The Journal of investigative dermatology最新文献

Pachyonychia congenita (PC) is a rare and painful skin disorder caused by dominant pathogenic variants in keratin genes (KRT6A/KRT6B/KRT6C/KRT16/KRT17), with no effective treatment. We developed a scalable, in-depth and miniaturized MS-based proteomics and phospho-proteomics analysis of full-thickness skin biopsies applied to 10 PC patients to elucidate pathogenic mechanisms and pinpoint therapeutic targets. We quantified 7200 Protein Groups (PGs) on average from 2mm snap-frozen skin samples, the most in-depth proteome coverage reported to date from a single-shot MS analysis. Among the identified PGs, ∼1400 proteins were differentially abundant in lesional vs. non-lesional samples. Enrichment analysis points towards impaired mitochondrial function, hyper-keratinization, enhanced immune response and a significant increase in cholesterol biosynthesis. Phosphoproteomics revealed hyper-phosphorylation of specific sites in PC-related keratins, confirmed the hyper-activation of EGFR and downstream kinases, including PKC and Src, and disclosed p38 MAPK activation. All of these kinases have been reported to phosphorylate keratins. Our study expands upon current understanding of the consequences of EGFR pathway activation, including increased cholesterol biosynthesis, thereby renewing interest in the use of statins for PC. Above all, it provides a solid foundation for the continued exploration of EGFR inhibitors and offers therapeutic avenues, particularly those using multikinase inhibitors.

Prediction models that accurately predict patient prognosis and treatment response enable the development of personalized treatment plans in dermatology as well as outside dermatology. This can improve patient care and reduce the use of ineffective, potentially harmful treatments. Developing representative models for all patients can be a significant challenge, particularly in cases involving rare outcomes or expensive molecular biomarkers. The former requires large cohorts, whereas the latter requires a significant budget to measure these in a large volume of samples. Nested case-control and case-cohort designs are cost-effective designs that enable the development and validation of prediction models using only a proportion of samples of the source cohort, without compromising their applicability to the total population. These epidemiological designs are relatively unknown, and there is a lack of clear guidance on how to develop and validate models using these studies. We aim to inspire other researchers to apply these designs to their (skin) disease of interest and facilitate the development of prediction models that can have a high clinical impact on patient care.

While regulatory T cells (Tregs) control autoimmune diseases (AID), the role of evolutionarily older Foxp3⁺ γδTregs is much less understood. We noted that both lesional and non-lesional skin of patients with alopecia areata (AA), one of the most common AID, contains significantly more Vδ1⁺/Foxp3⁺ γδTregs than healthy scalp skin. Therefore, we investigated how human γδTregs impact experimentally induced AA in human scalp skin xenotransplants on SCID/beige mice in vivo. Peripheral autologous human Vδ2⁺/Foxp3⁺ γδTregs were expanded and pre-activated in vitro and then injected intradermally into scalp skin xenografts before or after induction of AA. These γδTregs reduced the perifollicular lymphocytic infiltrate, restored hair follicle immune privilege (HF-IP), prevented AA onset, and promoted hair regrowth in established AA lesions. In parallel, γδTregs co-cultured with organ-cultured, MICA/B-overexpressing human scalp HFs suppressed pathogenic CD8⁺/NKG2D⁺ T-cell activity and counteracted all AA hallmarks ex vivo-including HF-IP collapse, HF dystrophy, and premature IFNγ-induced catagen-via IL-10 and TGF-β1 secretion, contact-dependent inhibition, and adenosine generation through CD39/CD73. These findings in a model human AID introduce human γδTregs as clinically important regulatory lymphocytes and invite the use of autologous peripheral Vδ2⁺/Foxp3⁺ γδTregs as a cell-based therapy for AA and possibly other CD8⁺ T cell-dependent AIDs characterized by IP collapse.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition associated with an increased risk of all-cause mortality. Though it is known to be influenced by genetic and environmental factors, the genetic contributors remain poorly characterized. We performed a large-scale meta-analysis involving patients from the Million Veteran Program (MVP), UK Biobank, and FinnGen, including a total of 3,941 cases and 1,435,603 controls. We identified 9 genome-wide significant loci, five of which have not been previously reported. Using a variant-to-gene analysis pipeline, we mapped these variants to 11 lead genes, supporting prior candidates while revealing previously unreported ones, to our knowledge, including SMPD4 and PSMA4, which we demonstrate are differentially expressed in HS skin lesions. Using expression quantitative trait loci and protein quantitative trait loci, two-sample Mendelian randomization identified additional genes likely involved in the pathogenesis of HS, including MPO. We subsequently probed the protein interactome network of these candidates to reveal drug targets for prioritization in future studies. These results reaffirm the previously suspected role of KLF5 in HS while linking the pathogenesis of the disease to pathways related to lipid and skin barrier homeostasis, proteasome function, and oxidative stress.

Dermatomyositis (DM) is an autoimmune disease classically affecting the skin, muscles, and lungs. Patients with DM have poor QOL, and current treatments fail to work in half of patients with DM. There is a need for an effective and safer therapeutic option. Lenabasum is a nonimmunosuppressive, nonpsychoactive cannabinoid receptor type 2 (CB2) agonist that promotes resolution of innate immune responses. The activation of CB2 reduces several proinflammatory cytokines implicated in DM. The purpose of this study was to conduct a multiplexed analysis of DM skin and PBMCs to examine the effect of lenabasum on inflammatory and itch-promoting cytokines. Our data show that lenabasum has anti-inflammatory effects, particularly on CD4+ T cells, T helper 1 cells, and myeloid cell lineages such as monocyte-derived dendritic cells. Lenabasum suppressed T helper 1-derived IL-31 and monocyte-derived dendritic cell-derived IL-31, a cytokine implicated in DM pruritus. CB2 knockdown of cells eluted from DM skin abrogated these anti-inflammatory effects. The higher CB2 expression and stronger lenabasum response in cells eluted from DM skin than from DM PBMCS indicate that local tissue environment shapes inflammatory cell behavior. Our results show that lenabasum acts through the CB2, promoting the downregulation of proinflammatory cytokines. This may explain lenabasum's greater effect on skin than in muscle in human studies.

Prurigo nodularis (PN) is a chronic pruritic skin disease characterized by hyperkeratotic nodules and intense itching, yet its pathological mechanisms remain unclear, especially at the protein level and in comparison with atopic dermatitis. We performed parallel analyses of proteomic data (4-dimensional data-independent acquisition) from lesions of PN, atopic dermatitis, and healthy controls. Single-cell RNA-sequencing data were integrated from publicly available datasets (eg, GSE222840) representing comparable cohorts. Our analysis revealed a PN-specific proteomic signature dominated by myeloid-driven immunity, profound tissue remodeling, and mitochondrial metabolic reprogramming. From this signature, we identified a set of PN-enriched molecules. Among them, ADGRE2 (adhesion G protein-coupled receptor E2)-a known mechanosensory receptor-emerged as the most selectively upregulated in PN myeloid subsets. Critically, the expression of ADGRE2 demonstrated a strong positive correlation with clinical itch severity, as measured by Peak Pruritus Numerical Rating Scale and Dermatology Life Quality Index. It was also further confirmed to be predominantly expressed in myeloid cells of PN lesions, showing higher abundance than in atopic dermatitis or healthy controls. This study refines the PN framework, highlighting myeloid-enriched molecules such as ADGRE2, which provides mechanistic insights into the unique inflammatory and sensory landscape and offers therapeutic avenues.