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Representation of the three types of 3D skin models relevant for HS studies. The scaffold-based reconstructed skin model, the hair follicle organoids and the skin explant cocultured with sebocytes.
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Hidradenitis suppurativa (HS) is a recurrent inflammatory skin disease with a complex etiopathogenesis whose treatment poses a challenge in the clinical practice. Here, we present a novel integrated pipeline produced by the European consortium BATMAN (Biomolecular Analysis for Tailored Medicine in Acne iNversa) aimed at investigating the molecular...
Citations
... Inclusion of the epigenomic component is of paramount importance for unraveling the nuanced regulatory mechanisms governing HS pathogenesis (Figure 3). Integrating genomics [62], transcriptomics [63,64], proteomics [65], and epigenomics [11] is pivotal for achieving a holistic understanding of HS [66]. Genomic studies have unveiled potential susceptibility genes and risk loci associated with disease-onset; transcriptomic analyses have provided insights into gene expression signatures while proteomics is helping to elucidate the complex protein landscapes. ...
... By fostering a culture of knowledge-sharing and collaborative exploration, researchers can collectively contribute to a deeper understanding of HS, ultimately paving the way for innovative therapeutic interventions and personalized treatment strategies. Integrating genomics [62], transcriptomics [63,64], proteomics [65], and epigenomics [11] is pivotal for achieving a holistic understanding of HS [66]. Genomic studies have unveiled potential susceptibility genes and risk loci associated with disease-onset; transcriptomic analyses have provided insights into gene expression signatures while proteomics is helping to elucidate the complex protein landscapes. ...
Hidradenitis suppurativa (HS) is a chronic autoinflammatory skin disorder, which typically occurs during puberty or early adulthood. The pathogenesis of HS is complex and multifactorial; a close interaction between hormonal, genetic, epigenetics factors, host-specific aspects, and environmental influences contributes to the susceptibility, onset, severity, and clinical course of this disease, although the exact molecular mechanisms are still being explored. Epigenetics is currently emerging as an interesting field of investigation that could potentially shed light on the molecular intricacies underlying HS, but there is much still to uncover on the subject. The aim of this work is to provide an overview of the epigenetic landscape involved in HS. Specifically, in this in-depth review we provide a comprehensive overview of DNA methylation/hydroxymethylation, histone modifications, and non-coding RNAs (such as microRNA—miRNA-132, miRNA-200c, miRNA-30a-3p, miRNA-100-5b, miRNA-155-5p, miRNA-338-5p) dysregulation in HS patients. An interesting element of epigenetic regulation in HS is that the persistent inflammatory milieu observed in HS lesional skin could be exacerbated by an altered methylation profile and histone acetylation pattern associated with key inflammatory genes. Deepening our knowledge on the subject could enable the development of targeted epigenetic therapies to potentially restore normal gene expression patterns, and subsequentially ameliorate, or even reverse, the progression of the disease. By deciphering the epigenetic code governing HS, we strive to usher in a new era of personalized and effective interventions for this enigmatic dermatological condition.
... An accurate clinical phenotyping requires full-skin examination through objective assessment and in-vivo noninvasive skin imaging such as high-frequency ultrasound, thermography, and threedimensional (3D) skin topography. The production of holistic health records through a smartphone application, already available for patients on Android platform [6], represents an innovative way to complement medical observations and remotely monitor the patient's psychophysical condition, thus enhancing integration of clinical and lifestyle data [7]. Histology of HS lesional skin, while not recommended by current HS guidelines, is important for the differential diagnosis of complex phenotypes and for marking the disease development. ...
... Histology of HS lesional skin, while not recommended by current HS guidelines, is important for the differential diagnosis of complex phenotypes and for marking the disease development. In addition, biobanking is a critical step involving an accurate sampling strategy of lesional, perilesional, and healthy control skinfrom cutaneous biopsies and/or resected tissues specimensand other biological samples such as saliva, plasma, serum, and peripheral blood mononuclear cells [7]. These samples could reveal biomarkers useful for stratifying HS patients into therapeutic subcategories related to clinical response, thus reserving great potential for advancing knowledge of HS pathophysiology and improving clinical management of HS patients through the identification of novel therapeutic targets. ...
... These studies involve immunostaining techniques on patients' skin biopsies as well as on ex vivo models represented by skin fibroblast cell cultures, reconstructed epidermal models (both 2D and 3D), and organoidstissue-engineered cell-based in vitro models that sum up different aspects of both the structure and function of the corresponding in vivo tissueable to recapitulate the complex pathogenetic scenario of HS and its syndromic forms. Cultivation of outer root sheathderived keratinocytes from HS patients, carrying genetic variations associated with the disease, represents a useful strategy for in vitro studies on molecular markers, candidate genes, and biological signaling pathways possibly involved and druggable in HS [7]. ...
b> Background: The pathophysiological picture underlying hidradenitis suppurativa (HS) and its syndromic forms is still patchy, thus presenting a great challenge for dermatologists and researchers since just by better understanding the pathogenesis of disease we could identify novel therapeutic targets. Methods: We propose a practical framework to improve subcategorization of HS patients and support the genotype-phenotype correlation, useful for endotype-directed therapies development. Results: This framework includes (i) clinical work-up that involves the collection of demographic, lifestyle, and clinical data as well as the collection of different biological samples; (ii) genetic-molecular work-up, based on multi-omics analysis in combination with bioinformatics pipelines to unravel the complex etiology of HS and its syndromic forms; (iii) functional studies, – represented by skin fibroblast cell cultures, reconstructed epidermal models (both 2D and 3D) and organoids –, of candidate biomarkers and genetic findings necessary to validate novel potential molecular mechanisms possibly involved and druggable in HS; (iv) genotype-phenotype correlation and clinical translation in tailored targeted therapies. Conclusion: Omic findings should be merged and integrated with clinical data; moreover, the skin-omic profiles from each HS patient should be matched and integrated with the ones already reported in public repositories, supporting the efforts of the researchers and clinicians to discover novel biomarkers and molecular pathways with the ultimate goal of providing faster development of novel patient-tailored therapeutic approaches.
This perspective delves into the integration of artificial intelligence (AI) to enhance early diagnosis in hidradenitis suppurativa (HS). Despite significantly impacting Quality of Life, HS presents diagnostic challenges leading to treatment delays. We present a viewpoint on AI-powered clinical decision support system designed for HS, emphasizing the transformative potential of AI in dermatology. HS diagnosis, primarily reliant on clinical evaluation and visual inspection, often results in late-stage identification with substantial tissue damage. The incorporation of AI, utilizing machine learning and deep learning algorithms, addresses this challenge by excelling in image analysis. AI adeptly recognizes subtle patterns in skin lesions, providing objective and standardized analyses to mitigate subjectivity in traditional diagnostic approaches. The AI integration encompasses diverse datasets, including clinical records, images, biochemical and immunological data and OMICs data. AI algorithms enable nuanced comprehension, allowing for precise and customized diagnoses. We underscore AI's potential for continuous learning and adaptation, refining recommendations based on evolving data. Challenges in AI integration, such as data privacy, algorithm bias, and interpretability, are addressed, emphasizing the ethical considerations of responsible AI deployment, including transparency, human oversight, and striking a balance between automation and human intervention. From the dermatologists' standpoint, we illustrate how AI enhances diagnostic accuracy, treatment planning, and long-term follow-up in HS management. Dermatologists leverage AI to analyze clinical records, dermatological images, and various data types, facilitating a proactive and personalized approach. AI's dynamic nature supports continuous learning, refining diagnostic and treatment strategies, ultimately reshaping standards of care in dermatology.
Hidradenitis suppurativa (HS), recognized as a chronic and debilitating skin disease, presents significant challenges in both diagnosis and treatment. This review explores the clinical manifestations, genetic landscape, and molecular mechanisms underlying HS. The disease’s association with a predisposing genetic background, obesity, smoking, and skin occlusion underscores the complexity of its etiology. Genetic heterogeneity manifests in sporadic, familial, and syndromic forms, with a focus on mutations in the γ-secretase complex genes, particularly NCSTN. The dysregulation of immune mediators, including TNF-α, IL-17, IL-1β, and IL-12/23, plays a crucial role in the chronic inflammatory nature of HS. Recent advancements in genetic research have identified potential therapeutic targets, leading to the development of anti-TNF-α, anti-IL-17, anti-IL-1α, and anti-IL-12/23 therapies and JAK inhibitors. These interventions offer promise in alleviating symptoms and improving the quality of life for HS patients.
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease with a multifactorial aetiology that involves a strict interplay between genetic factors, immune dysregulation and lifestyle. Familial forms represent around 40% of total HS cases and show an autosomal dominant mode of inheritance of the disease. In this study, we conducted a whole-exome sequence analysis on an Italian family of 4 members encompassing a vertical transmission of HS. Focusing on rare damaging variants, we identified a rare insertion of one nucleotide (c.225dupA:p.A76Sfs*21) in the DCD gene encoding for the antimicrobial peptide dermcidin (DCD) that was shared by the proband, his affected father and his 11-years old daughter. Since several transcriptome studies have shown a significantly decreased expression of DCD in HS skin, we hypothesised that the identified frameshift insertion was a loss-of-function mutation that might be associated with HS susceptibility in this family. We thus confirmed by mass spectrometry that DCD levels were diminished in the affected members and showed that the antimicrobial activity of a synthetic DCD peptide resulting from the frameshift mutation was impaired. In order to define the consequences related to a decrease in DCD activity, skin microbiome analyses of different body sites were performed by comparing DCD mutant and wild type samples, and results highlighted significant differences between the groins of mutated and wild type groups. Starting from genetic analysis conducted on an HS family, our findings showed, confirming previous transcriptome results, the potential role of the antimicrobial DCD peptide as an actor playing a crucial part in the etio-pathogenesis of HS and in the maintenance of the skin’s physiological microbiome composition; so, we can hypothesise that DCD could be used as a novel target for personalised therapeutic approach.
