Chang HR, Boull C, Cotton CH
… +11 more, Eichenfield DZ, García-Romero MT, Hawryluk EB, Lara-Corrales I, Oza VS, Wan J, Weiss M, PeDRA Focused Study Group Leads, Siegel M, Wine Lee L, Yu J
J Invest Dermatol
· 2026 Jul · PMID 41931068
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Cutaneous human papillomaviruses (HPVs), particularly those of the β-genus, have traditionally been viewed as harmless constituents of the skin microbiome. However, a debate has emerged over the past few years regarding...Cutaneous human papillomaviruses (HPVs), particularly those of the β-genus, have traditionally been viewed as harmless constituents of the skin microbiome. However, a debate has emerged over the past few years regarding their possible contribution to cancer development. In immunocompetent hosts, commensal β-HPVs may contribute to immune education and cutaneous homeostasis. In contrast, under immunosuppression, their increased viral load (combined with UV-induced DNA damage) can promote early oncogenic events and facilitate cancer initiation, through a "hit-and-run" mechanism. This context-dependent behavior defines β-HPVs as dynamic modulators of skin health, capable of exerting protective or pathogenic effects within the cutaneous ecosystem depending on host and environmental factors.
Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease primarily affecting apocrine gland-bearing areas. Although T helper (Th) 17-mediated inflammation is well-described in advanced HS (Hurley II-III), th...Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease primarily affecting apocrine gland-bearing areas. Although T helper (Th) 17-mediated inflammation is well-described in advanced HS (Hurley II-III), the immune mechanisms driving early disease remain unclear. To characterize the cellular and molecular environment of early HS lesions and identify potential early drivers of disease, full-thickness skin biopsies from papular inflammatory HS lesions in patients with Hurley stages I-II were analyzed using spatial RNA sequencing and imaging mass cytometry. Distinct immune phenotypes were identified, including B cells, T cells, macrophages, plasma cells, and neutrophils. Early HS lesions showed a marked increase in plasma cells and memory B cells within dermal infiltrates, with high expression of Ig genes and plasma cell markers. T cells aggregated around blood vessels in ectopic lymphoid structures but lacked expression of canonical Th1, Th2, or Th17 cytokines. Early HS is characterized by B-cell activation and plasma cell differentiation, preceding full Th17 pathway activation. These findings highlight B cells and plasma cells as potential early therapeutic targets before the transition to Th17-driven chronic inflammation.
Chuprin J, Lopes CS, MingJie Gao K
… +10 more, Chiang K, Afshari K, Haddadi N, Daga M, Dekker O, Garber M, Koupenova M, Fitzgerald KA, Marshak-Rothstein A, Rashighi M
Gain-of-function mutations in STING (STimulator of IFN Genes) cause STING-associated vasculopathy with onset in infancy (SAVI), a rare autoinflammatory disease characterized by debilitating inflammatory lung disease and...Gain-of-function mutations in STING (STimulator of IFN Genes) cause STING-associated vasculopathy with onset in infancy (SAVI), a rare autoinflammatory disease characterized by debilitating inflammatory lung disease and hallmark skin manifestations, such as chilblains and progressive, nonhealing ulcers. Mice expressing the most common SAVI-associated variant, STING (denoted as VM), recapitulate many clinical features of SAVI, including inflammatory lung disease, but do not develop spontaneous skin lesions. In this study, we show that a single low-dose of UVB irradiation, which induces only transient skin inflammation in wild-type mice, causes severe and progressive skin injury in VM mice that did not require type I IFNs. Notably, this phenotype persisted in VM mice depleted of hematopoietic cells and reconstituted with wild-type bone marrow, demonstrating that STING expression in nonhematopoietic cells is sufficient to drive persistent skin inflammation. Further analysis of our VM conditional knock-in mice, crossed to an endothelial specific Cre strain, identified STING-expressing endothelial cells as the primary driver of the cutaneous phenotype. These findings establish a critical link between endothelial cell STING activation and exacerbated skin inflammation, providing insight into the mechanisms underlying SAVI-associated skin pathology.
Tissue function and homeostasis are sustained through dynamic interactions between resident cells and their surrounding microenvironment. In the skin, these niche-specific signals coordinate epithelial metabolism and sec...Tissue function and homeostasis are sustained through dynamic interactions between resident cells and their surrounding microenvironment. In the skin, these niche-specific signals coordinate epithelial metabolism and secretory activity. Although reduced sweating is a widely recognized phenomena of aging, the cellular and molecular mechanisms underlying eccrine sweat glands decline, particularly those involving age-associated niche remodeling, remain poorly understood. In this study, we combine multiomics profiling with functional assays to define an immune-epithelial circuit that governs sweat gland metabolism and is disrupted during aging. Spatial transcriptomics, single-cell RNA-sequencing, and immunostaining of aged murine paw and human palm skin reveal that structural shrinkage of eccrine sweat glands, elevated senescence-associated secretory phenotype factors, and dendritic cells (DCs) around sweat gland coils (SGCs) were significantly reduced. In youthful skin, DCs support sweat secretion by promoting oxidative phosphorylation SGCs through nicotinamide phosphoribosyltransferase-insulin receptor signaling. However, this signaling axis was perturbed with aging where SGCs secreted macrophage migration inhibitory factor, which signaled through major histocompatibility complex class II invariant chain (CD74) to impair the expression of lysosomal membrane protein and lysosomal protease in DCs through cytochrome b-245 beta chain, exacerbating DC dysfunction and reinforcing a deteriorating glandular niche. Our findings identify DCs as guardians of SGC metabolic homeostasis, revealing a reversible niche-dependent mechanism through DC-SGC crosstalk that drives age-related glandular decline.
Vitiligo is an acquired and polygenetic autoimmune disorder with limited effective treatments. Dermal fibroblasts play a key role in vitiligo by responding to IFN-γ and secreting chemokines to recruit and activate CD8 T...Vitiligo is an acquired and polygenetic autoimmune disorder with limited effective treatments. Dermal fibroblasts play a key role in vitiligo by responding to IFN-γ and secreting chemokines to recruit and activate CD8 T cells. Although narrowband UVB (NB-UVB) is a common treatment for vitiligo, it can cause side effects such as phototoxicity. This study investigated the relationship between NB-UVB and fibroblast senescence in vitiligo and the mechanisms through which NB-UVB may trigger disease progression in some cases of vitiligo. Analysis of publicly available single-cell and bulk RNA-sequencing data revealed that NB-UVB irradiation induces dermal fibroblast senescence and activates both the MAPK and p53 pathways. In vitro, high-dose NB-UVB exposure leads to increased senescence and inflammation in vitiligo fibroblasts. In mice with vitiligo, low-dose NB-UVB treatment significantly reduced the number of CD8 T cells and increased skin pigmentation. In contrast, high-dose NB-UVB induces a senescent, proinflammatory microenvironment and exacerbates vitiligo progression in some cases. In mouse skin, high-dose NB-UVB treatment induces cell senescence and the expression of chemokines and cytokines increases, thereby disrupting the skin microenvironment and homeostasis.
Melanoma is an aggressive skin cancer with a rising global incidence, yet its lipidomic alterations remain understudied. We applied desorption electrospray ionization mass spectrometry imaging to 137 frozen skin specimen...Melanoma is an aggressive skin cancer with a rising global incidence, yet its lipidomic alterations remain understudied. We applied desorption electrospray ionization mass spectrometry imaging to 137 frozen skin specimens (65 paired normal, 57 melanomas, 15 melanocytic nevi) and developed a lipidomics-based machine learning model for diagnostic evaluation. At the clinically relevant lesion level, the model achieved 90.24% accuracy (37/41; 95% confidence interval [CI] = 77.0%-96.3%) in distinguishing melanoma from nonmelanoma tissues, comprising normal skin and nevi. Pixel-level evaluation showed 94.71% accuracy (95% CI = 94.23%-95.15%), with 93.76% sensitivity (95% CI = 93.09-94.37%) and 96.14% specificity (95% CI = 95.47%-96.72%). In differentiating melanoma from melanocytic nevi, the model achieved a lesion-level accuracy of 80.95% (17/21; 95% CI = 60.00%-92.33%) and a pixel-level accuracy of 93.10% (95% CI = 92.42%-93.73%). Further analysis revealed distinct lipidomic signatures in melanoma, characterized by elevated phospholipids and decreased triglycerides compared with those in nonmelanoma tissues. Spatially resolved desorption electrospray ionization mass spectrometry imaging enabled generation of probability heatmaps that accurately delineated melanoma regions, including early-stage lesions. In summary, integration of desorption electrospray ionization mass spectrometry imaging with machine learning demonstrates potential as a diagnostic adjunct for melanoma lipidomic profiling.