Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease of the pilosebaceous unit, clinically consisting of painful nodules, abscesses, and sinus tracts mostly in, but not limited to, intertriginous skin areas. HS can be defined as a complex skin disease with multifactorial etiologies, including—among others—genetic, immunologic, epigenetic, and environmental factors. Based on genetic heterogeneity and complexity, three different forms can be recognized and considered separately as sporadic, familial, and syndromic. To date, several genetic variants associated to disease susceptibility, disease-onset, and/or treatment response have been reported; some of these reside in genes encoding the gamma-secretase subunits whereas others involve autoinflammatory and/or keratinization genes. The aim of this perspective work is to provide an overview of the contribution of several genetic studies encompassing family linkage analyses, target candidate gene studies, and -omic studies in this field. In our viewpoint, we discuss the role of genetics in Hidradenitis suppurativa considering findings based on Sanger sequencing as well as the more recent Next Generation Sequencing (i.e., exome sequencing or RNA Sequencing) with the aim of better understanding the etio-pathogenesis of the disease as well as identifying novel therapeutic strategies.

Keratinocyte differentiation is an essential process for epidermal stratification and stratum corneum formation. Keratinocytes proliferate in the basal layer of the epidermis and start their differentiation by changing their functional or phenotypical type; this process is regulated via induction or repression of epidermal differentiation complex (EDC) genes that play a pivotal role in epidermal development. Epidermal development and the keratinocyte differentiation program are orchestrated by several transcription factors, signaling pathways, and epigenetic regulators. The latter exhibits both activating and repressive effects on chromatin in keratinocytes via the ATP-dependent chromatin remodelers, histone demethylases, and genome organizers that promote terminal keratinocyte differentiation, and the DNA methyltransferases, histone deacetylases, and Polycomb components that stimulate proliferation of progenitor cells and inhibit premature activation of terminal differentiation-associated genes. In addition, microRNAs are involved in different processes between proliferation and differentiation during the program of epidermal development. Here, we bring together current knowledge of the mechanisms controlling gene expression during keratinocyte differentiation. An awareness of epigenetic mechanisms and their alterations in health and disease will help to bridge the gap between our current knowledge and potential applications for epigenetic regulators in clinical practice to pave the way for promising target therapies.

The global outbreak of human monkeypox virus (hMPXV1) in 2022 highlighted the usefulness of dermatological manifestations for its diagnosis. Infection by the human monkeypox virus thus necessitated inclusion in the diagnostic repertoire of dermatopathology. To assess the histopathological and microscopical findings of cutaneous lesions related to hMPXV infection, we analyzed skin biopsies from patients with positive MPXV DNA polymerase chain reaction presenting with a typical course of hMPXV1 infection. The most prominent histopathological findings were ascribable to a pustular stage in which epidermal necrosis with areas of non-viable keratinocytes and a “shadow cell” appearance were evident; in some cases, the deep portion of the hair follicle and the acrosyringial epithelium were affected. The main cytopathic modifications included ballooning keratinocytes, followed by Guarnieri bodies and a ground glass appearance of the keratinocytes’ nuclei, together with a dense mixed inflammatory cell infiltrate with prominent neutrophil exocytosis. Transmission electron microscopy analysis demonstrated viral particle aggregates in the cytoplasm of keratinocytes, without any involvement of the nucleus. Interestingly, we also found the presence of viral particles in infected mesenchymal cells, although to a lesser extent than in epithelial cells. Through this study, we contributed to expanding the histological and microscopic knowledge of the human mpox virus, a key step to understanding current and potential future trends of the disease, as well as of other Orthopoxvirus infections.

Pyoderma gangrenosum (PG) is a rare inflammatory skin disease belonging to the group of neutrophilic dermatoses. The pathogenesis of PG involves a predisposing genetic background that facilitates a dysregulated innate and adaptive immune response, with an imbalance between pro-inflammatory and anti-inflammatory mediators, leading to neutrophil-driven inflammatory damage. Several immunosuppressants and immunomodulatory drugs are currently available for the treatment of PG, in combination with topical therapies, wound management and pain control strategies. Systemic corticosteroids and cyclosporine remain the first-line treatment options with the best evidence. However, in recent years, the rise of knowledge about different pathogenic mechanisms has led to a significant increase in studies attesting the efficacy and safety of biologic therapies including, among others, antagonists of tumour necrosis factor (TNF)-α and interleukin (IL)-23, becoming the drug of choice in specific clinical setting. Similarly, different small molecules such as JAK-STAT (Janus kinase/signal transducer and activator of transcription) inhibitors are showing promising results for the treatment of PG. We review established and emerging pathogenesis-driven treatments, also providing a therapeutic algorithm and informing future directions in the management of PG.