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Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent inflammatory lesions, which affect skin and hair follicles in intertriginous areas. HS has a multifactorial aetiology resulting in barrier dysfunction associated with aberrant immune activation. There is increased evidence for the role of inflammasomes in the pathophysiology of inflammatory skin diseases, including HS. Inflammasomes are multiprotein complexes activated following exposure to danger signals, including microbial ligands and components of damaged host cells. Inflammasome activation induces many signalling cascades and subsequent cleavage of proinflammatory cytokines – most notably interleukin (IL)-1β – which have a role in HS pathogenesis. Limited immunotherapies are approved for treating moderate-to-severe HS, with variable response rates influenced by disease heterogeneity. Inflammasomes represent attractive targets to suppress multiple inflammatory pathways in HS, including IL-1β and IL-17. This review aims to summarize the role of inflammasomes in HS and to evaluate evidence for inflammasomes as therapeutic targets for HS treatment. [ABSTRACT FROM AUTHOR]

Background Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated kinase (MEKi) induce a folliculitis in 75–90% of patients, the pathobiology of which remains insufficiently understood. Objectives To characterize changes in the skin immune status and global transcriptional profile of patients treated with EGFRi; to investigate whether EGFRi affects the hair follicle's (HF) immune privilege (IP); and to identify early proinflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo. Methods Scalp biopsies were taken from patients exhibiting folliculitis treated long term with EGFRi ('chronic EGFRi' group, n = 9) vs. healthy scalp skin (n = 9) and patients prior to commencing EGFRi treatment and after 2 weeks of EGFRi therapy ('acute EGFRi' group, n = 5). Healthy organ-cultured scalp HFs were exposed to an EGFRi (erlotinib, n = 5) or a MEKi (cobimetinib, n = 5). Samples were assessed by quantitative immunohistomorphometry, RNA sequencing (RNAseq) and in situ hybridization. Results The 'chronic EGFRi' group showed CD8+ T-cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated major histocompatibility complex (MHC) class I, β2-microglobulin (B2 M) and MHC class II, and decreased transforming growth factor-β1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of human leucocyte antigen (HLA)-A, HLA-DR and B2 M transcripts. RNAseq analysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and interleukin (IL)-26 in biopsies from the 'chronic EGFRi' cohort, as well as increased IL-33 and decreased IL-37 expression in HF biopsies from the 'acute EGFRi' group and in organ-cultured HFs. Conclusions The data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33. [ABSTRACT FROM AUTHOR]

Background Hidradenitis suppurativa (HS) is a chronic, painful disease affecting flexures and other skin regions, producing nodules, abscesses and skin tunnels. Laser treatment targeting hair follicles and deroofing of skin tunnels are standard HS interventions in some countries but are rarely offered in the UK. Objectives To describe current UK HS management pathways and influencing factors to inform the design of future randomized controlled trials (RCTs). Methods THESEUS was a nonrandomized 12-month prospective cohort study set in 10 UK hospitals offering five interventions: oral doxycycline 200 mg daily; oral clindamycin and rifampicin both 300 mg twice daily for 10 weeks, extended for longer in some cases; laser treatment targeting hair follicles; deroofing; and conventional surgery. The primary outcome was the combination of clinician-assessed eligibility and participant hypothetical willingness to receive each intervention. The secondary outcomes were the proportion of participants selecting each intervention as their final treatment option; the proportion who switch treatments; treatment fidelity; and attrition rates. THESEUS was prospectively registered on the ISRCTN registry: ISRCTN69985145. Results The recruitment target of 150 participants was met after 18 months, in July 2021, with two pauses due to the COVID-19 pandemic. Baseline demographics reflected the HS secondary care population: average age 36 years, 81% female, 20% non-White, 64% current or ex-smokers, 86% body mass index ≥ 25, 68% with moderate disease, 19% with severe disease and 13% with mild disease. Laser was the intervention with the highest proportion (69%) of participants eligible and willing to receive treatment, then deroofing (58%), conventional surgery (54%), clindamycin and rifampicin (44%), and doxycycline (37%). Laser was ranked first choice by the greatest proportion of participants (41%). Attrition rates were 11% and 17% after 3 and 6 months, respectively. Concordance with doxycycline was 52% after 3 months due to lack of efficacy, participant choice and adverse effects. Delays with procedural interventions were common, with only 43% and 26% of participants starting laser and deroofing, respectively, after 3 months. Uptake of conventional surgery was too small to characterize the intervention. Switching treatment was uncommon and there were no serious adverse events. Conclusions THESEUS has established laser treatment and deroofing for HS in the UK and demonstrated their popularity with patients and clinicians for future RCTs. [ABSTRACT FROM AUTHOR]

The article discusses the impact of epidermal growth factor receptor (EGFR) and mitogen-activated kinase (MEK) inhibitors on hair follicles, leading to a condition known as EGFRi/MEKi folliculitis. This skin toxicity affects 75-90% of patients receiving these inhibitors, impacting their quality of life and potentially leading to treatment discontinuation. The study explores the collapse of hair follicle immune privilege and excessive interleukin-33 secretion as potential factors contributing to this skin toxicity. [Extracted from the article]

This article discusses the experiences of a patient with CYLD Cutaneous Syndrome (CCS), a genetic condition characterized by the growth of various types of skin tumors. The patient describes the impact of these tumors on their quality of life, including physical and emotional pain, the need for frequent surgical procedures, and the challenges of managing their appearance. The article also highlights the need to reevaluate the classification of these tumors as "benign" due to their progressive growth and potential for serious complications. The authors argue for increased awareness, research, and a change in the narrative surrounding CCS to improve care for patients. [Extracted from the article]

Introduction and aims Public engagement is an essential part of research design. It provides opportunities for both scientists and the public to learn, and inspires the next generation of researchers. We are fortunate to have a public engagement centre within our institution, which contains digital games, an established and effective way to engage children. We developed a new game for school-age children to engage them in the Paediatric Human Cell Atlas, a collaborative project that aims to map single-cell profiles and spatial characterization of gene expression across human tissues and organs throughout development. Our aim was to develop a game that involved different skin cell types, variation in skin colour and common skin disorders. Methods Initial steps included brainstorming with our public engagement staff about content and then developing a lay summary and agreeing on the following key themes: the skin as a barrier, the cells of the skin, and eczema, a common skin disorder. The game was based on the arcade game Breakout. It features a customizable paddle representing the skin, demonstrating how changes in quantities of different skin components can change appearance/function (e.g. melanin production, adipocytes, hair follicles), which players must move across the screen to keep pathogens and allergens out and keep water and protein in. In the last level, barrier function is impaired by eczema and the children can catch cream to repair the barrier. Results The game was developed for our public engagement centre where it has undergone testing by target audiences. Conclusions We have created a game as an innovative way to engage and educate paediatric communities in our research. It was challenging to simplify scientific content for use in a game while staying true to the scientific concepts. We will increase reach by adapting the game for desktop and app-based formats. [ABSTRACT FROM AUTHOR]

Introduction and aims Androgenetic alopecia (AGA) is defined by hair loss from the frontal, parietal and vertex regions of the scalp; however, occipital follicles are spared. Hair follicles in AGA undergo miniaturization, which is the transition of terminal follicles into vellus follicles. Similarly with age, the diameter of the hair shaft decreases with loss of pigmentation, which is also seen in miniaturized follicles. To investigate whether frontal follicles have accelerated ageing compared with occipital follicles, we looked at methylation levels of genes associated with ageing. As the thickness and pigmentation of hair fibre are influenced by the dermal papilla (DP), we conducted microarray analysis of frontal and occipital DP to establish whether accelerated ageing of follicles is driven by DP. Methods The biological age of frontal and occipital follicles was calculated using methylation status of ELOVL2, ASPA, EDARADD and PDE4C (n = 3). For microarray analysis, DP was microdissected from the frontal (FDP) and occipital (ODP) follicles from patients undergoing hair transplantation surgeries to treat AGA (n = 4). Results Frontal follicles were found to have significantly higher biological age compared with patient-matched occipital follicles suggesting accelerated ageing of follicles in AGA. Transcriptomic analysis revealed significant increase in expression of several genes in FDP and notably EGR1 , HSPB1 , DNAJB1 and APOD, which have been shown to be upregulated in the DP of aged mice compared with young mice. We found downregulation of TRPS1 in FDP, which represses EGR1. Mutations in TRPS1 underlie trichorhinophalangeal syndrome which is associated with vellus-type hair. Conclusions Our transcriptional and molecular analysis revealed that FDP and frontal follicles have an advanced biological age relative to ODP. This increased age is also reflected in the transcriptional signature of FDP. We hypothesize that these changes are in part due to regulation of signalling by the transcriptional repressor TRPS1 , whose expression is decreased in FDP. [ABSTRACT FROM AUTHOR]

Introduction and aims CYLD cutaneous syndrome (CCS) is an inherited hair follicle tumour syndrome where biallelic loss of function of the deubiquitinase enzyme CYLD gives rise to cylindroma skin tumours. The role of CYLD in skin biology is not well characterized but it is known to regulate several cell signalling pathways through deubiquitination of effector proteins. We aimed to determine how loss of CYLD function can lead to CCS skin tumour formation by studying the ubiquitome of CCS tumours and healthy skin. Methods Healthy skin (n = 5) and CCS tumour tissue (n = 5) were collected from flash frozen samples. Lysed homogenates were trypsin-digested and the resulting peptides underwent diglycine immunopurification for subsequent liquid chromatography–tandem mass spectrometry analysis on a Bruker Tims-TOF HT (Billerica, MA, USA) mass spectrometer. We utilized a data-independent acquisition method adapted for diglycine-containing peptides to generate mass spectrometry data. Peptide identification was performed by searching mass spectrometry data against an in silico neural network derived spectral library with diglycine modification. Results We identified 1273 ubiquitination sites across 649 proteins in CCS tumour and control samples. After performing t -tests (P < 0.05), we found 305 ubiquitination sites that were either unique to their respective condition or were differentially regulated. Analysis of ubiquitinated peptide sequences uncovered cell surface receptors with increased ubiquitination in CCS tumour samples including the insulin receptor, which had ubiquitination modifications at its kinase domain, suggesting increased insulin signalling in CCS tumours. Gene set enrichment analysis of CCS tumour ubiquitinated substrates revealed increased ubiquitination of secretory granules and extracellular exosomes, suggesting that loss of CYLD may disrupt regulation of protein secretion processes. Conclusions Our findings describe the ubiquitome of CCS keratinocytes, providing insights into how loss of CYLD function can affect biological processes in skin. [ABSTRACT FROM AUTHOR]

Background: Bazex–Dupré–Christol syndrome (BDCS; MIM301845) is a rare X‐linked dominant genodermatosis characterized by follicular atrophoderma, congenital hypotrichosis and multiple basal cell carcinomas (BCCs). Previous studies have linked BDCS to an 11·4‐Mb interval on chromosome Xq25‐q27.1. However, the genetic mechanism of BDCS remains an open question. Objectives: To investigate the genetic aetiology and molecular mechanisms underlying BDCS. Methods: We ascertained multiple individuals from eight unrelated families affected with BDCS (F1–F8). Whole‐exome (F1 and F2) and genome sequencing (F3) were performed to identify putative disease‐causing variants within the linkage region. Array comparative genomic hybridization and quantitative polymerase chain reaction (PCR) were used to explore copy number variations, followed by long‐range gap PCR and Sanger sequencing to amplify the duplication junctions and to define the head–tail junctions. Hi‐C was performed on dermal fibroblasts from two affected individuals with BDCS and one control. Public datasets and tools were used to identify regulatory elements and transcription factor binding sites within the minimal duplicated region. Immunofluorescence was performed in hair follicles, BCCs and trichoepitheliomas from patients with BDCS and sporadic BCCs. The ACTRT1 variant c.547dup (p.Met183Asnfs*17), previously proposed to cause BDCS, was evaluated with t allele frequency calculator. Results: In eight families with BDCS, we identified overlapping 18–135‐kb duplications (six inherited and two de novo) at Xq26.1, flanked by ARHGAP36 and IGSF1. Hi‐C showed that the duplications did not affect the topologically associated domain, but may alter the interactions between flanking genes and putative enhancers located in the minimal duplicated region. We detected ARHGAP36 expression near the control hair follicular stem cell compartment, and found increased ARHGAP36 levels in hair follicles in telogen, in BCCs and in trichoepitheliomas from patients with BDCS. ARHGAP36 was also detected in sporadic BCCs from individuals without BDCS. Our modelling showed the predicted maximum tolerated minor allele frequency of ACTRT1 variants in control populations to be orders of magnitude higher than expected for a high‐penetrant ultra‐rare disorder, suggesting loss of function of ACTRT1 variants to be an unlikely cause for BDCS. Conclusions: Noncoding Xq26.1 duplications cause BDCS. The BDCS duplications most likely lead to dysregulation of ARHGAP36. ARHGAP36 is a potential therapeutic target for both inherited and sporadic BCCs. What is already known about this topic?Bazex–Dupré–Christol syndrome (BDCS) is a rare X‐linked basal cell carcinoma susceptibility syndrome linked to an 11·4‐Mb interval on chromosome Xq25‐q27.1.Loss‐of‐function variants in ACTRT1 and its regulatory elements were suggested to cause BDCS. What does this study add?BDCS is caused by small tandem noncoding intergenic duplications at chromosome Xq26.1.The Xq26.1 BDCS duplications likely dysregulate ARHGAP36, the flanking centromeric gene.ACTRT1 loss‐of‐function variants are unlikely to cause BDCS. What is the translational message?This study provides the basis for accurate genetic testing for BDCS, which will aid precise diagnosis and appropriate surveillance and clinical management.ARHGAP36 may be a novel therapeutic target for all forms of sporadic basal cell carcinomas. [ABSTRACT FROM AUTHOR]

Introduction and aims The human dermal papilla (DP) is a population of cells located at the base of the hair follicle, which signals to surrounding matrix cells facilitating their incorporation into the layers of the hair fibre and the hair follicle. The DP controls the process of hair follicle induction, reflecting its critical role in orchestrating processes integral in hair growth. We hypothesize that distinct functional subgroups exist within the structure, which would mean that there are different types of DP cells within each follicle. Methods To begin testing this, we reanalysed the single-cell RNA sequencing (RNA-Seq) dataset of the human anagen hair follicle used in the 2022 study by Shim et al. To expand on this, we are now generating single-cell RNA-Seq datasets of patient-matched pigmented and nonpigmented hair follicles (n = 4 patients). These datasets will be used to explore heterogeneity in the human DP, and to investigate which subpopulations are potentially changed in the case of pigmentation loss. This will allow us to explore a potentially undiscovered role of the DP in controlling hair fibre pigmentation. Results We found four distinct subpopulations in the DP with statistically significant marker genes in the Shim dataset. This confirms transcriptional heterogeneity in the human DP, hinting at clusters of DP cells with specialized functions within each hair follicle. One subcluster, which expressed S100B, endothelin-3 and bone morphogenetic protein (BMP)4, was of particular interest and gene ontology analysis of the genes in this cluster revealed terms associated with skeletal development and BMP signalling. We hypothesize that this DP cluster regulates melanin transfer from bulbar melanocytes to neighbouring keratinocytes, owing to the known involvement of the mentioned genes in both melanogenesis and melanin transfer. Conclusions The human DP is a heterogeneic structure, with a potentially unexplored role in controlling hair fibre pigmentation. [ABSTRACT FROM AUTHOR]

Introduction and aims Birt–Hogg–Dubé (BHD) syndrome is a rare multisystem disorder caused by germline pathogenic variants in the FLCN gene. BHD skin tumours predominantly affect facial skin, confer a significant psychosocial burden, and there is a lack of nonsurgical therapies. Here we report a novel ex vivo human model to study the impact of FLCN loss in human hair follicles (HFs), the putative origin of BHD skin tumours. Methods Organ-cultured human anagen HFs and scalp skin were treated with small interfering RNA targeting FLCN (n = 2 donors) for 6 days ex vivo , followed by quantitative real-time polymerase chain reaction (qRT-PCR), and quantitative immunohistomorphometry (qIHM). Results Successful FLCN knockdown was confirmed at both the mRNA (34% reduction compared with nontargeting control levels measured by qRT-PCR) and protein level (12% reduction in FLCN expression measured by qIHM). In FLCN-silenced HFs (n = 14, two donors), our preliminary Results demonstrated an increase in p-S6 expression, a direct downstream kinase of mechanistic target of rapamycin complex (mTORC)1 signalling. This was spatially restricted to the hair bulb and proximal outer root sheath keratinocytes, and was significantly greater than quantified in nontargeting control HFs (P < 0.05). Conclusions FLCN silencing in ex vivo cultured, healthy human HFs and scalp skin provides a novel, instructive and accessible preclinical research model. We aim to delineate whether FLCN interacts with the key endogenous inhibitor of mTORC1 activity, TSC2, in future work, to gain insight into the role of FLCN in the pathobiology of BHD and the maintenance of healthy human HFs. [ABSTRACT FROM AUTHOR]

Introduction and aims The human hair follicle (HF) is a miniorgan in the skin that possesses a rich microenvironment composed of a complex assembly of sensory nerves that surround it. Recent studies have explored the effects of this perineural niche on the HF, but the influence of HF on the nervous system from a folliculocentric and skin-centric perspective remains underexplored. To explore the potential bidirectionality of the HF–nervous system connection in the context of nerve development, we asked whether the HF influences the differentiation and maturation of sensory neuron subtypes around it through the release of distinct neurotransmitters and neurotrophic factors. Methods To first identify which cell types might be involved in directing sensory neuron development, we reanalysed available skin and HF single-cell RNA sequencing (scRNA-Seq) datasets. Next, to evaluate neurotransmitter release from these cell types, we used fast-scan cyclic voltammetry (FSCV). Lastly, to interrogate the role of the HF on directing neuronal development in vitro , we used induced pluripotent stem cell-derived sensory neurons as a model for developing nerves. Results We found that a higher percentage of KRT14 - (epithelial) and PDGFRA -expressing (mesenchymal) cells in the HF coexpressed genes encoding specific neurotrophic factors and enzymatic machinery for neurotransmitter production compared with equivalent cells in the skin, suggesting that the HF possesses a greater capacity to signal to the nervous system compared with interfollicular skin. Using FSCV, we then found that follicular outer root sheath and directionally selective cells are capable of releasing neurotransmitters such as serotonin and histamine. Conclusions We postulate that HF-derived neurotransmitters are important for aspects of sensory neuron development such as axonal growth, as serotonin has previously been shown to be an attractive guidance cue for neuronal growth cones. Overall, our work sheds light on the HF–nervous system connection and how the HF may regulate its microenvironment in the skin. [ABSTRACT FROM AUTHOR]

Introduction and aims Molecular regulation of mammalian skin development has been largely derived from murine studies. The lack of human studies stems primarily from the difficulties in prenatal human skin access. There is an important need to study human prenatal skin owing to the notable differences between human and mouse skin and the paucity of mechanistic understanding of congenital skin disorders. Methods We assembled the first comprehensive multiomic reference atlas of prenatal human skin (21 samples from 7 to 16 postconception weeks), combining single-cell (235 201 cells) and spatial transcriptomic data. We followed 84 skin organoids (SkOs) using single-cell analysis over a 5-month culture period and characterized the spatial organization of the skin in mature SkOs. Prenatal skin, SkO and any relevant pre-existing single-cell RNA-Seq datasets were integrated into the analysis. Cell–cell interactions and cell-lineage determination were explored using CellPhoneDB and trajectory inferences. We evaluated the differentiation trajectory alignment between prenatal skin and SkO using the Genes2Genes analysis. Results Our findings reveal predicted factors regulating the epithelial–mesenchymal crosstalk during human hair follicle formation; progressive expression of scar-promoting genes in later gestation, potentially contributing to scarless healing properties of human prenatal skin observed during the early stages of gestation and expression of genes causing genetic skin disorders in the same cell types in prenatal human skin and SkO. We also found that SkOs morphologically recapitulate human skin development from early (periderm formation and shedding) to late (cornification and hair follicle formation) stages. We also demonstrated that SkO and prenatal skin mesenchyme differentiation into hair follicle dermal condensate and dermal papilla is highly conserved at the cellular and molecular level. Conclusions SkOs faithfully recapitulate human prenatal skin development and are a valuable model for mechanistic studies on skin development including hair follicle biology and congenital skin disorders. [ABSTRACT FROM AUTHOR]

This work reports 30 cases of folliculitis decalvans (FD) in patients with dystrophic epidermolysis bullosa (DEB) among a cohort of 125 DEB patients seen between 2010 and 2021 in 2 French expert centers for the management of inherited epidermolysis bullosa. Interestingly, although skin fragility in DEB concerns the entire skin surface, chronic folliculitis leading to FD occurs mainly on the scalp, which suggests a scalp hair follicle-specific condition that could be linked to the specificity of the scalp microbiota. GLO:F03/01dec22:bjd21796-toc-0001.jpg PHOTO (COLOR): . gl Dear Editor, Folliculitis decalvans (FD) is a rare chronic neutrophilic folliculitis of the scalp leading to scarring alopecia. [Extracted from the article]

Summary: Background: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease of the hair follicle defined by recurrent nodules, tunnels and scarring involving the intertriginous regions. HS is associated with microbial dysbiosis and immune dysregulation. In HS, an increasing number of studies have investigated antimicrobial peptides (AMPs). Objectives: To provide an overview of the literature on AMPs in HS, and to discuss the potential role of AMPs in the pathogenesis of HS. Methods: PubMed, Embase and the Cochrane Library were searched. The titles, abstracts and full texts of all articles were manually screened. Additionally, the reference lists of the included articles were screened and hand searched for relevant studies. Results: The final literature sample comprised 18 retrospective and prospective studies (no reviews or commentaries) published between 2009 and 2020. Conclusions: This review demonstrates the multitude of AMPs in HS. Although the methodology of the studies varied, the included studies indicate a consistent overexpression of human β‐defensin (hBD)‐2, S100A7, S100A8 and S100A9 at both the mRNA and protein levels, and a decreased expression of hBD‐1. Overall, the studies point to a dysregulation of AMPs in both lesional and nonlesional HS skin. Whatis already known about this topic?Various studies have investigated the level of antimicrobial peptides (AMPs) in hidradenitis suppurativa (HS). Whatdoes this study add?The data presented in this systematic review point to a dysregulation of AMPs in both lesional and nonlesional skin in HS. Linked Comment: S.L. Schell and A.M. Nelson. Br J Dermatol 2022; 186:204–205. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Background: Permanent chemotherapy‐induced alopecia (pCIA), for which preventive interventions remain limited, can manifest with scarring. While the underlying pathomechanisms of pCIA are unclear, depletion of epithelial hair follicle (HF) stem cells (eHFSCs) is likely to play a role. Objectives: To explore the hypothesis that, besides apoptosis, eHFSCs undergo pathological epithelial–mesenchymal transition (EMT) in pCIA, thus explaining the scarring phenotype. Furthermore, we tested whether a peroxisome proliferator‐activated receptor (PPAR)‐γ modulator could prevent pCIA‐associated pathomechanisms. Methods: Organ‐cultured human scalp HFs were treated with the cyclophosphamide metabolite 4‐hydroperoxycyclophosphamide (4‐HC). Additionally, HFs were pretreated with the agonistic PPAR‐γ modulator N‐acetyl‐GED‐0507‐34‐Levo (NAGED), which has previously been shown to promote K15 expression and antagonize EMT in eHFSCs. Results: In accordance with anticipated hair bulb cytotoxicity, dystrophy and catagen induction, 4‐HC promoted apoptosis along with increased p53 expression, DNA damage and pathological EMT in keratin 15+ (K15) eHFSCs, as evidenced by decreased E‐cadherin expression and the appearance of fibronectin+ and vimentin+ cells in the hair bulge. Pretreatment with NAGED protected against 4‐HC‐induced hair bulb cytotoxicity/dystrophy, and apoptosis, p53 upregulation and EMT in the bulge, thereby significantly preventing depletion of K15+ human eHFSCs ex vivo. Conclusions: Since a key cyclophosphamide metabolite alone suffices to damage and deplete human scalp eHFSCs by promoting apoptosis, DNA damage and EMT ex vivo, strategies to prevent pCIA need to target these pathomechanisms. Given the ability of NAGED to prevent chemotherapy‐induced eHFSCs damage ex vivo, our study introduces the stimulation of PPAR‐γ signalling as a novel intervention strategy for the prevention of pCIA. What is already known about this topic? Chemotherapy can lead to permanent hair loss, which can manifest as scarring alopecia. Unfortunately, the pathomechanism of this phenomenon is unknown, and efficient preventive interventions are lacking. What does this study add? Repeated treatment of organ‐cultured human hair follicles (HFs) with 4‐hydroperoxycyclophosphamide (4‐HC) led not only to expected dystrophic changes in the bulb, but also resulted in DNA damage, apoptosis and pathological epithelial–mesenchymal transition (EMT) of epithelial HF stem cells (eHFSCs).Pretreatment with a peroxisome proliferator‐activated receptor (PPAR)‐γ modulator hindered 4‐HC‐induced hair bulb cytotoxicity/dystrophy, and protected K15+ human eHFSCs from apoptosis and EMT, thereby significantly preventing their depletion ex vivo. What is the translational message? Stimulation of PPAR‐γ signalling is a promising novel intervention strategy for the prevention of permanent chemotherapy‐induced alopecia. Linked Comment: K. Natsuga. Br J Dermatol 2022; 186:14–15. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Background: Skin adnexal tumours (SATs) comprise a diverse range of neoplasms, which are difficult to diagnose clinically. They present in paediatric and adult populations, and may be indicative of an underlying genetic syndrome. There is a lack of recent data on the presentation of these tumours in clinical practice in European populations. Objectives: To characterize the clinical and pathological features of SATs received at a single tertiary centre over a 5‐year period. Methods: A retrospective health record audit of SATs received at the Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, during the period November 2012 to October 2017 was performed. Results: In total, 107 144 skin cases were received during the audit period. A total of 1615 cases of SATs from 1359 patients were included; 1570 (97·2%) were benign and 45 (2·8%) were malignant. Overall, the average age at presentation was 55 years (range 11 months to 97 years) and the male to female ratio was 0·77 : 1. Sweat gland and hair follicle SATs were most frequently excised; in adults, the most frequent tumour was hidrocystoma, and in children, pilomatrixoma occurred most often. Prebiopsy diagnosis was correct in 28% of cases. Benign SATs are often markers of an associated genetic condition, which warrants improved discrimination of sporadic from genetically related SATs. Conclusions: SATs are difficult to diagnose clinically, and clinicopathological correlation may help enhance discrimination of genetically related SATs from sporadic cases. These data have implications for clinical and dermatopathological training provision, the development of reporting standards, and genetic assessment of selected patients. What is already known about this topic? Skin adnexal tumours (SATs) comprise a diverse range of neoplasms, which arise from the hair follicle, sebaceous and eccrine glands.Clinical diagnosis is difficult owing to the lack of discriminatory features.Selected SATs are recognized markers of underlying genetic conditions, but the proportion of these tumours occurring in unselected European populations is not known. What does this study add? Prebiopsy diagnosis of SATs was correct in only 28% of cases.Clinicopathological correlation may aid discrimination of sporadic from genetically related SATs, with implications for genetic testing and cancer screening.Pathology reports of SATs that flag known linked genetic diagnoses to the referring surgeon should be part of the standard of care for patients from whom SATs are excised. Linked Comment: Z. Marušić and E. Calonje. Br J Dermatol 2022; 186:16–17. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Human hair follicles (HFs) carry complex microbial communities that differ from the skin surface microbiota. This likely reflects that the HF epithelium differs from the epidermal barrier in that it provides a moist, less acidic, and relatively ultraviolet light‐protected environment, part of which is immune‐privileged, thus facilitating microbial survival. Here we review the current understanding of the human HF microbiome and its potential physiological and pathological functions, including in folliculitis, acne vulgaris, hidradenitis suppurativa, alopecia areata and cicatricial alopecias. While reviewing the main human HF bacteria (such as Propionibacteria, Corynebacteria, Staphylococci and Streptococci), viruses, fungi and parasites as human HF microbiome constituents, we advocate a broad view of the HF as an integral part of the human holobiont. Specifically, we explore how the human HF may manage its microbiome via the regulated production of antimicrobial peptides (such as cathelicidin, psoriasin, RNAse7 and dermcidin) by HF keratinocytes, how the microbiome may impact on cytokine and chemokine release from the HF, and examine hair growth‐modulatory effects of antibiotics, and ask whether the microbiome affects hair growth in turn. We highlight major open questions and potential novel approaches to the management of hair diseases by targeting the HF microbiome. [ABSTRACT FROM AUTHOR]

Traumatic anserine folliculosis (TAF) is an infrequently reported condition, presenting with grouped follicular papules, usually on the face of young people, induced by repeated frictional trauma or pressure. A suggestive history may allow clinical differentiation of TAF from other folliculocentric keratotic disorders. We present three children diagnosed with TAF in our department: (i) A 12-year-old boy with asymmetry of the mental protuberance, presented with a 1-year history of scaly, lichenified erythema with monomorphic nonpigmented papules over the more prominent side; histology showed mild hyperkeratosis and some rudimentary hair follicles with keratin-filled follicular openings. (ii) A 7-year-old boy with a 1-year history of a hyperpigmented patch on the chin with multiple skin-coloured papules and a sandpaper feel; dermoscopy showed follicular papules with keratin plug; he had a habit of reading with his chin resting on his knee; the skin changes improved with topical retinoid and postural changes. (iii) A boy with follicular papules on one cheek since the age of 8 years, with history of persistent leaning his hand on his cheek while reading; the papules resolved with a change in posture, but similar changes arose at a new pressure area on his chin. The clinical features of grouped monomorphic skin-coloured follicular papules on an erythematous or hyperpigmented background, and a suggestive history, may allow the diagnosis of TAF. Described histological findings are hyperkeratosis, rudimentary follicles and dilated follicular openings filled with keratotic material. Management includes identifying and correcting postural habits; topical keratolytic agents and retinoids may also be beneficial. [ABSTRACT FROM AUTHOR]

Summary: Background: Human hair is highly responsive to stress, and human scalp hair follicles (HFs) contain a peripheral neuroendocrine equivalent of the systemic hypothalamic–pituitary–adrenal (HPA) stress axis. Androgenetic alopecia (AGA) is supposed to be aggravated by stress. We used corticotropin‐releasing hormone (CRH), which triggers the HPA axis, to induce a stress response in human ex vivo male AGA HFs. Caffeine is known to reverse testosterone‐mediated hair growth inhibition in the same hair organ culture model. Objectives: To investigate whether caffeine would antagonize CRH‐mediated stress in these HFs. Methods: HFs from balding vertex area scalp biopsies of men affected by AGA were incubated with CRH (10−7 mol L−1) with or without caffeine (0·001% or 0·005%). Results: Compared to controls, CRH significantly enhanced the expression of catagen‐inducing transforming growth factor‐β2 (TGF‐β2) (P < 0·001), CRH receptors 1 and 2 (CRH‐R1/2) (P < 0·01), adrenocorticotropic hormone (ACTH) (P < 0·001) and melanocortin receptor 2 (MC‐R2) (P < 0·001), and additional stress‐associated parameters, substance P and p75 neurotrophin receptor (p75NTR). CRH inhibited matrix keratinocyte proliferation and expression of anagen‐promoting insulin‐like growth factor‐1 (IGF‐1) and the pro‐proliferative nerve growth factor receptor NGF‐tyrosine kinase receptor A (TrkA). Caffeine significantly counteracted all described stress effects and additionally enhanced inositol trisphosphate receptor (IP3‐R), for the first time detected in human HFs. Conclusions: These findings provide the first evidence in ex vivo human AGA HFs that the stress mediator CRH induces not only a complex intrafollicular HPA response, but also a non‐HPA‐related stress response. Moreover, we show that these effects can be effectively antagonized by caffeine. Thus, these data strongly support the hypothesis that stress can impair human hair physiology and induce hair loss, and that caffeine may effectively counteract stress‐induced hair damage and possibly prevent stress‐induced hair loss. What is already known about this topic? Caffeine stimulates hair growth in male and female human hair follicles (HFs) in vitro. What does this study add? For the first time, corticotropin‐releasing hormone induction of the hypothalamic–pituitary–adrenal (HPA) stress axis is documented in male human HFs from biopsies (balding vertex area) of men with androgenetic alopecia.First time, the non‐HPA neurogenic stress axis is shown in the same male human HFs.Caffeine counteracts both stress axes.Inositol trisphosphate receptor was newly identified in human HFs. What is the translational message? Stress can impair human hair physiology and induce hair loss.Caffeine may effectively counteract stress‐induced hair damage and possibly prevent stress‐induced hair loss. Linked Comment:Ohyama. Br J Dermatol 2021; 184:7–8. [ABSTRACT FROM AUTHOR]

Summary: Background: Frontal fibrosing alopecia (FFA) is traditionally regarded as a variant of lichen planopilaris (LPP) based on histological features. Distinct clinical presentation, demographics and epidemiology suggest that differing pathogenic factors determine the final phenotype. Objectives: To map the hair follicle immune system in LPP and FFA by systematically comparing key inflammatory markers in defined hair follicle compartments. Methods: Lesional scalp biopsies from LPP and FFA and healthy controls were stained with the following immunohistochemical markers: CD1a and CD209, CD4, CD8, CD56, CD68, CD123, CXCR3, forkhead box (FOX)P3, mast cell tryptase and cKit. Macrophage polarization was explored using CD206, CD163, CD86, receptor for advanced glycation end products (RAGE), interleukin (IL)‐4 and IL‐13 on paired lesional and nonlesional LPP and FFA samples. Results: Increased numbers of CD8+, CXCR3+ and FOXP3+ T cells and CD68+ macrophages were identified in the distal hair follicle epithelium and perifollicular mesenchyme in both LPP and FFA compared with controls. In both LPP and FFA, total and degranulated mast cells and CD123+ plasmacytoid dendritic cells were increased in the perifollicular mesenchyme adjacent to the bulge and infundibulum, whereas numbers of CD1a+ and CD209+ dendritic cells were significantly reduced in the infundibulum connective tissue sheath. However, only with CD68 staining was a significant difference between LPP and FFA identified, with greater numbers of CD68+ cells in LPP samples. Furthermore, the identified macrophage polarization markers downregulated CD86 and upregulated CD163 and IL‐4 expression in lesional LPP compared with FFA samples. Conclusions: This comparative immunopathological analysis is the first to profile systematically the hair follicle immune system in LPP and FFA. Our analysis highlights a potential role of macrophages in disease pathobiology and suggests that macrophage polarization may differ between LPP and FFA, allowing microscopic differentiation. Linked Comment: Kinoshita‐Ise. Br J Dermatol 2020; 183:419–420. What is already known about this topic? Lichen planopilaris (LPP) and frontal fibrosing alopecia (FFA) are lymphocytic scarring alopecias characterized by bulge immune privilege collapse and a T helper 1‐biased cytotoxic T‐cell infiltrate. What does this study add? We reveal a prominent role of innate and adaptive immune responses in both LPP and FFA.Increased T cells, plasmacytoid dendritic cells, mast cells and macrophages are mapped to define hair follicle epithelial and mesenchymal compartments.We identify a significant difference in CD68+ cell numbers between LPP and FFA and highlight that macrophage polarization may differ between LPP and FFA. What is the translational message? Macrophage polarization markers may help to distinguish LPP from FFA microscopically, and ultimately lead to macrophage‐targeted therapeutic interventions tailored for each disorder. Linked Comment: Kinoshita‐Ise. Br J Dermatol 2020; 183:419–420. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Background: Hypotrichosis simplex of the scalp (HSS) is characterized by progressive loss of scalp hair that results in almost complete baldness at a young age. HSS is often caused by dominant nonsense mutations in CDSN encoding corneodesmosin, leading to the formation of an amyloid‐like material, which interferes with normal hair follicle cycle. Objectives: As gentamicin has been shown to mediate ribosomal read‐through, we aimed to ascertain its therapeutic efficacy in a small series of patients carrying a recurrent mutation in CDSN. Methods: We used a green fluorescence reporter assay system, confocal microscopy and Western blot analysis to ascertain in vitro the ability of gentamicin to induce translational read‐through across a causative CDSN mutation. Results: Using a reporter assay, we initially showed that gentamicin induces read‐through activity across an HSS‐causing nonsense mutation. Gentamicin was further shown to rescue corneodesmosin translation in primary keratinocytes obtained from a patient with HSS. To validate the in vitro data, we conducted a pilot clinical trial where the scalp of four patients was treated topically with gentamicin for 6 months, demonstrating significant improvement as ascertained by the Severity of Alopecia Tool score. Conclusions: Our findings indicate that topical gentamicin should be considered as a potential therapeutic modality in HSS. What's already known about this topic? Hypotrichosis simplex of the scalp (HSS) is caused by nonsense mutations in CDSN encoding corneodesmosin.The mutant corneodesmosin has been hypothesized to be toxic to the hair follicles, leading to hypotrichosis.Disorders caused by nonsense mutations are amenable to ribosomal read‐through using gentamicin. What does this study add? Gentamicin enhanced read‐through activity and promoted full‐length corneodesmosin synthesis in primary keratinocytes derived from patients carrying a nonsense mutation in CDSN.Topical treatment with gentamicin was found to rescue the hypotrichosis phenotype partially in four patients with HSS. What is the translational message? Topical gentamicin should be considered as a potential treatment for HSS. Linked Comment: Kibbi and Rajan. Br J Dermatol 2020; 183:11. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Background: Given that unwanted hair growth (hirsutism, hypertrichosis) can cause major psychological distress, new pharmacological treatment strategies with safe and effective hair growth inhibitors that do not destroy the hair follicle (HF) and its stem cells need to be developed. Objectives: To establish if osteopontin‐derived fragments may modulate human hair growth given that human HFs express the multifunctional, immunomodulatory glycoprotein, osteopontin. Methods: Our hypothesis was tested ex vivo and in vivo by using a newly generated, toxicologically well‐characterized, modified osteopontin‐derived peptide (FOL‐005), which binds to the HF. Results: In organ‐cultured human HFs and scalp skin, and in human scalp skin xenotransplants onto SCID mice, FOL‐005 treatment (60 nmol L−1 to 3 μmol L−1) significantly promoted premature catagen development without reducing the number of keratin 15‐positive HF stem cells or showing signs of drug toxicity. Genome‐wide DNA microarray, quantitative reverse‐transcriptase polymerase chain reaction and immunohistochemistry revealed decreased expression of the hair growth promoter, fibroblast growth factor‐7 (FGF7) by FOL‐005, while cotreatment of HFs with recombinant FGF7 partially abrogated FOL‐005‐induced catagen promotion. Conclusions: With caveats in mind, our study identifies this osteopontin‐derived peptide as an effective, novel inhibitory principle for human hair growth ex vivo and in vivo, which deserves systematic clinical testing in hirsutism and hypertrichosis. What's already known about this topic? The treatment of unwanted hair growth (hypertrichosis, hirsutism) lacks pharmacological intervention, with only few and often unsatisfactory treatments available.Osteopontin is prominently expressed in human HFs and has been reported to be elevated during catagen in the murine hair cycle. What does this study add? We tested the effects on hair growth of a novel, osteopontin‐derived fragment (FOL‐005) ex vivo and in vivo.In human hair follicles, high‐dose FOL‐005 significantly reduces hair growth both ex vivo and in vivo. What is the translational message? High‐dose FOL‐005 may provide a new therapeutic opportunity as a treatment for unwanted hair growth. Linked Comment:Weiss. Br J Dermatol 2020; 182:1324–1325. [ABSTRACT FROM AUTHOR]

Summary: Background: The signals that induce anagen (growth) in 'quiescent' human telogen hair follicles (HFs) are as yet unknown. Their identification promises better targeted therapeutic hair growth interventions. Objectives: Recognizing the central role of Wnt signalling in hair biology, the aim was to delineate the differential expression of key agonists, antagonists and target genes of this pathway during the telogen‐to‐anagen transformation of human scalp HFs. Methods: This differential expression was studied by in situ hybridization in human telogen and early‐anagen scalp HF sections. Results: On anagen induction, gene expression of the Wnt ligands WNT3,WNT4 and WNT10B, the Wnt ligand secretion regulator WLS, and the Wnt target genes AXIN2 and LEF1, is significantly increased within the secondary hair germ and the dermal papilla. Conversely, expression of the secreted Wnt inhibitor SFRP1 (secreted frizzled‐related protein 1) is reduced. Human epithelial HF stem cells upregulate WNT4 and WNT10A expression, suggesting that these Wnt agonists are important for stem cell activation. Conclusions: We provide the first evidence that key changes in Wnt signalling that drive murine anagen induction also occur in human scalp HFs, yet with notable differences. This provides a rational basis for Wnt‐targeting therapeutic interventions to manipulate human hair growth disorders. What's already known about this topic? Upregulation of Wnt agonists and downregulation of Wnt antagonists in the secondary hair germ and/or dermal papilla drives hair growth (anagen) induction in mice.Autocrine Wnt signalling in murine epithelial hair follicle stem cells is required to maintain their stem cell function.Reduction of Wnt ligands or increased expression of Wnt antagonists induces dysregulation of the murine hair follicle cycle and causes alopecia. What does this study add? This study demonstrates for the first time that key Wnt pathway regulatory agonists, antagonists and target genes, are expressed in the human telogen‐to‐early‐anagen transformation.On human anagen induction the Wnt ligands WNT3, WNT4 and WNT10B are increased in the regenerating epithelium, whereas the Wnt antagonist, SFRP1 (secreted frizzled‐related protein 1), is reduced.Human anagen induction has fundamental differences in the expression of Wnt ligands compared with the murine system. What is the translational message? Regulation of these Wnt ligands permits targeted therapeutic interventions in human hair growth disorders and informs development of new drugs that promote or suppress anagen induction. Linked Comment: Philpott. Br J Dermatol 2020; 182:1084. Plain language summary available online Respond to this article [ABSTRACT FROM AUTHOR]

Summary: Background: Hidradenitis suppurativa (HS) is a rare, debilitating neutrophilic dermatosis characterized by chronic inflammation of hair follicles. Many inflammatory conditions may accompany HS. Objectives: To investigate the association of variants of the MEFV gene with a complex HS phenotype. Methods: Firstly, we identified the clinical characteristics of 119 patients with HS with a complex phenotype (Hurley stage III disease and/or additional inflammatory symptoms). Then, we searched for MEFV variants among these patients. The odds ratios (ORs) for pathogenic MEFV mutations were calculated using data from these patients with HS and 191 healthy controls. Results: The male/female ratio was higher, and the mean age of onset was earlier, in our complex HS group compared with patients with HS in general. Five of the patients with HS (4·2%) had a diagnosis of familial Mediterranean fever (FMF) with a standardized morbidity ratio of 45 [95% confidence interval (CI) 16·50–99·84, P < 0·001] when compared with the frequency of FMF in the general Turkish population. Of the patients with complex HS, 38% were positive for pathogenic variants of MEFV. The OR for carrying a pathogenic MEFV allele was 2·80 (95% CI 1·31–5·97, P < 0·001). Conclusions: The frequency of MEFV mutations in the group of patients with complex HS was higher than that in healthy controls, suggesting that MEFV mutations may contribute to the pathogenesis of HS. Understanding the role of autoinflammation in HS is of fundamental importance for the development of novel therapies. What's already known about this subject? Hidradenitis suppurativa (HS) is a neutrophilic dermatosis with an unclear pathogenesis, but immune dysregulation has been implicated.MEFV mutations are reported in several patients with PASH syndrome (pyoderma gangrenosum, acne and HS), which is a syndromic form of HS. What does this study add? Pathogenic MEFV variants are more frequent in patients with complex HS than in healthy controls.HS in syndromic forms [PASH, PAPASH (pyrogenic arthritis, pyoderma gangrenosum, acne and HS)], severe HS and HS with additional inflammatory symptoms all belong to the category of autoinflammatory spectrum neutrophilic skin diseases. What is the translational message? The co‐occurence of inflammatory diseases with HS and the severity of HS, which we called 'complex HS', may indicate a more specific association with autoinflammation.The complex HS group represented a distinct population characterized by the early onset of HS. Pathogenic MEFV variants were increased not only in patients with PASH but also among patients fulfilling the criteria for 'complex HS'.The proinflammatory status caused by mutations in the MEFV gene may contribute to pathogenicity in complex HS. Linked Comment: Contrassot and French. Br J Dermatol 2019; 180:1294–1295. Plain language summary available online Respond to this article [ABSTRACT FROM AUTHOR]

Summary: Background: The skin is the first organ that manifests changes in response to zinc deficiency. However, the molecular mechanism underlying how zinc is involved in skin homeostasis, especially its epigenetic regulation, is largely unknown. Objectives: In this study we demonstrate the importance of zinc levels and the zinc transporter ZIP10 in the epigenetic maintenance of human epidermal homeostasis. Methods: Adult human skin, including skin appendages, were stained with anti‐ZIP10 antibody. Histone acetyltransferase (HAT) activity was assessed after treating human keratinocytes with ZIP10 small interfering (si)RNAs or the zinc chelator TPEN. ZIP10‐ or HAT‐regulated genes were analysed based on limma bioinformatics analysis for keratinocytes treated with ZIP10 siRNAs or a HAT inhibitor, or using a public database for transcription factors. A reconstituted human skin model was used to validate the role of ZIP10 in epidermal differentiation and the functional association between ZIP10 and HAT. Results: ZIP10 is predominantly expressed in the interfollicular epidermis, epidermal appendages and hair follicles. ZIP10 depletion resulted in epidermal malformations in a reconstituted human skin model via downregulation of the activity of the epigenetic enzyme HAT. This decreased HAT activity, resulting from either ZIP10 depletion or treatment with the zinc chelator TPEN, was readily restored by zinc supplementation. Through bioinformatics analysis for gene sets regulated by knockdown of SLC39A10 (encoding ZIP10) and HAT inhibition, we demonstrated that ZIP10 and HATs were closely linked with the regulation of genes related to epidermal homeostasis, particularly filaggrin and metallothionein. Conclusions: Our study suggests that ZIP10‐mediated zinc distribution is crucial for epidermal homeostasis via HATs. Therefore, zinc‐dependent epigenetic regulation could provide alternatives to maintaining healthy skin or alleviating disorders with skin barrier defects. What's already known about this topic? The skin is the first organ that demonstrates changes in response to zinc deficiency.Zinc levels are tightly regulated by zinc‐transporting proteins: the ZIP family and the zinc transporter family. ZIP10 is a crucial zinc transporter in murine epidermal development by supplying zinc to p63.Epigenetic changes by histone deacetylases and histone acetyltransferases (HATs) profoundly influence epidermal morphogenesis.The molecular mechanism underlying how zinc is involved in epigenetic regulation of skin homeostasis is largely unknown. What does this study add? ZIP10 is expressed in adult human skin, including skin appendages.ZIP10 regulates the activity of the zinc‐dependent epigenetic enzyme HAT, and ZIP10 depletion resulted in epidermal malformations in a reconstituted human skin model. What is the translational message? Based on bioinformatics analysis for gene sets regulated by ZIP10 knockdown and HAT inhibition, ZIP10 and HATs were closely linked with the regulation of genes related to epidermal homeostasis, particularly filaggrin and metallothionein. Linked Comment:Ogawa. Br J Dermatol 2019; 180:707–709. Respond to this article [ABSTRACT FROM AUTHOR]

GLO:F03/01mar21:bjd19593-fig-0001.jpg PHOTO (COLOR): 1 (a, e) Anagen eyelash hair follicle (ELHF) demonstrating Ki-67+ cells in the proximal bulb and outer root sheath (a) and prominent melanin staining (e). For this it is essential to examine ELHFs at the tissue level, and to develop ELHF organ culture assays that permit analysis I ex vivo i .5,6 The current pilot study represents a first step in this direction. ELHFs in early anagen showed a club hair and compacted DP, partially surrounded by a crescent-shaped secondary hair germ containing localized Ki-67 SP + sp cells (Figure 1c, g). [Extracted from the article]

Pilomatrixoma is a benign tumour that arises from the base of the hair follicle matrix. Anetodermic changes overlying the tumour occur in only 2% of the cases. The aim of this study is to evaluate a case series of paediatric patients who presented with anetodermic pilomatrixoma to our Paediatric Dermatology department. A retrospective analysis of all our paediatric cases with a clinical diagnosis of anetodermic pilomatrixoma within the last 4 years was made. Data were collected according to age at time of presentation, suspected clinical diagnosis, histopathological features, treatment and postoperative outcomes. Five cases were identified. All were referred as a rapidly growing tumour. The median age of onset was 15 years. The male : female ratio was 3 : 2; one presented on the neck, two on the upper limbs and two on the back. Two out of three patients reported that the lesions were painful. Clinical suspicion of anetodermic pilomatrixoma (large, atrophic, wrinkled lesion overlying a firm subcutaneous mass) was made prior to surgical removal. Four were confirmed histopathologically. Simple excision was carried out without any postoperative complications. There have been no recurrences. Anetodermic pilomatrixoma, also referred to as pseudobullous pilomatrixoma, is a rare variant of pilomatrixomas, occurring more frequently in the upper body. It presents with identifiable features but should be differentiated from other skin tumours. Pain can be a symptom due to the size of the lesion. Surgical removal is the gold standard treatment with a low recurrence rate. [ABSTRACT FROM AUTHOR]

Dear Editor, Wnt signalling is one of the most fundamental molecular pathways for modulating the human hair cycle and is essential for maintaining hair growth.1 We recently identified that the Wnt antagonist, secreted frizzled related protein 1 (SFRP1), prematurely induces catagen in microdissected human scalp hair follicles (HFs) I ex vivo i .1 SFRP1 is inhibited by the potent hypertrichosis-inducing immunosuppressant ciclosporin A (CsA), and the specific SFRP1 antagonist WAY-316606, both of which prevent spontaneous catagen development.1 Collectively, this establishes SFRP1 antagonists as attractive candidate therapeutics for management of hair loss disorders. Identifying novel strategies for treating human hair loss disorders: cyclosporine A suppresses the Wnt inhibitor, SFRP1, in the dermal papilla of human scalp hair follicles. [Extracted from the article]

Https://doi.org/10.1093/bjd/ljac023 Dear Editor, The differential diagnosis between benign pigmented macules and lentigo maligna (LM) is clinically challenging. Moreover, RCM revealed complete disappearance of I Demodex i , normal hair follicles and scattered pigmented keratinocytes (Figure 1h, i). Reflectance confocal microscopy (RCM) has been used to show that this pattern corresponds to an increased number of melanocytes in the follicular epithelium and/or an increased number of melanocytes in the rete ridges.[2] A 55-year-old woman was referred for a pigmented facial macule. [Extracted from the article]

Enhanced topical psoralen-ultraviolet A therapy via targeting to hair follicles Dear Editor, Renewed interest in psoralen-ultraviolet A (PUVA) therapy driven by impressive recent results in this field has encouraged researchers and clinicians to shift momentum back in its favour.[[1], [3]] While administration of low cumulative UVA doses minimizes the negative risks, the search for efficient modalities decreasing the frequency of sessions may help this therapeutic option.[3] In this regard, targeted delivery of psoralen looks promising, especially in terms of vitiligo or alopecia areata treatment. The morphology of root sheaths of the control hairs of this volunteer (without treatment) is similar to the rat ones presented in our previous work.[6] Topical application of the psoralen solution does not affect the root sheath morphology. [Extracted from the article]

Summary: Background: Alopecia areata is a disorder that results in nonscarring hair loss. The psychological impact can be significant, leading to feelings of depression and social isolation. Objectives In this article, we seek to review the pathophysiological mechanisms proposed in recent years in a narrative fashion. Methods: We searched MEDLINE and Scopus for articles related to alopecia areata, with a particular emphasis on its pathogenesis. Results: The main theory of alopecia areata pathogenesis is that it is an autoimmune phenomenon resulting from a disruption in hair follicle immune privilege. What causes this breakdown is an issue of debate. Some believe that a stressed hair follicle environment triggers antigen presentation, while others blame a dysregulation in the central immune system entangling the follicles. Evidence for the latter theory is provided by animal studies, as well investigations around the AIRE gene. Different immune‐cell lines including plasmacytoid dendritic cells, natural killer cells and T cells, along with key molecules such as interferon‐γ, interleukin‐15, MICA and NKG2D, have been identified as contributing to the autoimmune process. Conclusions: Alopecia areata remains incurable, although it has been studied for years. Available treatment options at best are beneficial for milder cases, and the rate of relapse is high. Understanding the exact mechanisms of hair loss in alopecia areata is therefore of utmost importance to help identify potential therapeutic targets. What's already known about this topic? Alopecia areata is an autoimmune phenomenon resulting from disturbances in hair follicle immune privilege.This is mediated through major histocompatibility complex presentation and interferon‐γ expression.Polymorphisms in genes related to the immune system, structural proteins and antioxidant enzymes increase susceptibility to alopecia areata. What does this study add? There are four theories explaining immune privilege collapse: central immune dysregulation, stress‐induced MICA expression on hair follicles, activation of the innate immune system via Toll‐like receptors, and activation of mast cells via neuroendocrine stimuli.Immune privilege collapse is a necessary step but not sufficient without the further participation of other immune pathways (e.g. interleukin‐15, T helper 17).Treatment strategies should focus on re‐establishment of immune privilege along with induction of anagen. Linked Editorial:Ohyama. Br J Dermatol 2018; 179:1023–1024. Plain language summary available online [ABSTRACT FROM AUTHOR]

Summary: Background: Disintegration of the infundibula of terminal hair follicles (HFs) in intertriginous skin areas exhibits the histological hallmark of hidradenitis suppurativa (HS)/acne inversa, featuring a dissecting terminal hair folliculitis. Elevated serum levels of interleukin (IL)‐17 and local increase in the ratio of proinflammatory T helper (Th)17 cells and anti‐inflammatory regulatory T cells (Tregs) have been reported. Perifollicular Tregs play a key role in HF stem cell homeostasis and infundibular integrity. Objectives: In this review, we evaluate the Th17/Treg ratio in HS, its aggravating conditions and associated comorbidities. Furthermore, we intended to clarify whether drugs with reported beneficial effects in the treatment of HS readjust the deviated Th17/Treg axis. Methods: PubMed‐listed, peer‐reviewed original research articles characterizing Th17/Treg regulation in HS/acne inversa and associated comorbidities were selected for this review. Results: This review presents HS as a disease that exhibits an increased Th17/Treg ratio. Perifollicular deficiencies in Treg numbers or function may disturb HF stem cell homeostasis, initiating infundibular dissection of terminal HFs and perifollicular inflammation. The Th17/Treg imbalance is aggravated by obesity, smoking and decreased Notch signalling. In addition, HS‐associated autoimmune diseases exhibit a disturbed Th17/Treg axis resulting in a Th17‐dominant state. All drugs that have beneficial effects in the treatment of HS normalize the Th17/Treg ratio. Conclusions: HS immunopathogenesis is closely related to deviations of the Th17/Treg balance, which may negatively affect Treg‐controlled HF stem cell homeostasis and infundibular integrity. Pharmacological intervention should not only attenuate Th17/IL‐17 signalling, but should also improve Treg function in order to stabilize HF stem cell homeostasis and infundibular integrity. [ABSTRACT FROM AUTHOR]

Summary: Background: Transition of hair shaft keratinocytes from actively respiring, nucleated cells to structural cells devoid of nucleus and cytoplasm is key to hair production. This form of cell ‘death’, or cornification, requires cellular organelle removal to allow the cytoplasm to become packed with keratin filament bundles that further require cross‐linking to create a strong hair fibre. Although these processes are well described in epidermal keratinocytes, there is a lack of understanding of such mechanisms, specifically in the hair follicle. Objectives: To gain insights into cornification mechanisms within the hair follicle and thus improve our understanding of normal hair physiology. Methods: Scalp biopsies and hair‐pluck samples were obtained from healthy human donors and analysed microscopically after immunohistochemical staining. Results: A focal point of respiratory activity was evident in keratogenous zone cells within the hair shaft, which also exhibited nuclear damage. Nuclear degradation occurred via both caspase‐dependent and caspase‐independent pathways. Conversely, mitophagy was driven by Bnip3L and restricted to the boundary of the keratogenous zone at Adamson's Fringe. Conclusions: We propose a model of stepwise living–dead transition within the first 1 mm of hair formation, whereby fully functional, nucleated cells first consolidate required functions by degrading nuclear DNA, yet continue to respire and provide the source of reactive oxygen species required for keratin cross‐linking. Finally, as the cells become packed with keratin bundles, Bnip3L expression triggers mitophagy to rid the cells of the last remaining ‘living’ characteristic, thus completing the march from ‘living’ to ‘dead’ within the hair follicle. [ABSTRACT FROM AUTHOR]

Summary: Background: Eccrine sweat glands (ESGs) are critical for thermoregulation and are involved in wound healing. ESGs have traditionally been considered as separate skin appendages without connection to the pilosebaceous unit (PSU). However, recent preliminary evidence has encouraged the hypothesis that the PSU and ESG are more interconnected than previously thought. Objectives: To re‐evaluate the morphology of human skin adnexa with an integrated three‐dimensional (3D) perspective in order to explore the possible interconnections that the PSU and the ESG may form. Methods: A systematic 3D reconstruction method of skin sections, direct visualization of human scalp follicular unit transplant grafts and a scalp strip ex vivo were used to validate and further explore the hypothesis. Results: We demonstrate that the coiled portion of most ESGs is morphologically integrated into the PSU of human scalp skin and forms a structural unit that is embedded into a specific, hair follicle‐associated region of dermal white adipose tissue (dWAT). This newly recognized unit is easily accessible and experimentally tractable by organ culture of follicular units and can be visualized intravitally. Conclusions: We propose a model of functional human skin anatomy in which ESGs are closely associated with the PSU and the dWAT to form a common homeostatic tissue environment, which may best be encapsulated in the term ‘adnexal skin unit’. The challenge now is to dissect how each component of this superstructure of human skin functionally cooperates with and influences the other under physiological conditions, during regeneration and repair and in selected skin diseases. [ABSTRACT FROM AUTHOR]

CYLD is a tumour-suppressor gene encoding a deubiquitinase, targeting K63- and M1-linked ubiquitin chains and thereby influencing a variety of cellular processes. Loss of function in patients with CYLD cutaneous syndrome (CCS) results in the formation of benign cutaneous cylindromas, spiradenomas and trichoepitheliomas. These CCS skin tumours originate from the hair follicle and appear from adolescence onwards. We used an unbiased proteomics approach to analyse CCS tumour and control samples (n  = 8). Label-free quantification of 627 proteins revealed significant changes in 139 proteins with a fold change > 1.75 and P -value <0.05, between control and tumour samples. Gene Ontology analysis identified upregulation of nuclear factor-κB (NF-κB) and immune signalling proteins alongside an increased prevalence of spliceosome proteins in tumour samples. Collagen 7, collagen 4, agrin and thrombospondin-1 were increased in tumour samples, providing, for the first time, an unbiased set of extracellular matrix (ECM) proteins generated by CCS tumour cells. Conversely, CCS tumour samples demonstrated a decreased abundance of proteins associated with collagen organization and fibril formation compared to normal skin. Further analysis of CCS tumours through immunoblotting revealed a reduction of collagen I, while collagen VII was highly upregulated in both tumour lysate and secretome. Our findings indicate that loss of CYLD function impacts on cellular signalling pathways such as NF-κB signalling, and is associated with hypersecretion of select ECM proteins. [ABSTRACT FROM AUTHOR]

Actinic keratoses (AKs) represent the precursor skin lesions in the pathogenesis of up to 82% of cutaneous squamous cell carcinoma (cSCCs). However, current treatment of AK lesions leads, at best, to only a 75% reduction in cSCCs for 1 year, and relies on therapies using topical chemotherapy, immune stimulants or surgical destruction. We have previously shown that 44% of AK tissue sample histologies contain koilocytes, and genotyping universally identified human papillomavirus 8 (HPV8). To determine the cell signalling basis for HPV8 Lrig1 hair follicle junctional zone keratinocyte stem cell proliferation and expansion, we sought to identify the integral early region gene(s). Skin histology of HPVtg mice expressing individual early-region genes (E2, E4, E6 and E7) identified both E2 and E6 mouse skin as having broadened hair follicle infundibulum. Whole-mount immunofluorescent labelling demonstrated Lrig1 proliferation and expansion in E6 mice only, which we confirmed by flow cytometric analysis. Compared to wild-type (WT) mice, E6 mice Lrig1 flow-sorted cells had lower expression of the differentiation marker keratin 10 but comparable levels of Sox9 and cMyc, consistent with expansion of keratinocyte stem cells, as confirmed by colony-forming efficiency assay (WT 0.05 ± 0.043 vs. E6 0.24 ± 0.11). E6-transduced, but not E7-transduced, HaCaT keratinocytes demonstrated reduced differentiation and increased p63 expression with induced differentiation using calcium shift. Compared to vector control and E7-transduced, E6-transduced HaCaT keratinocytes demonstrated increased migration and colony-forming efficiency but similar proliferation, consistent with greater expression of pSTAT3 and ΔNP63. Ingenuity pathway analysis of previously determined E6 binding partners identified p300 as a regulator of STAT3 activation. Small interfering RNA targeting P300 in E6-transduced HaCaT cells led to a reduction in pSTAT3 and ΔNP63. Pull-down experiments show that E6 bound acetylated p300, which, in turn, led to increased expression of STAT3 regulated genes. The E6K137N mutation in transgenic mice, wherein E6 does not bind p300, do not develop papilloma or cSCC. Our findings show that E6, not E7, as often observed in α-serotype HPV, was responsible for HPV8-induced Lrig1 hair follicle junctional zone keratinocyte stem cell expansion. [ABSTRACT FROM AUTHOR]

Actinic keratoses (AKs) represent the precursor skin lesions in the pathogenesis of up to 87% of cutaneous squamous cell carcinomas (cSCCs). However, current treatment of AK lesions, at best, lead to only a 25% reduction in cSCC and relies on therapies that target abnormal keratinocytes using topical chemotherapy, immune stimulants or surgical resection. We have previously shown that 44% of AK tissue sample histologies contain koilocytes, wherein genotyping universally identified human papillomavirus 8 (HPV8). To determine the role of HPV8 in the pathogenesis of AKs, we used the K14–HPV8 complete early region (HPV8tg) to generate triple cross-lineage tracing transgenic mice: HPV8:K5-CreERT2:R26R-LoxP-flanked-Brainbow2.1 (Confetti reporter); HPV8:Lrig1-CreERT2:R26R-LoxP-flanked-Brainbow2.1; and HPV8:K15-PGR:R26R-LoxP-flanked-Brainbow2.1. Upon Cre activation, progeny clones exhibit one of four fluorescent colours. Compared to wild-type mice, all HPV8tg mice exhibited an expansion of keratinocytes in the hair follicle infundibulum (77.09 mm3 and 253.43 ± 54.15 mm3) and overlying epidermis. Clones from the Lrig1, but not K15, keratinocyte stem cell population were responsible for keratinocyte expansion of both the hair follicle infundibulum and overlying epidermis. Compared with wild-type mice, HPV8tg mice exhibited greater colony-forming efficiency (1.75 ± 0.69% vs. 6.27 ± 2.41%; n = 3), and, consistent with keratinocyte stem cell expansion, ΔNp63 expression was increased 4.14 ± 2.10-fold (P  < 0.05, n = 5). Flow-sorted epidermal clones from wild-type and HPV8tg mice were examined by RNA sequencing (n = 5). Warthin–Starry staining showed that the expanded population had no melanin 'cap' in our mouse models and human AK samples. In summary, expression of HPV8 early-region genes is associated with AK, wherein there is an expansion of the Lrig1, but not K15, keratinocyte stem cell population that results in epidermal thickening reminiscent of human AK pathology. These findings suggest that HPV8 results in translocation of hair follicle keratinocyte stem cells into the interfollicular epidermis without melanin production, making these cells susceptible to ultraviolet light transformation. [ABSTRACT FROM AUTHOR]

A second cohort of patients was recruited pretreatment (V1) and after 2 weeks of EGFRi treatment (V2) prior to the onset of a folliculitis (acute, I n i = 5). David Rutkowski, SP 1,2 sp Richard Warren, SP 1,2 sp Christropher Griffiths SP 1,2 sp and Ralf Paus SP 1,3,4 sp SP I 1 i sp I Centre for Dermatology Research, University of Manchester, and NIHR Manchester Biomedical Research Centre, Manchester, UK; i SP I 2 i sp I Northern Care Alliance NHS Foundation Trust, Salford, UK; i SP I 3 i sp I Dr. Phillip Frost Dept. of Dermatology & Cutaneous Surgery, Miami, FL, USA; and i SP I 4 i sp I Monasterium Laboratory, Münster, Germany i Epidermal growth factor receptor inhibitors (EGFRi) used for cancer therapy induce a painful, "sterile", mostly neutrophilic folliculitis in 65-80% of patients; the underlying mechanisms of the folliculitis are not fully understood. [Extracted from the article]

The article offers information on the various article published in the periodical including histamine metabolism in human keratinocytes; genetic cluster of patients with variant xeroderma pigmentosum; and multifaceted role of hair follicle dermal cells in bioengineered skins.

Background The method of generating bioengineered skin constructs was pioneered several decades ago; nowadays these constructs are used regularly for the treatment of severe burns and nonhealing wounds. Commonly, these constructs are comprised of skin fibroblasts within a collagen scaffold, forming the skin dermis, and stratified keratinocytes overlying this, forming the skin epidermis. In the past decade there has been a surge of interest in bioengineered skins, with researchers seeking alternative cell sources, or scaffolds, from which constructs can be established, and for more biomimetic equivalents with skin appendages. Objectives To evaluate whether human hair follicle dermal cells can act as an alternative cell source for engineering the dermal component of engineered skin constructs. Methods We established in vitro skin constructs by incorporating into the collagenous dermal compartment: (i) primary interfollicular dermal fibroblasts, (ii) hair follicle dermal papilla cells or (iii) hair follicle dermal sheath cells. In vivo skins were established by mixing dermal cells and keratinocytes in chambers on top of immunologically compromised mice. Results All fibroblast subtypes were capable of supporting growth of overlying epithelial cells, both in vitro and in vivo. However, we found hair follicle dermal sheath cells to be superior to fibroblasts in their capacity to influence the establishment of a basal lamina. Conclusions Human hair follicle dermal cells can be readily interchanged with interfollicular fibroblasts and used as an alternative cell source for establishing the dermal component of engineered skin both in vitro and in vivo. [ABSTRACT FROM AUTHOR]

We found that ruxolitinib reduces keratinocyte-mediated inflammation in cell culture, suggesting treatments targeting epidermal inflammation may be of benefit to patients with HS. We used skin samples from 87 patients with HS and 39 healthy controls to understand how epidermal inflammation influences HS disease severity. As keratinocyte-mediated inflammation was high in HS samples, we tested whether we could block this inflammation using a broad inflammation inhibitor called ruxolitinib. [Extracted from the article]

Linked Article:Liu et al. Br J Dermatol 2022; 187:936–947. [ABSTRACT FROM AUTHOR]

Background Multiple biomarkers have been associated with hair loss in women, but studies have shown inconsistent results. Objectives We investigated the associations between markers of cardiovascular disease risk (e.g. serum lipid levels and hypertension) and ageing [e.g. 25-hydroxyvitamin D and insulin-like growth factor (IGF)] with hair loss in a population of middle-aged women. Methods In a random subgroup of 323 middle-aged women (mean age 61·5 years) from the Leiden Longevity Study, hair loss was graded by three assessors using the Sinclair scale; women with a mean score > 1·5 were classified as cases with hair loss. Results Every 1 SD increase in high-density lipoprotein ( HDL) cholesterol was associated with a 0·65-times lower risk [95% confidence interval ( CI) 0·46-0·91] of hair loss. For IGF-1 the risk was 0·68 times lower (95% CI 0·48-0·97) per 1 SD increase, independently of the other studied variables. Women with both IGF-1 and HDL cholesterol levels below the medians of the study population had a 3·47-times higher risk (95% CI 1·30-9·25) of having hair loss. Conclusions Low HDL cholesterol and IGF-1 were associated with a higher risk of hair loss in women. However, further studies are required to infer causal relationships. [ABSTRACT FROM AUTHOR]

Background ATP-binding cassette ( ABC) transporters are involved in the active transport of an extremely diverse range of substrates across biological membranes. These transporters are commonly implicated in the development of multidrug resistance and are also involved in numerous physiological and homeostatic processes, including lipid transport, cell migration and differentiation. Objectives To close the knowledge gap in the expression of ABC transporters in the human hair follicle ( HF). Methods Quantitative polymerase chain reaction ( qPCR) of ABC genes and immunofluorescence microscopy analysis of cryosections of human HFs. Results By qPCR analysis, numerous members of the ABC transporter superfamily, such as ABCB1, ABCG2 and ABCA12, were found to be transcribed in full-length human scalp HFs. Immunofluorescence microscopy demonstrated that the intrafollicular protein expression of different xenobiotic ABC transporters ( ABCB1, ABCC1, ABCC4, ABCG2) varies greatly, with ABCG2 expression restricted primarily to the epithelial stem cell region of the outer root sheath (bulge), whereas expression of ABCB1, ABCC1 and ABCC4 was more widespread. Lipid transporters ABCA1, ABCA12 and ABCA4 were almost uniformly expressed throughout the HF epithelium. Functional ABCB1/G2 activity was demonstrated by exclusion of the substrate dye, Hoechst 33342. In the bulge, this was reversed by ABCB1 and ABCG2 inhibition. Conclusions These data encourage further investigation of ABC transporters as potentially important regulators of HF epithelial biology. Clinically, pharmacological modulation of the activity of selected intrafollicular ABC transporters may permit novel therapeutic interventions, such as protecting HF stem cells from chemotherapy-induced damage, counteracting cholesterol-associated hypertrichosis, and manipulating the intrafollicular prostaglandin balance in androgenetic alopecia. [ABSTRACT FROM AUTHOR]

This loss of focal hypertrichosis in a congenital melanocytic naevus in a patient with FFA has not been reported previously. The clinical changes are striking and histology confirms a lichenoid scarring alopecia. [Extracted from the article]

A second cohort of patients was recruited pretreatment (V1) and after 2 weeks of EGFRi treatment (V2) prior to the onset of a folliculitis (acute, I n i =5). David Rutkowski, SP 1,2 sp Richard Warren, SP 1,2 sp Christopher Griffiths SP 1,2 sp and Ralf Paus SP 1,3,4 sp SP I 1 i sp I Centre for Dermatology Research, University of Manchester, and NIHR Manchester Biomedical Research Centre, Manchester, UK; i SP I 2 i sp I Northern Care Alliance NHS Foundation Trust, Salford, UK; i SP I 3 i sp I Dr. Phillip Frost Dept. of Dermatology & Cutaneous Surgery, Miami, FL, USA; and i SP I 4 i sp I Monasterium Laboratory, Münster, Germany i Epidermal growth factor receptor inhibitors (EGFRi) used for cancer therapy induce a painful, "sterile", mostly neutrophilic folliculitis in 65-80% of patients; the underlying mechanisms of the folliculitis are not fully understood. [Extracted from the article]