Overexpressed perforin contributes to the melanocyte destruction via epigenetic regulation in patients with vitiligo.

BACKGROUND: Perforin (PRF), a pivotal cytotoxic effector molecule of activated CD8+ T cells, has a crucial role in the pathogenesis of vitiligo. However, the mechanisms leading to the abnormal perforin expression remain poorly understood in the CD8+ T cells of vitiligo patients. OBJECTIVE: To investigate the contributions of DNA methylation to the abnormal expression of perforin in CD8+ T cells of vitiligo patients. METHODS: Skin samples and CD8+ T cells from peripheral blood were collected to detect the expression levels of perforin in vitiligo patients. The methylation status of the perforin promoter was investigated by bisulfite sequencing. The apoptosis of melanocytes co-cultured with CD8+ T cells was evaluated to determinate the cytotoxic role of perforin. RESULTS: Increased CD8+ and perforin+ cells were found in lesion of vitiligo patients. The expression levels of perforin were elevated in the CD8+ T cells from peripheral blood of vitiligo patients and their culture supernatants. The perforin promoter was hypomethylated in vitiligo CD8+ T cells. Treatment of normal CD8+ T cells with the DNA methylation inhibitor 5-Azacytidine (5-Azac) reduced the perforin methylation level and caused perforin overexpression. The methylation levels of perforin were inversely correlated with its mRNA expression in CD8+ T cells. The apoptosis rates of the melanocytes co-cultured with vitiligo- and 5-Azac-treated-normal CD8+ T cells were significantly increased compared with normal-untreated CD8+ T cells. And the apoptosis rates of melanocytes co-cultured with si-PRF-treated-vitiligo CD8+ T cells were significantly decreased compared with vitiligo-untreated CD8+ T cells. CONCLUSION: Hypomethylation of the perforin promoter contributes to its overexpression in CD8+ T cells from vitiligo patients, which then mediates the melanocyte destruction in vitiligo.

Occludin Promotes Adhesion of CD8+ T Cells and Melanocytes in Vitiligo via the HIF-1α Signaling Pathway.

Loss of melanocytes induced by activated CD8+ T cells is the pathological hallmark of vitiligo. Melanocyte-specific CD8+ T cells are recruited to the skin via chemokines, thereby releasing perforin, granzyme, and other cytotoxic substances that destroy the melanocytes. However, the mechanism of CD8+ T cells to adhere to melanocytes is unknown. Previous transcriptome sequencing results published by our group showed that the occluding (OCLN) gene was significantly upregulated in CD8+ T cells from skin lesions of vitiligo. Occludin is a crucial component of the tight junction between cells; in cells without tight junction, occludin mediates the adhesion of two cells in the form of a self-ligand. This study demonstrated that OCLN gene expression was elevated in the CD8+ T cells of vitiligo patients, and occludin mediates the adherence of CD8+ T cells to melanocytes. Besides, pathological changes in vitiligo skin lesions reveal that CD8+ T cells continuously persist in the skin lesions, which is related to the persistence of the disease. In this regard, we found that fibroblasts from vitiligo patients significantly express occludin, which may participate in the continuous retention of CD8+ T cells in the skin lesions. The pathogenesis of vitiligo is closely related to oxidative stress, and our data suggest that overexpression of hypoxia-inducible factor-1α (HIF-1α) increases the expression of occludin. Besides, ChIP-qPCR of CD8+ T cells revealed that HIF-1α directly binds to the OCLN promoter. Thus, occludin upregulation promotes the adhesion of CD8+ T cells and melanocytes via the HIF-1α signaling pathway. Our study results suggested a critical role for OCLN in the occurrence, progression, and maintenance of vitiligo. Therefore, inhibiting the expression of OCLN gene may be a potential targeted treatment strategy.

Meta-Analytic Review of High Anxiety Comorbidity among Patients with Vitiligo.

BACKGROUND: Vitiligo is a disfiguring skin disease with profound psychosocial impacts, such as anxiety, but the reported effect sizes of associations vary. We aimed to conduct a meta-analysis to quantify the strength of association between anxiety and vitiligo and to estimate the prevalence of anxiety among individuals with vitiligo. METHODS: A systematic literature search was performed in five online databases (MEDLINE, Embase, Web of Science, Cochrane Library, and PsycINFO) from inception until March 20, 2020. All of the eligible studies were comprehensively reviewed, and all of the available data were analyzed according to our predefined criteria. RESULTS: Twenty-one studies involving 3259 patients in 11 countries were included in this meta-analysis. Compared with the healthy control group, patients with vitiligo often had concomitant anxiety (OR = 6.14 [95% CI: 3.35-11.24], I 2 = 30.1%). The pooled prevalence of anxiety in female patients was significantly higher than that in males (OR = 2.24 [95% CI: 1.31-3.84], I 2 = 0.0%). Subgroup analysis showed that the pooled prevalence of clinical anxiety disorder and anxiety symptoms was 12% (95% CI: 7%-16%, I 2 = 76.3%) and 34% (95% CI: 21%-46%, I 2 = 94.7%), respectively. No publication bias has been detected by Begg's funnel plot and Egger's test. CONCLUSION: Patients with vitiligo have high anxiety comorbidity, with female predominance. Dermatologists and psychiatrists should be vigilant to the presence of anxiety, apply appropriate interventions to reduce the psychological impacts in a timely manner, and thus promote recovery in vitiligo patients. However, due to some objective limitations (poor information about the OR and diversity in assessment tools among included studies), findings should be interpreted with caution.

Particulate matter promotes hyperpigmentation via AhR/MAPK signaling activation and by increasing α-MSH paracrine levels in keratinocytes.

Particulate matter with an aerodynamic equivalent diameter of 2.5 µm or less in ambient air (PM2.5) has become a global public and environmental problem, and the control of the PM2.5 concentration in air is an urgent problem. PM2.5 can easily penetrate the skin, activating the inflammatory response in skin, unbalancing the skin barrier function, and inducing skin aging. Hyperpigmentation is the main manifestation of skin aging and has a considerable impact on quality of life worldwide. To date, no research on the influence of PM2.5 on hyperpigmentation has been conducted. Here, we illustrate that PM2.5 can induce melanogenesis in vivo and in vitro by regulating TYR, TYRP1, TYRP2, and MITF expression via AhR/MAPK signaling activation. Furthermore, PM2.5 increased α-MSH paracrine levels, which in turn promote hyperpigmentation. Our results provide a deeper understanding of how PM2.5 disrupts skin homeostasis and function. Treatment with AhR antagonists may be a potential therapeutic strategy for hyperpigmentation induced by PM2.5.

Integrative Analysis of MicroRNA and Gene Interactions for Revealing Candidate Signatures in Prostate Cancer.

MicroRNA (miRNA)-gene interactions are well-recognized as involved in the progression of almost all cancer types including prostate cancer, which is one of the most common cancers in men. This study explored the significantly dysregulated genes and miRNAs and elucidated the potential miRNA-gene regulatory network in prostate cancer. Integrative analysis of prostate cancer and normal prostate transcriptomic data in The Cancer Genome Atlas dataset was conducted using both differential expression analysis and weighted correlation network analysis (WGCNA). Thirteen genes (RRM2, ORC6, CDC45, CDKN2A, E2F2, MYBL2, CCNB2, PLK1, FOXM1, CDC25C, PKMYT1, GTSE1, and CDC20) were potentially correlated with prostate cancer based on functional enrichment analyses. MiRNAs targeting these genes were predicted and eight miRNAs were intersections between those miRNAs and the hub miRNAs obtained from miRNA WGCNA analysis. Three genes (E2F2, RRM2, and PKMYT1) and four miRNAs (hsa-mir-17-5p, hsa-mir-20a-5p, hsa-mir-92a-3p, and hsa-mir-93-5p) were key factors according to the interaction network. RRM2 and PKMYT1 were significantly related to survival. These findings partially elucidated the dysregulation of gene expressions in prostate cancer. Efficient manipulations of the miRNA-gene interactions in prostate cancer may be exploited as promising therapeutics.

The Emerging Epigenetic Role of CD8+T Cells in Autoimmune Diseases: A Systematic Review.

Autoimmune diseases are usually complex and multifactorial, characterized by aberrant production of autoreactive immune cells and/or autoantibodies against healthy cells and tissues. However, the pathogenesis of autoimmune diseases has not been clearly elucidated. The activation, differentiation, and development of CD8+ T cells can be affected by numerous inflammatory cytokines, transcription factors, and chemokines. In recent years, epigenetic modifications have been shown to play an important role in the fate of CD8+ T cells. The discovery of these modifications that contribute to the activation or suppression of CD8+ cells has been concurrent with the increasing evidence that CD8+ T cells play a role in autoimmunity. These relationships have been studied in various autoimmune diseases, including multiple sclerosis (MS), systemic sclerosis (SSc), type 1 diabetes (T1D), Grave's disease (GD), systemic lupus erythematosus (SLE), aplastic anemia (AA), and vitiligo. In each of these diseases, genes that play a role in the proliferation or activation of CD8+ T cells have been found to be affected by epigenetic modifications. Various cytokines, transcription factors, and other regulatory molecules have been found to be differentially methylated in CD8+ T cells in autoimmune diseases. These genes are involved in T cell regulation, including interferons, interleukin (IL),tumor necrosis factor (TNF), as well as linker for activation of T cells (LAT), cytotoxic T-lymphocyte-associated antigen 4 (CTLA4), and adapter proteins. MiRNAs also play a role in the pathogenesis of these diseases and several known miRNAs that are involved in these diseases have also been shown to play a role in CD8+ regulation.

Transcriptome Analysis and Emerging Driver Identification of CD8+ T Cells in Patients with Vitiligo.

Activated CD8+ T cells play important roles in the pathogenesis of vitiligo. However, driving factors about the activation and migration of CD8+ T cells remain obscure. In this study, we aim to identify differentially expressed genes (DEGs) and uncover potential factors that drive the disease in melanocyte-specific CD8+ T cells in vitiligo. A total of 1147 DEGs were found through transcriptome sequencing in CD8+ T cells from lesional skin of vitiligo patients and normal controls. Based on KEGG pathway enrichment analysis and PPI, 16 upregulated and 23 downregulated genes were identified. Ultimately, 3 genes were figured out after RT-qPCR verification. The mRNA and protein expression levels of PIK3CB, HIF-1α, and F2RL1 were all elevated in CD8+ T cells from peripheral blood in vitiligo. HIF-1α and PIK3CB were significantly increased in lesional skin of vitiligo. Two CpG sites of the HIF-1α promoter were hypomethylated in vitiligo CD8+ T cells. In conclusion, HIF-1α, F2RL1, and PIK3CB may act as novel drivers for vitiligo, which are all closely associated with reactive oxygen species and possibly contribute to the activation and/or migration of melanocyte-specific CD8+ T cells in vitiligo. In addition, we uncovered a potential role for DNA hypomethylation of HIF-1α in CD8+ T cells of vitiligo.

Imbalance between T helper 17 and regulatory T cell subsets plays a significant role in the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is a rare autoimmune disease that is characterized by fibrosis, inflammation, and vasculopathy of the skin and internal organs. The etiopathogenesis of SSc remains unclear. However, the pivotal role of T lymphocytes with an aberrant immune response in SSc is well established. Among T cells, IL-17-producing helper T (Th17) cell and regulatory T (Treg) cell subsets have recently been found to play crucial roles in SSc pathogenesis. Generally speaking, Th17 cell subsets up-regulate inflammation, fibrosis, and autoimmunity, which are present in SSc, while Treg cell subsets have an immunosuppressive function and resist the immunological performance of Th17 cells. Up-to-date evidence has pointed out that the imbalance and abnormal functions of Th17/Treg cells may contribute to SSc. Therefore, this review aims to summarize the current understanding of the vital cytokines and signaling pathways that are involved in Th17/Treg differentiation and functions, and their roles in the pathogenesis of SSc, thus providing novel insights about targeting the Th17/Treg balance as a potential therapy for SSc treatment in the near future.

Cutaneous sarcoidosis and secondary open-angle glaucoma in a patient: case report and literature review.

The current report presents the case of a 41-year-old male patient with a two-month history of asthenopia and plaques in the frontotemporal region. Computed tomography revealed bilateral hilar and mediastinal lymphadenopathy. Ophthalmological examination showed elevated intraocular pressure. Skin biopsy demonstrated aa dermal inflammatory infiltrate composed mainly of epithelioid cells and a few multinucleated giant cells, but no obvious lymphocytes. Findings of thorough physical examinations and auxiliary examinations suggested the presence of cutaneous sarcoidosis and secondary open-angle glaucoma. Treatment consisted mainly of oral methylprednisolone. Skin lesions, bilateral hilar, and mediastinal lymphadenopathy resolved completely. Cutaneous sarcoidosis is often accompanied by extracutaneous organ involvement. Dermatologists must be aware of the disease's extracutaneous manifestations to ensure accurate diagnosis for further treatments.

Bullous pemphigoid associated with milia, increased serum IgE, autoantibodies against desmogleins, and refractory treatment in a young patient.

Bullous pemphigoid is a blistering autoimmune disease characterized by two hemidesmosomal proteins (anti-BP180 and 230). Pemphigus, by contrast, is characterized by two autoantibodies (anti-desmoglein 1 and 3). Coexistence of autoantibodies of bullous pemphigoid and pemphigus in a patient is rare. A 25-year-old male patient was admitted to our hospital, reporting a 3-month history of multiple papules, vesicles, and erosions over an extensive erythema on the entire body. Laboratory tests showed high levels of serum IgE, anti-BP180 antibodies, and anti-desmoglein 1 and 3. Histopathologic and immunopathologic features were characterized by bullous pemphigoid. No improvement was seen with systemic corticosteroid therapy, however, pulse corticosteriod therapy combined with methylprednisolone, immunosuppressants, immunomodulators, and plasmapheresis led to the recovery of his condition with numerous milia.

Severe cutaneous adverse drug reactions of Chinese inpatients: a meta-analysis.

BACKGROUND: The rate of severe cutaneous adverse drug reactions is low, and these reactions can result in death or disability. An evidence-based epidemiological study of severe cutaneous adverse drug reactions in China has not been reported. OBJECTIVE: The aim of this study was to analyze epidemiology and characteristics of severe cutaneous adverse drug reactions of Chinese inpatients during the recent 15 years with meta-analysis. METHODS: We retrospectively reviewed Chinese literature reporting severe cutaneous adverse drug reactions and collecting data from 2000 to 2015, which were in accordance with our inclusion criteria. All included data were analyzed with the Launch Open Meta-Analyst software. RESULTS: Twenty-five articles involving 928 cases with severe cutaneous adverse drug reactions were included. Men to women ratio was 1.14:1. Twenty-one per cent of the patients had drug allergy history. Antibiotics (26.0%), sedative hypnotics and anticonvulsants (21.6%), and antipyretic analgesics (17.1%) were the most common causative drugs. The most frequent clinical subtype was Stevens-Johnson syndrome (50.1%), followed by toxic epidermal necrolysis (25.4%), exfoliative dermatitis (21.0%) and drug-induced hypersensitivity syndrome (1.6%). In addition to skin rashes, patients with severe cutaneous adverse drug reactions suffered mostly from fever (73%), and blood routine abnormality (66.7%). STUDY LIMITATIONS: This meta-analysis is limited by its retrospective design and by its methodological variation. CONCLUSION: The most common causative drugs were antibiotics and sedative hypnotics and anticonvulsants. Stevens-Johnson syndrome was the most frequent clinical subtype of severe cutaneous adverse drug reactions. In addition to skin rashes, patients with severe cutaneous adverse drug reactions suffered mostly from fever, mucosal lesion, and hematologic abnormalities.

Cutaneous sarcoidosis and secondary open-angle glaucoma in a patient: case report and literature review

Abstract The current report presents the case of a 41-year-old male patient with a two-month history of asthenopia and plaques in the frontotemporal region. Computed tomography revealed bilateral hilar and mediastinal lymphadenopathy. Ophthalmological examination showed elevated intraocular pressure. Skin biopsy demonstrated aa dermal inflammatory infiltrate composed mainly of epithelioid cells and a few multinucleated giant cells, but no obvious lymphocytes. Findings of thorough physical examinations and auxiliary examinations suggested the presence of cutaneous sarcoidosis and secondary open-angle glaucoma. Treatment consisted mainly of oral methylprednisolone. Skin lesions, bilateral hilar, and mediastinal lymphadenopathy resolved completely. Cutaneous sarcoidosis is often accompanied by extracutaneous organ involvement. Dermatologists must be aware of the disease's extracutaneous manifestations to ensure accurate diagnosis for further treatments.

Severe cutaneous adverse drug reactions of Chinese inpatients: a meta-analysis

Abstract Background: The rate of severe cutaneous adverse drug reactions is low, and these reactions can result in death or disability. An evidence-based epidemiological study of severe cutaneous adverse drug reactions in China has not been reported. Objective: The aim of this study was to analyze epidemiology and characteristics of severe cutaneous adverse drug reactions of Chinese inpatients during the recent 15 years with meta-analysis. Methods: We retrospectively reviewed Chinese literature reporting severe cutaneous adverse drug reactions and collecting data from 2000 to 2015, which were in accordance with our inclusion criteria. All included data were analyzed with the Launch Open Meta-Analyst software. Results: Twenty-five articles involving 928 cases with severe cutaneous adverse drug reactions were included. Men to women ratio was 1.14:1. Twenty-one per cent of the patients had drug allergy history. Antibiotics (26.0%), sedative hypnotics and anticonvulsants (21.6%), and antipyretic analgesics (17.1%) were the most common causative drugs. The most frequent clinical subtype was Stevens-Johnson syndrome (50.1%), followed by toxic epidermal necrolysis (25.4%), exfoliative dermatitis (21.0%) and drug-induced hypersensitivity syndrome (1.6%). In addition to skin rashes, patients with severe cutaneous adverse drug reactions suffered mostly from fever (73%), and blood routine abnormality (66.7%). Study limitations: This meta-analysis is limited by its retrospective design and by its methodological variation. Conclusion: The most common causative drugs were antibiotics and sedative hypnotics and anticonvulsants. Stevens-Johnson syndrome was the most frequent clinical subtype of severe cutaneous adverse drug reactions. In addition to skin rashes, patients with severe cutaneous adverse drug reactions suffered mostly from fever, mucosal lesion, and hematologic abnormalities.

Bullous pemphigoid associated with milia, increased serum IgE, autoantibodies against desmogleins, and refractory treatment in a young patient

Abstract: Bullous pemphigoid is a blistering autoimmune disease characterized by two hemidesmosomal proteins (anti-BP180 and 230). Pemphigus, by contrast, is characterized by two autoantibodies (anti-desmoglein 1 and 3). Coexistence of autoantibodies of bullous pemphigoid and pemphigus in a patient is rare. A 25-year-old male patient was admitted to our hospital, reporting a 3-month history of multiple papules, vesicles, and erosions over an extensive erythema on the entire body. Laboratory tests showed high levels of serum IgE, anti-BP180 antibodies, and anti-desmoglein 1 and 3. Histopathologic and immunopathologic features were characterized by bullous pemphigoid. No improvement was seen with systemic corticosteroid therapy, however, pulse corticosteriod therapy combined with methylprednisolone, immunosuppressants, immunomodulators, and plasmapheresis led to the recovery of his condition with numerous milia.