Neurofibromin deficiency drives a pro-inflammatory tumor microenvironment via neuro-immune crosstalk. However, whether this local dysregulation translates into a clinically relevant systemic inflammatory phenotype remain...Neurofibromin deficiency drives a pro-inflammatory tumor microenvironment via neuro-immune crosstalk. However, whether this local dysregulation translates into a clinically relevant systemic inflammatory phenotype remains unclear. Using the TriNetX global network, we identified 23,218 individuals with NF1 and propensity score-matched them 1:1 with controls. The primary outcomes were new diagnoses of atopic multimorbidity, including atopic dermatitis (AD), asthma, allergic rhinitis (AR), urticaria, and atopic keratoconjunctivitis (AKC). Cox proportional hazard regression models were used to estimate adjusted hazard ratios (aHRs). Our analysis revealed that NF1 patients exhibited profoundly elevated risks of AD (aHR 7.45; 95% CI 4.18 - 13.28), asthma (aHR 4.68; 95% CI 3.72 - 5.90), AR (aHR 7.15; 95% CI 5.52 - 9.25), urticaria (aHR 3.54; 95% CI 2.28 - 5.48), and notably, AKC (aHR 17.35; 95% CI 6.92 - 43.50) (all p < 0.0001). Subgroup analyses indicated that these associations were generally more pronounced in adults, females, and non-White individuals. These findings provide epidemiological validation that the neuro-inflammatory drive in NF1 is not confined to tumorigenesis but manifests as a pervasive systemic neuro-immune dysregulation. This implies that targeting shared pathways could offer dual benefits for tumor control and systemic inflammation.
Melanoma incidence is rising, whereas access to dermatologists remains limited. In this review, we identified 114 diagnostic-accuracy studies evaluating 11 noninvasive imaging modalities for melanoma detection: photograp...Melanoma incidence is rising, whereas access to dermatologists remains limited. In this review, we identified 114 diagnostic-accuracy studies evaluating 11 noninvasive imaging modalities for melanoma detection: photography-based, dermoscopy, electrical impedance spectroscopy, reflectance confocal microscopy, optical coherence tomography based, multispectral/hyperspectral imaging, high-frequency ultrasound, Raman/surface-enhanced Raman spectroscopy, infrared/thermal imaging, multiphoton tomography, and elastic scattering spectroscopy. Across modalities, sensitivities ranged from 37 to 100%, and specificities ranged from 15 to 100%. Dermoscopy (32 studies/34,700 lesions) and reflectance confocal microscopy (33 studies/10,365 lesions) studies had the largest evidence base. Integrating accuracy with regulatory, reimbursement, and cost data, we propose a 3-tier deployment model from home-based triage to specialist clinic based.
Itch is the cardinal symptom contributing to patient burden in atopic dermatitis. Multiple validated itch scales are used in clinical trials, generating heterogeneous datasets. In addition, recent studies suggest an asso...Itch is the cardinal symptom contributing to patient burden in atopic dermatitis. Multiple validated itch scales are used in clinical trials, generating heterogeneous datasets. In addition, recent studies suggest an association between cytokine levels and disease severity in atopic dermatitis. This study aimed to compare the performance of different validated itch instruments and their relationship to blood cytokine profiles. Forty-nine adults with severe atopic dermatitis and severe itch were treated with 300 mg dupilumab for 16 weeks. At the initial assessment and after treatment, itch intensity and QOL were evaluated using various assessment tools. Peripheral blood samples were collected at both time points for cytokine profiling. All itch intensity scales demonstrated comparable responsiveness, irrespective of their dimension; however, the numerical rating scale consistently yielded higher scores than the visual analog scale. Macrophage-derived chemokine, CCL26, B-cell-activating factor, and IL-2R levels were significantly reduced after treatment and correlated with all (macrophage-derived chemokine and B-cell-activating factor) or subsets (CCL26 and IL-2R) of itch intensity and QOL scores. In conclusion, all validated itch intensity scales are suitable for routine clinical use; however, adhering to one instrument is recommended. The observed correlations between cytokine levels and itch scales suggest their potential as markers of disease burden in atopic dermatitis.
Behlock Y, Gavan SP, Graier T
… +12 more, Guevara BE, He J, Giles RH, Wright AK, Ashcroft DM, Lim HW, De La Cruz C, French LE, Foley P, Lwin S, Griffiths CEM, Van de Kerkhof PCM
The introduction of biosimilars for the treatment of moderate-to-severe psoriasis has demonstrated efficacy and safety comparable to those of originator biologics, with the potential to improve cost-effectiveness. We exp...The introduction of biosimilars for the treatment of moderate-to-severe psoriasis has demonstrated efficacy and safety comparable to those of originator biologics, with the potential to improve cost-effectiveness. We explored the potential for biosimilars to improve access to biologics for psoriasis, especially in low- and middle-income countries, where costs often limit access to originators. The analysis was based on a systematic review conducted as part of the submission process to include adalimumab and ustekinumab in the World Health Organization Essential Medicines List for psoriasis. Among the 17 studies included in the systematic review, we focused on those that provided data evaluating the cost and/or cost-effectiveness of biosimilars versus originators in the treatment of psoriasis. Two studies met the inclusion criteria. The first was a cohort-based Markov model, which showed that biosimilar adalimumab was cost-effective compared with the originator adalimumab for moderate-to-severe psoriasis. The second, using a cost-per-responder model, found that the adalimumab biosimilar had the lowest cost-per PASI complete clearance (PASI100) responder among the anti-TNF therapies. Biosimilars have a key role in reducing costs and expanding treatment availability for patients with psoriasis. Further health economic studies focusing on psoriasis are required to demonstrate how biosimilars can improve access to biologics in this condition.
Diabetes is a major growing public health concern, but the impact on cellular impairments in chronic wounds remains incompletely understood. Fibroblasts, key players in all phases of wound healing, are particularly respo...Diabetes is a major growing public health concern, but the impact on cellular impairments in chronic wounds remains incompletely understood. Fibroblasts, key players in all phases of wound healing, are particularly responsive to mechanotransduction. In this study, we characterize fibroblast heterogeneity in genetically induced and pathophysiologic diabetic murine wounding models across all wound healing phases. Full-thickness excisional wounds were created on the dorsum of C57BL/6 nondiabetic wild-type mice (denoted as N-DB); wild-type mice fed a high-fat diet to create pathophysiologic diabetes (denoted as P-DB); and leptin-receptor-deficient mice, a genetically induced diabetic model (denoted as G-DB). Tissue was submitted for single-cell RNA sequencing at postoperative days 0, 2, 7, and 30. Both G-DB and P-DB significantly impaired wound healing compared with N-DB. N-DB expressed distinct myeloid-like Cd14+/C1qa+ angiogenic fibroblasts at postoperative days 2 and 7. Mechanotransduction pathways, focal adhesion kinase (FAK) and mitogen-activated protein kinase (MAPK), were consistently upregulated in N-DB fibroblasts and depleted in both diabetic models. G-DB upregulated WNT-activated Dpp4+ fibrotic fibroblasts at postoperative day 7 compared with N-DB. Thus, mechanotransduction pathways are present in physiologically healing fibroblasts and are selectively depleted in both pathophysiologic and genetically induced diabetes. In genetically induced diabetes, overactivation of canonical and noncanonical WNT pathways overwhelms cells and impairs healing processes. Transcriptomic insights into these mechanotransducive perturbations may lead to new therapies for diabetic wound repair.
Rabies is a fatal zoonotic infection caused by rabies virus (RABV), which is transmitted through the saliva of infected animals. Although most cases are caused by dog bites, superficial exposures such as bat bites or scr...Rabies is a fatal zoonotic infection caused by rabies virus (RABV), which is transmitted through the saliva of infected animals. Although most cases are caused by dog bites, superficial exposures such as bat bites or scratches can also lead to infection, although the underlying mechanisms remain poorly understood. We recently detected RABV-positive keratinocytes in skin samples of experimentally infected mice and naturally infected dogs, prompting us to investigate their role in rabies pathogenesis and the antiviral immune response. We confirmed that both the keratinocyte cell line HaCaT and primary keratinocytes are susceptible to RABV infection in vitro, with higher infection rates observed for the attenuated SAD P5/88 Potsdam and silver-haired bat RABV strains than for a dog-related strain. Keratinocytes showed a significant immune activation in response to these 2 strains, as measured by expression of relevant surface markers and cytokine release. To explore whether RABV can be transmitted from infected keratinocytes to neurons, we developed a coculture model using HaCaT and a neuronal cell line separated by a microporous membrane. Virus transfer to the neurons was observed while the barrier integrity remained intact, suggesting that keratinocytes may contribute to RABV transmission and neuroinvasion after superficial exposure.
The homeostatic skin represents a tissue niche promoting the survival of several immune cell types. Mast cells (MCs) are resident immune cells distributed throughout the dermal compartment. Their differentiation and surv...The homeostatic skin represents a tissue niche promoting the survival of several immune cell types. Mast cells (MCs) are resident immune cells distributed throughout the dermal compartment. Their differentiation and survival depend on KIT ligand (KITLG), also known as stem cell factor, and signaling through the KIT receptor expressed by MCs. Although several cutaneous cell types can express KITLG, their specific roles in maintaining MC homeostasis in vivo are still under debate. In this study, we used immunofluorescence analysis of Kitl mice and single-cell RNA sequencing to identify KITLG-expressing cells in mouse ear skin. On the basis of these findings, we studied MC homeostasis using 6 mouse models with conditional Kitl deletion in epidermal and stromal populations. Our results indicate that keratinocyte-derived KITLG is dispensable for MC survival in unchallenged mouse skin. Instead, we identify dermal fibroblasts and perivascular cells as critical KITLG sources for maintaining MCs in the dermis. Overall, our study provides a detailed characterization of KITLG-expressing cells across skin regions and reveals how stromal cell types shape local KITLG availability and MC homeostasis in unchallenged mouse skin.
Kim M, Manson M, Liu Y
… +12 more, Rangel S, Kaplan N, Rabbaa L, Choate K, Bose S, Metukuru R, Lin X, Largen J, Shah M, Estrada YD, Paller AS, Guttman-Yassky E
Prior studies in ichthyosis have demonstrated cutaneous and/or systemic immune abnormalities with barrier defects; however, the transcriptomes of the major orphan forms of ichthyosis have yet to be characterized through...Prior studies in ichthyosis have demonstrated cutaneous and/or systemic immune abnormalities with barrier defects; however, the transcriptomes of the major orphan forms of ichthyosis have yet to be characterized through tape stripping, a minimally invasive sampling method validated in other inflammatory skin diseases. Skin tape strips from 27 patients with ichthyosis (9 with Netherton syndrome, 6 with congenital ichthyosiform erythroderma, 7 with lamellar ichthyosis, and 5 with epidermolytic ichthyosis) and 18 demographically matched healthy controls were analyzed with RNA sequencing. Differential expression was defined as fold change >2 and false discovery rate <0.05. All subtypes shared significant T helper (Th)17/Th22 upregulation (eg, S100A7/8/9, PI3, CCL20), and Th2 products (eg, TNFRSF4, IL13, CCR4) were particularly increased in Netherton syndrome. Tape strips additionally captured common increases in Th1 (IL1B, OASL) and IL4R upregulation in Netherton syndrome, lamellar ichthyosis, and epidermolytic ichthyosis. Although modulation of lipid markers was variable across subtypes, several epidermal differentiation complex/cornified envelope genes were increased in all or most subtypes. Disease-severity metrics were moderately correlated with increases in ceramide synthase CERS3 and Th17/Th22 and late cornified envelope markers. Changes in immune and epidermal differentiation complex/cornified envelope tape-strip markers correlated significantly and positively with those measured in biopsies. Our findings highlight tape stripping as a minimally invasive approach to profiling ichthyosis, which could provide future pathogenic and therapeutic insights.
Klein K, Johnson L, Rîca R
… +10 more, Sarcevic M, Carta G, Seiser S, Elbe-Bürger A, Langer F, Rahhal N, Rademacher C, Wawrzinek R, Quattrone F, Sparber F
Despite the success of mRNA therapeutics, challenges remain in optimizing immune responses and minimizing side effects. Cell-specific antigen delivery may help reduce required doses and improve vaccine efficacy. In this...Despite the success of mRNA therapeutics, challenges remain in optimizing immune responses and minimizing side effects. Cell-specific antigen delivery may help reduce required doses and improve vaccine efficacy. In this study, we report on a targeted delivery system for mRNA to a specific subset of skin-resident antigen-presenting cells: Langerhans cells. By functionalizing lipid nanoparticles with a langerin-specific glycomimetic ligand, we achieve selective mRNA delivery to both murine and human primary Langerhans cells with minimal off-target uptake, at the same time resulting in significantly increased mRNA translation. This targeted mRNA delivery not only enhances antigen presentation and T-cell responses but also enables dose-sparing and superior antitumor immunity compared with conventional immunization in a B16-OVA tumor model. Importantly, our platform's high compatibility with various lipid nanoparticle formulations offers a flexible and precise tool for skin-directed mRNA delivery.
Second primary invasive cutaneous melanomas (SPICMs) are common and pose an increased risk of death compared with single invasive melanoma only. Using data from the Queensland Oncology Repository, we investigated changes...Second primary invasive cutaneous melanomas (SPICMs) are common and pose an increased risk of death compared with single invasive melanoma only. Using data from the Queensland Oncology Repository, we investigated changes in the cumulative incidence of SPICMs for people diagnosed with a first primary invasive cutaneous melanoma between 1982 and 2022, with follow-up until December 31, 2023. Death due to any cause was treated as a competing risk. Among the 101,035 people in the study cohort, 9% (n = 9224) were diagnosed with a metachronous SPICM. Estimated 40-year cumulative incidence of SPICMs was 16.3% (95% confidence interval = 15.8-16.8%). Ten-year cumulative incidence was 4.9% between 1982 and 1991, 7.0% for 1992-2001, 7.9% for 2002-2011, and 7.3% between 2012 and 2022. After multivariable analysis, people first diagnosed between 2012 and 2022 were 23% more likely to subsequently be diagnosed with a SPICM within 10 years than those first diagnosed in 1982-1991 (subhazard ratio = 1.23, 95% confidence interval = 1.11-1.35), whereas the subhazard ratio was 1.38 (95% confidence interval = 1.26-1.52) for 2002-2011. These results provide evidence that the cumulative incidence of SPICM may have plateaued within a population having the highest rates of melanoma in the world, possibly owing to the impact of long-running sun safety campaigns in Australia combined with increased surveillance.
Sebaceous glands (SGs) contribute to skin physiology by producing sebum, which forms a lipid barrier preventing dehydration. Various skin conditions, including acne vulgaris and seborrheic dermatitis, are linked to their...Sebaceous glands (SGs) contribute to skin physiology by producing sebum, which forms a lipid barrier preventing dehydration. Various skin conditions, including acne vulgaris and seborrheic dermatitis, are linked to their dysfunction. Several questions remain concerning the formation and regulation of these glands because there are few human tridimensional models available to address them. In this study, we investigated the conditions that allow SG formation in human tissue-engineered skin substitutes. We tested whether the source of epithelial cells, fibroblasts, and the extracellular environment influence the SG formation in vitro and after grafting onto mice. Our results showed that SGs formed in substitutes produced with epithelial cells derived from scalp but were absent in those generated from foreskin or breast skin tissues, whereas the fibroblast origin did not affect this process. However, no SG was found in substitutes produced from decellularized dermal matrices that were recellularized with fibroblasts and scalp epithelial cells, suggesting that some extracellular cues lost after decellularization play a major role in SG formation. Our work establishes an unprecedented model to study human SG formation and function and will likely be instrumental to investigate the pathogenesis of various diseases of the SG in the future.
Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder characterized by systemic anhidrosis or hypohidrosis of unknown etiology. Although autoimmune responses targeting eccrine glands and/or ducts have been...Acquired idiopathic generalized anhidrosis (AIGA) is a rare disorder characterized by systemic anhidrosis or hypohidrosis of unknown etiology. Although autoimmune responses targeting eccrine glands and/or ducts have been proposed as a potential mechanism, the pathophysiology remains largely unclear. Corticosteroid pulse therapy is widely used for treatment, yet its mechanism of action is not fully understood. To elucidate the underlying mechanisms, we analyzed skin lesions from patients with AIGA before and after corticosteroid pulse therapy through histological and single-cell RNA-sequencing analyses. AIGA cases were histologically classified into pauci-inflammatory, mild inflammatory, and severe inflammatory types on the basis of lymphocytic infiltration around the eccrine unit. Corticosteroid pulse therapy improved sweating function across all groups, including pauci-inflammatory cases with little immune infiltration. Single-cell RNA sequencing of pauci-inflammatory AIGA skin revealed significant upregulation of eccrine marker genes such as MUCL1 and DCD alongside downregulation of cellular stress response pathways associated with unfolded protein responses after therapy. Immunohistochemistry confirmed increased expression of eccrine markers and reduced cellular stress markers, including advanced glycation end products and 4-hydroxynonenal, in eccrine glands after treatment. These findings suggest that unfolded protein response-associated cellular stress-mediated eccrine dysfunction contributes to AIGA pathogenesis, providing a basis for exploring cellular stress modulation as a potential therapeutic approach.