTB promoted a change from pyruvate kinase muscle 1 (PKM1) to PKM2, and silencing PKM2 substantially reduced the PTB-induced increase in the flow of glycolysis. Moreover, PTB and PKM2 could also regulate the key enzymes in the tricarboxylic acid (TCA) cycle. Assays of cell function demonstrated that PTB promoted the proliferation and migration of KFb in vitro, and this phenomenon could be interrupted by PKM2 silencing. In conclusion, our findings indicate that PTB regulates aerobic glycolysis and the cell functions of KFb via alternative splicing of PKM. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

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Review

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12 pages, 571 KiB

Open AccessReview

Skin Gene Expression Profiles in Systemic Sclerosis: From Clinical Stratification to Precision Medicine

by Devis Benfaremo, Silvia Agarbati, Matteo Mozzicafreddo, Chiara Paolini, Silvia Svegliati and Gianluca Moroncini

Int. J. Mol. Sci. 2023, 24(16), 12548; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241612548 - 08 Aug 2023

Viewed by 1046

Abstract

Systemic sclerosis, also known as scleroderma or SSc, is a condition characterized by significant heterogeneity in clinical presentation, disease progression, and response to treatment. Consequently, the design of clinical trials to successfully identify effective therapeutic interventions poses a major challenge. Recent advancements in skin molecular profiling technologies and stratification techniques have enabled the identification of patient subgroups that may be relevant for personalized treatment approaches. This narrative review aims at providing an overview of the current status of skin gene expression analysis using computational biology approaches and highlights the benefits of stratifying patients upon their skin gene signatures. Such stratification has the potential to lead toward a precision medicine approach in the management of SSc. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

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13 pages, 934 KiB

Open AccessReview

Neurologic and Psychiatric Manifestations of Bradykinin-Mediated Angioedema: Old and New Challenges

by Ilaria Mormile, Francesco Palestra, Angelica Petraroli, Stefania Loffredo, Francesca Wanda Rossi, Giuseppe Spadaro, Amato de Paulis and Maria Bova

Int. J. Mol. Sci. 2023, 24(15), 12184; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241512184 - 29 Jul 2023

Cited by 1 | Viewed by 1769

Abstract

Neurologic manifestations have been occasionally described in patients with bradykinin-mediated angioedema. The existing literature is currently limited to case series and case reports mainly described in the hereditary forms (HAE) concerning central nervous system (CNS) involvement. On the contrary, very little is known about peripheral and autonomic nervous system manifestations. CNS involvement in HAE may present with symptoms including severe headaches, visual disturbance, seizures, and various focal and generalized deficits. In addition, a stroke-like clinical picture may present in HAE patients. In turn, some drugs used in patients with cardiovascular and neurologic disorders, such as recombinant tissue plasminogen activator (r-tPA) and angiotensin-converting enzyme inhibitors (ACEI), may produce medication-induced angioedema, resulting in a diagnostic challenge. Finally, most patients with HAE have higher levels of psychological distress, anxiety, and depression. With this review, we aimed to provide an organized and detailed analysis of the existing literature on neurologic and psychiatric manifestations of HAE to shed light on these potentially invalidating symptoms and lay the foundation for further personalized diagnostic pathways for patients affected by this protean disease. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

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27 pages, 816 KiB

Open AccessReview

New Insight into the Molecular Pathomechanism and Immunomodulatory Treatments of Hidradenitis Suppurativa

by Elisa Molinelli, Helena Gioacchini, Claudia Sapigni, Federico Diotallevi, Valerio Brisigotti, Giulio Rizzetto, Annamaria Offidani and Oriana Simonetti

Int. J. Mol. Sci. 2023, 24(9), 8428; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24098428 - 08 May 2023

Cited by 5 | Viewed by 2370

Abstract

Hidradenitis suppurativa (HS) is an immune-mediated inflammatory disorder characterized by deep-seated nodules, abscesses, sinus tracts and scars localized in the intertriginous areas. It is accompanied by pain, malodourous secretion and a dramatically decreased quality of life. Although the pathogenesis has not been entirely elucidated, the primary event is follicular hyperkeratosis of the pilosebaceous apocrine unit. Since the registration of the tumor necrosis factor-alpha inhibitor Adalimumab in 2015, several cytokines have been implicated in the pathomechanism of HS and the research of novel therapeutic targets has been intensified. We provide an update on the inflammatory cytokines with a central role in HS pathogenesis and the most promising target molecules of future HS management. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

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18 pages, 691 KiB

Open AccessReview

Vitiligo, from Pathogenesis to Therapeutic Advances: State of the Art

by Federico Diotallevi, Helena Gioacchini, Edoardo De Simoni, Andrea Marani, Matteo Candelora, Matteo Paolinelli, Elisa Molinelli, Annamaria Offidani and Oriana Simonetti

Int. J. Mol. Sci. 2023, 24(5), 4910; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054910 - 03 Mar 2023

Cited by 10 | Viewed by 6822

Abstract

Vitiligo is an acquired hypopigmentation of the skin due to a progressive selective loss of melanocytes; it has a prevalence of 1–2% and appears as rounded, well-demarcated white macules. The etiopathology of the disease has not been well defined, but multiple factors contribute to melanocyte loss: metabolic abnormalities, oxidative stress, inflammation, and autoimmunity. Therefore, a convergence theory was proposed that combines all existing theories into a comprehensive one in which several mechanisms contribute to the reduction of melanocyte viability. In addition, increasingly in-depth knowledge about the disease’s pathogenetic processes has enabled the development of increasingly targeted therapeutic strategies with high efficacy and fewer side effects. The aim of this paper is, by conducting a narrative review of the literature, to analyze the pathogenesis of vitiligo and the most recent treatments available for this condition. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

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15 pages, 3219 KiB

Open AccessReview

The Importance of Immunological Disorders in the Pathogenesis of Lichen Sclerosus in Pediatric Patients: A Systematic Review

by Anna Torres, Monika Zaborek-Łyczba, Jakub Łyczba, Paulina Mertowska, Sebastian Mertowski and Ewelina Grywalska

Int. J. Mol. Sci. 2022, 23(22), 14212; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232214212 - 17 Nov 2022

Cited by 4 | Viewed by 1695

Abstract

Lichen sclerosus (LS) is defined as a chronic mucocutaneous inflammatory disease with a localization predominantly to the anus and genitals (vulvar sclerosus (VLS)). Pediatric lichen sclerosus (LS) is a chronic inflammatory skin condition with predilection for the anogenital area that if untreated can lead to scarring. Vulvar LS is characterized by two peaks in incidence: it occurs in prepubertal girls and in postmenopausal women. To date, several mechanisms and risk factors have been proposed in the pathogenesis of pediatric vulvar LS; however, the etiology of this condition is still not fully understood and constitutes a challenge for scientists and clinicians. The presented research aimed to systematically review the existing literature on the pathogenesis of pediatric LS and to identify possible underlying autoimmune mechanisms and molecular networks. The clinical presentation of pediatric lichen sclerosus and available treatment modalities are also presented to acquaint a broader audience with this underdiagnosed and undertreated condition. As a result of our review, we discuss several potential mechanisms, molecules, and pathways that have been recognized in this disease. The purpose of our review was also to summarize what we can induce in further studies, which will ultimately help to identify the mechanism responsible for the disease and aid in the development of new, more effective treatment strategies for diagnosis and treatment by clinicians and researchers. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

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15 pages, 1151 KiB

Open AccessReview

Could Targeted Pharmacotherapies Exert a “Disease Modification Effect” in Patients with Chronic Plaque Psoriasis?

by Francesco Bellinato, Andrea Chiricozzi, Stefano Piaserico, Giovanni Targher and Paolo Gisondi

Int. J. Mol. Sci. 2022, 23(21), 12849; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms232112849 - 25 Oct 2022

Cited by 5 | Viewed by 4367

Abstract

Chronic plaque psoriasis is an immune-mediated skin disease with a chronic relapsing course, affecting up to ~2–3% of the general adult population worldwide. The interleukin (IL)-23/Th17 axis plays a key role in the pathogenesis of this skin disease and may represent a critical target for new targeted pharmacotherapies. Cutaneous lesions tend to recur in the same body areas, likely because of the reactivation of tissue-resident memory T cells. The spillover of different pro-inflammatory cytokines into systemic circulation can promote the onset of different comorbidities, including psoriatic arthritis. New targeted pharmacotherapies may lead to almost complete skin clearance and significant improvements in the patient’s quality of life. Accumulating evidence supports the notion that early intervention with targeted pharmacotherapies could beneficially affect the clinical course of psoriatic disease at three different levels: (1) influencing the immune cells infiltrating the skin and gene expression, (2) the prevention of psoriasis-related comorbidities, especially psoriatic arthritis, and (3) the improvement of the patient’s quality of life and reduction of cumulative life course impairment. The main aim of this narrative review is to summarize the effects that new targeted pharmacotherapies for psoriasis may have on the immune scar, both at the molecular and cellular level, on psoriatic arthritis and on the patient’s quality of life. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

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11 pages, 288 KiB

Open AccessReview

Biological Treatments for Pediatric Psoriasis: State of the Art and Future Perspectives

by Federico Diotallevi, Oriana Simonetti, Giulio Rizzetto, Elisa Molinelli, Giulia Radi and Annamaria Offidani

Int. J. Mol. Sci. 2022, 23(19), 11128; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms231911128 - 22 Sep 2022

Cited by 15 | Viewed by 2514

Abstract

Psoriasis is a chronic systemic inflammatory disease that primarily affects the skin and is associated with multiple comorbidities with a considerable reduction in quality of life of affected patients. One-third of psoriasis cases begin in childhood and are associated with significant medical comorbidities such as obesity, metabolic syndrome, arthritis, and psychiatric disorders. In addition, because of its chronic nature and frequent relapses, psoriasis tends to require long-term treatment. Treatment of pediatric psoriasis usually involves the same methods used for adults. However, most treatments for pediatric psoriasis are used off-label, and research in this regard is still lacking. Targeted therapies involving the use of newly developed biologic drugs are also increasingly being applied to childhood psoriasis. This review summarizes the clinical features of pediatric psoriasis and focuses mainly on the updated concepts of pathogenesis and biological treatments of pediatric psoriasis. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

18 pages, 355 KiB

Open AccessReview

Immunomodulatory Drugs in the Treatment of Hidradenitis Suppurativa—Possibilities and Limitations

by Zuzanna Świerczewska, Miłosz Lewandowski, Agnieszka Surowiecka and Wioletta Barańska-Rybak

Int. J. Mol. Sci. 2022, 23(17), 9716; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23179716 - 26 Aug 2022

Cited by 11 | Viewed by 2573

Abstract

Hidradenitis suppurativa, also known as acne inversa, is a chronic, progressive, debilitating, recurrent inflammatory skin disease characterized by the occurrence of very severe, persistent, painful nodules, abscesses, and fistulas, most commonly found in the skin folds of the axilla, groin, gluteal, and perianal areas. Treatment is rather difficult and typically requires the use of multiple modalities. Regardless of the presence of several therapeutic options, treatment often turns out to be ineffective or poorly selected concerning the clinical picture of the disease. Thus, the search for new biologics and other target treatments of hidradenitis suppurativa is ongoing. The safety and efficacy of adalimumab, still the only U.S. Food and Drug Administration approved biologic in the hidradenitis suppurativa treatment, paved the way for new drugs to be compared with it. Several more drugs with new immunological targets are currently under investigation for the treatment of acne inversa. The aim of the article was to present the current and future targets of acne inversa treatment, simultaneously providing insights into the molecular pathomechanisms of the disease. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

Other

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4 pages, 1446 KiB

Open AccessBrief Report

Dimethyl Fumarate Used as an Effective Treatment for Granuloma Annulare Disseminatum: An Immunohistochemical Case Study

by Max Gabutti, Kristine Heidemeyer, S. Morteza Seyed Jafari, Simon Bossart, Robert E. Hunger, Laurence Feldmeyer and Nikhil Yawalkar

Int. J. Mol. Sci. 2023, 24(17), 13355; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241713355 - 28 Aug 2023

Viewed by 866

Abstract

This investigation demonstrates the use of dimethyl fumarate (DMF) for the treatment of disseminated granuloma annulare (GAD), a rare and chronic inflammatory skin disease. In this case, progressive GAD was treated with DMF, resulting in significant improvement of skin lesions within 5 weeks and complete healing within 7 months. Clinical response was associated with a reduction in inflammatory cells, including both T cell subsets (CD4+ > CD8+), CD183⁺/CXCR3⁺ cells, Langerhans cells (CD1a+), myeloid DCs, M1- and M2-like macrophages and the activation marker HLA-DR in immunohistochemical analysis. These findings support the use of DMF as a promising treatment option for this rare skin condition. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

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9 pages, 3776 KiB

Open AccessCase Report

Pyodermitis during Nivolumab Treatment for Non-Small Cell Lung Cancer: A Case Report and Review of the Literature

by Terenzio Cosio, Filadelfo Coniglione, Valeria Flaminio, Roberta Gaziano, Deborah Coletta, Rosalba Petruccelli, Emi Dika, Luca Bianchi and Elena Campione

Int. J. Mol. Sci. 2023, 24(5), 4580; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24054580 - 26 Feb 2023

Cited by 3 | Viewed by 1934

Abstract

Immunotherapy in oncology is replacing traditional therapies due to it specific action and limited side effects. Despite the high efficacy of immunotherapy, side effects such as bacterial infection have been reported. Bacterial skin and soft tissue infections represent one of the most important differential diagnoses in patients presenting with reddened and swollen skin and soft tissue. Among these infections, cellulitis (phlegmon) and abscesses are the most frequent. In most cases, these infections occur locally with possible contiguous spread, or as a multifocal manifestation, especially in immunocompromised patients. Herein, we report a case of pyodermitis in an immunocompromised district in a patient treated with nivolumab for non-small cell lung cancer. A 64-year-old, smoker male patient showed cutaneous lesions at a different evolution level in the left arm, all in a tattooed area, with one phlegmon and two ulcerated lesions. Microbiological cultures and gram staining revealed an infection caused by a methicillin-susceptible but erythromycin-resistant (ER-R), clindamycin-resistant (CL-R), and gentamicin-resistant (GE-R) Staphylococcus aureus strain. Despite immunotherapy becoming a milestone in oncologic treatment, more than the spectrum of immune-mediated toxicities of these agents needs to be investigated. This report highlights the importance of considering lifestyle and cutaneous background before starting immunotherapy for cancer treatment, with an emphasis on pharmacogenomics and the possibility of modified skin microbiota predisposing to cutaneous infections in patients treated with PD-1 inhibitors. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

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10 pages, 1664 KiB

Open AccessCase Report

Multi-Omics Profiling in PGM3 and STAT3 Deficiencies: A Tale of Two Patients

by Minnie Jacob, Afshan Masood and Anas M. Abdel Rahman

Int. J. Mol. Sci. 2023, 24(3), 2406; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms24032406 - 26 Jan 2023

Cited by 1 | Viewed by 1688

Abstract

Hyper-IgE Syndrome (HIES) is a heterogeneous group of primary immune-deficiency disorders characterized by elevated levels of IgE, eczema, and recurrent skin and lung infections. HIES that is autosomally dominant in the signal transducer and activator of transcription 3 (STAT3), and autosomal recessive mutations in phosphoglucomutase 3 (PGM3) have been reported in humans. An early diagnosis, based on clinical suspicion and immunological assessments, is challenging. Patients’ metabolomics, proteomics, and cytokine profiles were compared to DOCK 8-deficient and atopic dermatitis patients. The PGM3 metabolomics profile identified significant dysregulation in hypotaurine, hypoxanthine, uridine, and ribothymidine. The eight proteins involved include bifunctional arginine demethylase and lysyl hydroxylase (JMJD1B), type 1 protein phosphatase inhibitor 4 (PPI 4), and platelet factor 4 which aligned with an increased level of the cytokine GCSF. Patients with STAT3 deficiency, on the other hand, showed significant dysregulation in eight metabolites, including an increase in protocatechuic acid, seven proteins including ceruloplasmin, and a plasma protease C1 inhibitor, in addition to cytokine VEGF being dysregulated. Using multi-omics profiling, we identified the dysregulation of endothelial growth factor (EGFR) and tumor necrosis factor (TNF) signaling pathways in PGM3 and STAT3 patients, respectively. Our findings may serve as a stepping stone for larger prospective HIES clinical cohorts to validate their future use as biomarkers. Full article

(This article belongs to the Special Issue Skin, Autoimmunity and Inflammation)

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