Biallelic ITGA3 variants cause a rare subtype of junctional epidermolysis bullosa named interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa (ILNEB). ILNEB is characterized by extensive clinical heterogeneity, suggesting the existence of modifier genes. We studied a family with two siblings affected with ILNEB due to a homozygous ITGA3 variant. The disease severity was strikingly different in the two siblings. Whole exome sequencing revealed the presence of two different heterozygous variants in ITGB4 in each of the two patients: p.Arg977Cys in the more severely affected individual and p.Asp285Asn in the milder case. Accordingly, the ITGB4 p.Arg977Cys variant caused a significantly greater reduction in ITGB4 membrane localization compared to the p.Asp285Asn variant. In addition, the ITGB4 p.Arg977Cys variant resulted in significantly diminished activation of the FAK/AKT/mTOR/S6 pathway as compared with the p.Asp285Asn variant. Finally, using co-immunoprecipitation assays as well as confirmatory proximity ligation assays, we identified an hitherto unrecognized direct interaction between ITGA3 and ITGB4 which was more significantly compromised by the ITGB4 p.Arg977Cys than by the p.Asp285Asn variant. Our findings indicate that monoallelic ITGB4 genetic variants may modulate the severity of ITGA3-associated ILNEB.
The transcriptional co-activators YAP and TAZ are key regulators of cell proliferation, apoptosis, and differentiation, thereby maintaining tissue homeostasis and controlling organ size. While their roles in epithelial cancers and fibrosis are well established, their involvement in the physiological regulation of the dermal extracellular matrix (ECM) by fibroblasts is less understood. Here, we investigated the role of Yap/Taz during postnatal development of the dermal ECM. During postnatal growth, mouse skin steadily undergoes significant surface expansion. Postnatal deletion of Yap/Taz in dermal fibroblasts, the primary cells responsible for dermal ECM homeostasis, significantly impaired dermal ECM maturation, as evidenced by marked deficiencies in collagen expression, deposition, and organization. Isolated fibroblasts from Yap/Taz knockout mice showed reduced expression of Yap/Taz target genes (Ccn1, Ccn2, Col1a1), which were rescued by reintroduction of active Yap/Taz. RNA-seq, spatial transcriptomics, and proteomics of Yap/Taz knockout skin revealed substantial downregulation of ECM-related genes, including type I (Col1a1, Col1a2) and type III (Col1a3) collagens, which together constitute more than 90% of the skin's collagen content. Mechanistically, deletion of Yap/Taz impaired mouse dermal maturation, at least in part through suppression of TGF-β/Smad signaling, the primary pathway governing fibroblast collagen synthesis. These findings demonstrate that YAP/TAZ are essential for postnatal dermal ECM homeostasis.
Uveal melanoma (UM) is the most common intraocular malignancy, contributing to ∼5% of all melanomas. It arises from melanocytes in the uveal tract (choroid, ciliary body, and iris) and has a specific genetic and clinical profile. Important genetic alterations shown to drive UM pathogenesis and influence prognosis include GNAQ, GNA11, BAP1, SF3B1, and EIF1AX. In addition, monosomy 3 and 8q gains are strongly linked to poor outcomes, whereas disomy 3 and 6p gains are associated with better prognosis. Approximately half of patients with UM develop metastases, most commonly to the liver, leading to high mortality. Conventional chemotherapy has shown poor efficacy, and immune checkpoint inhibitors have demonstrated only modest benefits. The immunosuppressive tumor microenvironment, particularly in the liver, further limits treatment efficacy. NK cells offer a promising avenue to treat patients owing to their ability to recognize tumor cells independent of major histocompatibility complex. However, UM employs multiple immune evasion strategies, including the upregulation of HLA-E and the secretion of immunosuppressive factors inhibiting NK cell function. Despite these barriers, preclinical studies demonstrate that activated NK cells can reduce hepatic metastases. Emerging NK cell-based therapies, such as chimeric antigen receptor-engineered NK cells and NK cell engagers, could provide an effective therapeutic strategy to treat metastatic UM, warranting further clinical investigation.
KCTD1 and KCTD15 form pentameric complexes that regulate neural crest cell (NCC) and keratinocyte functions, and dominant-negative mutations in their genes cause aplasia cutis congenita (ACC) and craniofacial abnormalities. Although KCTD1/KCTD15 complexes have been proposed to modulate multiple developmental pathways in vitro, the key downstream mechanisms responsible for these phenotypes in vivo remain unclear. Here, we investigated the function of KCTD1/KCTD15 complexes specifically in NCCs. Using conditional mouse models, cell lineage tracing, and genetic epistasis approaches, we show that KCTD1/KCTD15 complexes regulate NCC-dependent craniofacial development and midline scalp skin formation primarily by repressing the transcriptional activity of AP-2α and AP-2β. Loss of KCTD1/KCTD15 in NCCs resulted in ACC, cranial suture abnormalities, nasal bone hypoplasia, incisor agenesis, eyelid defects, pigmentation abnormalities, and cleft palate. Genetic reduction of AP-2α and AP-2β dosage in NCCs lacking KCTD1/KCTD15 markedly rescued these defects, establishing derepressed AP-2 activity as the principal pathogenic mechanism. Conversely, NCC-specific loss of AP-2α/AP-2β produced partially overlapping craniofacial defects, demonstrating that craniofacial morphogenesis is highly sensitive to AP-2 dosage. These findings identify a KCTD1/KCTD15-AP-2 regulatory axis as a central mechanism controlling neural crest-derived craniofacial development and scalp skin formation and establish ACC as a neurocristopathy arising from dysregulated AP-2 activity.
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Vitiligo is an autoimmune disease characterized by depigmented skin lesions, caused by autoreactive-CD8-T-cells inducing melanocyte apoptosis. Effective treatment is challenging due to limited understanding of the processes underlying skin repigmentation. This study aimed to identify these processes using proteomics. Plasma and skin blister-fluid samples from 30 vitiligo patients starting standard-of-care treatment were analyzed. A large proteomic screen of 5080 proteins was measured with Somascan on samples collected at baseline and at 3-months of treatment. Analyses of proteins that changed and not changed under treatment, revealed 5 proteins associated with repigmentation. Higher baseline levels of TIM-1, TFF3 and NLRP1 in blister-fluid and an increase of KRT5 in plasma under treatment, were associated with repigmentation. TIM-1 and TFF3 have immunosuppressive effects, while NLRP1 and KRT5 can stimulate melanogenesis. The NLRP1-inflammasome pathway was enriched in these proteins. These proteins and pathways were distinct from the previously identified differences between lesional and non-lesional skin, indicating differential expression of melanocyte-specific pathways. This suggests that treatment-induced repigmentation in vitiligo involves processes other than simply reversing lesional skin to a non-lesional state. These findings enhance understanding of repigmentation in vitiligo and could guide future therapeutic strategies.
Acne vulgaris is one of the most common skin diseases around the world, affecting approximately 9.4% of the global population annually. Cellular and animal-based sebaceous gland models are widely employed to elucidate the pathophysiology and mechanisms behind acne. However, non-human animals do not develop acne, nor do they harbor Cutibacterium acnes as a commensal. Furthermore, cellular models are not the best as they cannot recapitulate progenitor-like characteristics of a sebaceous gland. Hence, there is a growing interest in sebaceous gland organoids (SGOs), which recapitulate the growth and differentiation of the gland. Here, we briefly review published SGOs protocols and describe our own model of "sebonoids." We discuss the advantages and disadvantages of various SGOs and provide a detailed protocol for generating our version.
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer with a poorly understood cell of origin and initiation process. Most MCC tumors feature monoclonal integration of Merkel cell polyomavirus (MCPyV) DNA, which expresses viral small T (sT-Ag) and large T antigens (LT-Ag), responsible for driving MCC tumors. The process by which MCPyV T antigens (T-Ags) transform cells to initiate MCC has been unclear, in part due to the lack of physiologically relevant in vivo models. Building upon our previous work, which demonstrated that SOX9-expressing (SOX9+) hair follicle Merkel cell progenitors are susceptible to T-Ag-mediated reprogramming, we establish a mouse model in which sT-Ag expression and Trp53 attenuation in SOX9+ cells produce metastatic neuroendocrine tumors with histopathologic and immunophenotypic features of human MCC. Importantly, while sT-Ag alone induces partial MCC-associated gene expression, suppression of p53 is required for sT-Ag to induce neuroendocrine lineage transdifferentiation in the hair follicle. Cumulatively, these studies enhance our knowledge of MCC biology and establish a de novo MCC tumorigenesis model in a tractable immunocompetent system that will be invaluable for further advancements in the field.
Staphylococcus aureus (S aureus) commonly causes skin infections and is abundant on the skin of patients with atopic dermatitis, where it worsens inflammation and drives skin barrier defects. Neutrophils help to control S aureus infection through their antimicrobial activity and by recruiting other immune cells; however, they can also promote S aureus skin colonization. Excessive neutrophil activity and release of neutrophil extracellular traps may impair the skin barrier and thereby promote colonization. Moreover, S aureus has evolved strategies to evade neutrophil defenses. This review explores neutrophil-skin interactions in healthy and inflamed skin and potential therapeutic strategies targeting these interactions to reduce S aureus colonization in diseases like atopic dermatitis.
The microbiome and host immune system maintain a dynamic homeostatic equilibrium at the skin interface. Prior studies have shown that the skin microbiome is profoundly altered in immunodeficient conditions. Patients with idiopathic CD4 lymphopenia (ICL), a rare clinical syndrome with obscure cause, and people living with HIV (PLWH) are two etiologically distinct groups of individuals with CD4 T-cell lymphopenia. We conducted shotgun metagenomic sequencing, metagenome assembly, and read-based mapping to characterize the multi-kingdom taxonomic diversity of skin microbiomes in patients with ICL and PLWH who were followed longitudinally before and after antiretroviral therapy (ART) initiation. Compared with healthy individuals, the skin microbiomes of patients with ICL and ART-naïve PLWH showed greater inter-individual variation and higher relative abundances of eukaryotic viruses. Both patient groups carried pathogenic microbes, including high-oncogenic-risk human papillomaviruses (HPVs) and dermatophytes such as Trichophyton rubrum, which were rarely seen in healthy individuals. In PLWH, high-oncogenic-risk HPV types persisted after 2 months of ART but were mostly cleared after 14 months. The loss of peripheral blood CD4 T-cells was associated with shifts in the skin microbiome and a relative expansion of pathogenic microbes. Investigating microbiome dynamics during immunodeficiency and subsequent immune reconstitution provides additional insights into host-microbial interactions.
Ultraviolet-B irradiation (UVB) induces an epidermal damage response including keratinocyte hyperplasia, immune cell infiltration, and the recruitment of follicular melanocyte stem cells to the interfollicular epidermis. Here, we establish the oncofetal chromatin remodeling factor High mobility group AT-hook 2 (Hmga2) as a regulator of these phenotypes through a cyclic-AMP (cAMP) driven process. In this study, we identify somatic tissue expression of Hmga2 in the basal layer of hyperplastic UVB-exposed keratinocytes. Loss of Hmga2 results in the near absence of epidermal hyperplasia, cutaneous neutrophil infiltration, and melanocyte stem cell migration to the interfollicular epidermis. RNAseq of UVB-exposed keratinocytes from wild-type and Hmga2 loss-of-function models reveals increased expression of Adenosine A1 receptor (Adora1), a negative regulator of cAMP. Administration of the cAMP pathway activator forskolin to Hmga2-/- animals is sufficient to rescue McSC migration, thus highlighting the Hmga2-cAMP axis as a regulator in the cutaneous UVB response.
Rituximab combined with short-term corticosteroids is the standard first-line treatment for pemphigus, but a subset of patients remains refractory, with limited effective alternatives. Daratumumab, an anti-CD38 monoclonal antibody targeting plasma cells, has emerged as a potential option in severe autoimmune diseases. We report two cases of life-threatening pemphigus refractory to rituximab and alternative therapies, successfully treated with daratumumab, with longitudinal clinical and immunological monitoring of anti-desmoglein responses. Rituximab failure was associated with incomplete B-cell depletion, with persistence of memory B cells and plasmablasts. Daratumumab induced rapid clinical improvement, depletion of CD38+ plasma cells, and reduction of anti-desmoglein antibodies. In one patient, relapse occurred after daratumumab discontinuation, with subsequent rituximab inefficacy due to anti-rituximab antibodies; combined daratumumab and belimumab led to sustained complete remission, likely through complementary targeting of plasma cells and prevention of autoreactive B-cell reconstitution. In the second patient, remission induced by daratumumab was consolidated with additional rituximab. No treatment-related adverse events were observed. These findings suggest that daratumumab, alone or in combination with B-cell-targeting agents, may represent a promising therapeutic strategy for rituximab-refractory pemphigus.
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Psoriasis is a common chronic inflammatory skin disease characterized by epidermal hyperproliferation and immune dysregulation. However, local metabolic interactions remain incompletely understood, and biomarkers for disease activity and treatment response are still lacking. Current approaches such as skin biopsies or tape stripping are disruptive to the skin barrier and may cause scarring, limiting their repeated use. In contrast, microdialysis enables minimally invasive sampling of soluble mediators from intact skin. We applied untargeted proteomic and metabolomic profiling of skin microdialysates from lesional and nonlesional sites in patients with psoriasis and healthy controls to explore local pathophysiology and evaluate this technique's potential for monitoring disease severity and treatment response. Principal component analysis revealed distinct molecular signatures in psoriatic lesions, with separation by disease severity, resulting from elevated proinflammatory proteins (SERPINB3/4, FABP5), purine and pyrimidine metabolites (adenosine-5-monophosphate, 5'-cytidine monophosphate) and polyamines (spermidine and spermine). Pathway analysis confirmed upregulated nucleotide metabolism and polyamine biosynthesis alongside reduced histidine metabolism, consistent with hyperproliferation, immune activation, and barrier disruption. Importantly, lesional metabolomic profiles normalized in patients responding to systemic therapy, highlighting the utility of microdialysate profiling for tracking therapeutic efficacy. This study establishes microdialysate proteometabolomics as a minimally invasive platform for mechanistic studies, biomarker discovery, and personalized monitoring in psoriasis.
Alopecia areata (AA) is a chronic autoimmune disease characterized by sudden patchy hair loss and persistent inflammation. To date, only JAK inhibitors have been approved for AA treatment, but FDA-issued black box warnings highlight the need for alternative therapies. We previously reported that an anti-γc antibody, hC2, inhibits autoreactive B, T, and NK cells by selectively attenuating JAK/STAT signaling induced by six γc cytokines, without affecting off-target TEC kinase pathways. Here, we sought to define the mechanism of action and efficacy of hC2 in AA by using an ex-vivo T cell platform and a xenogeneic AA-like mouse model induced by human T cell engraftment. Analyses showed that hC2 could restore hair follicle homeostasis and suppress hair loss by inhibiting autoreactive T cell activity and proliferation of tissue-resident memory T cells. Although JAK3 inhibitor ritlecitinib could potentially protect hair follicles through T cell depletion strategy in-vitro, severe side effects were associated with ritlecitinib treatment while no significant safety issues were noted after hC2 treatment in the xenogeneic AA-like mouse model. These findings suggest that hC2 might offer a safer and more effective therapeutic approach for AA patients in the future.
Artificial intelligence (AI) is reshaping dermatology through diagnostic image analysis, clinical documentation, and patient communication tools. However, AI's environmental costs remain largely invisible to clinicians. Because training large AI models requires substantial energy, data center electricity use has risen alongside AI adoption, and cooling AI infrastructure centers increases water demand. These environmental burdens disproportionately affect resource-constrained communities. This creates an urgent priority for dermatology. Climate change directly threatens dermatologic health through global warming, increased UV exposure, air pollution, microplastics, expanded ranges of infectious dermatoses, exacerbation of inflammatory dermatoses, and more. The American Dermatological Association's 2025 Policy Statement on Climate Change commits the specialty to environmental stewardship. Accordingly, AI implementation must align with this commitment, not undermine it. Dermatology can minimize AI's environmental footprint through the following strategic choices: selecting computationally efficient models, sharing datasets to eliminate redundant training, implementing AI selectively where clinical benefit justifies environmental cost, and partnering with vendors committed to transparent reporting. Professional organizations can establish sustainability standards, require environmental impact reporting in research, and advocate for regulatory frameworks mandating vendor accountability. By demonstrating that technological innovation and climate responsibility are compatible goals, dermatology can serve as a model for sustainable AI integration across medical specialties.
Atopic dermatitis (AD) is a common chronic inflammatory skin disease characterized by an aberrant T helper 2 immune response and impaired epidermal barrier function, regardless of phenotypes and endotypes. Historically, AD has been extensively studied in mouse models, which have intrinsic limitations, notably in the translatability of results to patients. Moreover, ethical concerns have driven the field toward the development of organotypic AD skin models. The recent steep increase in their use warrants an expert opinion on the advantages and limitations of such models and opportunities for their improvement, which are presented in this paper.
Ultraviolet (UV) radiation is a major public health concern, linked to skin cancer, eye damage, immune suppression, and premature aging. Yet despite decades of innovation, the gold standard for sunscreen evaluation, SPF and UVA-PF testing in human volunteers, remains empirical, ethically questionable, and highly variable. Here, we present an Assay for UV-A Radiation Assessment (AURA), a high-throughput, cell-based biosensor that luminesces in response to UV-A exposure (320-400 nm). AURA-transgenic human cells express a membrane-anchored, photocleavable PhoCl domain fused to the tetracycline repressor (TetR) and viral activator VP16, with nuclear export signals ensuring minimal basal activity. Upon UV-A illumination, PhoCl cleavage liberates TetR-VP16, which translocates to the nucleus and activates a tetracycline-responsive reporter. This molecular design enables sensitive detection of 365 nm and 395 nm light with up to 100-fold induction. By combining precision, reproducibility, and ethical advantages, AURA establishes a powerful platform for the high-throughput testing of UV-blockers and offers a transformative alternative to in vivo UVA-PF assessment.
Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare inborn error of immunity (IEI) caused by hyperfunctional pathogenic variants in CXC chemokine receptor 4 (CXCR4), predisposing individuals to recurrent bacterial skin and airway infections and warts. The targeted CXCR4 antagonist plerixafor has shown efficacy in wart regression and potential reduction in bacterial infection frequency. Here, we investigated skin microbiomes of 11 patients with WHIM syndrome using shotgun metagenomics, compared to healthy controls. WHIM skin microbial communities displayed greater inter-individual variability, with highly diverse human papillomavirus profiles and expansion of airway-associated pathogens on the skin. Among patients receiving plerixafor therapy, we observed shifts in the viral composition and a downward trend in viral abundances. Together, these findings demonstrate the distinctive and permissive skin microbiome in WHIM syndrome and highlight the potential microbiome-modulating effects of targeted CXCR4 antagonism.
Skin bleaching is a global practice driven by intersecting historical, cultural, psychological, and economic influences that equate lighter skin with beauty, status, and opportunity. Its prevalence remains high among skin-of-color populations globally. Traditional agents, such as hydroquinone, mercury, and corticosteroids, persist alongside newer agents and medicalized regimens with oral and injectable agents. Associated complications span dermatologic, systemic, and psychosocial domains, constituting the emerging skin bleaching phenomenon. Despite regulatory restrictions, enforcement remains inconsistent. This narrative review examines the global epidemiology, evolving demographics, complications, and regulatory landscapes and outlines collaborative clinical, public health, regulatory, and sociocultural strategies to address this persistent global health concern.