The Journal of investigative dermatology最新文献

Basal cell carcinoma (BCC) is driven in nearly all cases by mutations that constitutively activate upstream Hedgehog (HH) signaling, either through loss-of-function mutations in PTCH1 or gain-of-function mutations in SMO. Unlike other skin cancers such as squamous cell carcinoma, a clinically apparent precursor lesion for BCC has not been identified. Recent genomic analyses of both human and mouse tumors suggest that BCC formation requires not only PTCH1 or SMO mutations but also additional genetic changes. These findings imply that some BCCs may follow a stepwise tumor progression model, whereby the accumulation of multiple mutational "hits" is needed to convert an indolent precursor lesion into malignant disease. On the basis of studies in patients with Gorlin syndrome who harbor germline PTCH1 mutations and are genetically predisposed to forming BCC, we speculate that at least a subset of BCCs arises from a subclinical basaloid follicular hamartoma or similar precursor lesion. Altogether, convergent evidence suggests that activating upstream HH signaling is necessary but not sufficient for BCC formation. This evolving view of BCC has important implications for our basic understanding of these tumors, for our interpretation of findings from BCC mouse models, and for guiding treatment.

External insults can cause immune activation in immune cells, resulting in persistent molecular changes that can lead to innate immune memory changes in these cells. This study investigated the potential for cellular reprogramming in response to Cutibacterium acnes in keratinocytes. We exposed normal human epidermal keratinocytes (NHEKs) obtained by mammoplasty (denoted as NHEK-B) or abdominoplasty (denoted as NHEK-A) to C acnes, followed by stimulation with Pam3CSK4 to assess immune activation and cellular responses. In NHEK-B cells, C acnes and Pam3CSK4 treatment induced trained immunity-type responses, higher expression of selected immune target genes, and a diminished response compared with trained and Pam3CSK4-induced NHEK-A cells. Total transcriptome analysis delineated regional differences, with the activation of immune-related pathways in NHEK-B cells and alterations in keratinocyte differentiation processes in NHEK-A cells. We detected differences in metabolic regulation, and utilizing pharmacological inhibitors, we demonstrated the necessity of the optimal regulation of histone acetylation and DNA methylation for the changes mentioned earlier. This study demonstrated that C acnes triggers innate immune memory processes in keratinocytes, characterized by signaling, epigenetic, and metabolic reprogramming that influences cellular responses to subsequent stimuli. The observation that analogous insults might elicit skin region-specific responses offers insights into the etiology and mechanisms underlying common inflammatory skin diseases.

Central centrifugal cicatricial alopecia (CCCA) is the most common form of primary scarring alopecia in women of African descent, typically characterized by progressive hair loss originating at the vertex of the scalp. Although genetic susceptibility has been implicated in the pathogenesis of CCCA, only 1 gene (PADI3, encoding peptidyl arginine deiminase 3) has been thus far associated with CCCA. This study aimed to broaden our understanding of the genetic basis of CCCA by analyzing whole-exome sequences from 75 patients with clinically and histologically confirmed CCCA. We identified 9 pathogenic heterozygous variants in PADI3, including, to our knowledge, 4 previously unreported missense variants, all predicted to disrupt protein function. Functional analyses revealed reduced expression, abnormal intracellular localization, and diminished enzymatic activity in cells transfected with constructs expressing the PADI3 variants. More interestingly, pathogenic variants were identified in 2 additional genes, S100A3 and TCHH, which encode the main substrates of PADI3, S100 calcium-binding protein A3 and trichohyalin. Both proteins play critical roles in hair shaft integrity. The S100A3 variant was found to cause reduced citrullination by PADI3, whereas TCHH variants altered intracellular localization and resulted in significantly reduced expression of the protein. These findings provide further insights into disease mechanisms and may inform future strategies for genetic testing and targeted therapies.

Vitiligo is a chronic, disfiguring disease associated with autoimmune comorbidities and psychosocial burdens, although comprehensive Chinese population data remain limited. This study systematically characterizes the clinical and psychosocial profiles of treatment-seeking patients with vitiligo, addressing gaps in understanding disease severity, comorbidities, and mental health impacts to guide integrated management approaches. A cross-sectional analysis of 5227 Chinese patients with vitiligo after unsatisfactory conventional therapy was conducted. Among the 5227 patients with vitiligo, nonsegmental vitiligo (88.7%) predominated, with 73.2% in progressive stage. Family history was reported in 13.5%, and comorbidities (primarily thyroid disorders, 10.9%) occurred in 21.2%. Most patients (62%) developed vitiligo before the age of 30 years. All received prior treatments (79% received ≥2 therapies), and 94.2% had visible-area lesions (face/neck/hands), with ∼80% showing complete depigmentation. Severe vitiligo was significantly associated with male sex (adjusted OR [aOR] = 2.17), disease duration >10 years (aOR = 20.56), and nonsegmental subtype (aOR = 12.31). QOL impairment was observed in the following characteristics: female sex (aOR = 1.87), severe vitiligo (aOR = 1.66), depression (aOR = 1.81), low self-esteem (aOR = 2.83), and hopelessness (aOR = 2.59). Chinese patients with vitiligo face multidimensional burdens-chronicity, visible-area depigmentation, comorbidities, and psychological distress-exacerbated by fragmented treatments. Findings underscore the need for integrated management models combining dermatological, psychological, and systemic interventions beyond depigmentation-focused therapies.

UVB-induced dysfunction of dendritic cells (DCs) is a key mechanism for UVB-induced immune suppression, a major risk factor for skin cancer development. Mechanisms remain to be fully understood despite numerous efforts. This study found that the signaling pathway of TREM-1 (triggering receptor expressed on myeloid cells 1) was a top-upregulated canonical pathway in mouse and human skin after UVB. Blocking TREM-1 with an antagonistic peptide LP-17 significantly reversed UVB-induced suppression of immune responses, suppressed UVB-induced skin carcinogenesis, and prevented the UVB-induced suppression of antigen-specific CD8+ Tc1 and Tc17 effector cells. Further studies defined a TREM-1+ tolerogenic DC subset in the draining lymph nodes, which was induced by UVB. The conditional knockout of the Trem1 gene in CD11c+ DCs abolished UVB-induced suppression of contact hypersensitivity responses. In contrast, it did not affect the immune response in mice that were not exposed to UVB. Mechanistically, blocking TREM-1 significantly increased the expression level of the activation markers CD80 and CD86 by UVB-induced TREM-1+ DCs. In conclusion, our studies have identified a UVB-induced TREM-1+ tolerogenic DC subset and demonstrated an important mechanism for UVB-induced immune suppression and skin carcinogenesis.