Roles of blood metabolites in mediating the relationship between vitiligo and autoimmune diseases: Evidence from a Mendelian randomization study.

OBJECTIVE: This study employed Mendelian Randomization (MR) to investigate the causal relationship between genetic susceptibility to vitiligo and the risk of various autoimmune diseases, along with the mediating role of blood metabolites. METHODS: We performed two-sample MR analyses using aggregated genome-wide association studies (GWAS) data on 486 blood metabolites, vitiligo, and nine autoimmune diseases to investigate blood metabolites' causal effects on the susceptibility of vitiligo and the associations of vitiligo with nine autoimmune comorbidities. We also applied multivariable MR to unravel metabolites by which vitiligo influences the pathogenesis of autoimmune diseases. RESULTS: Our findings indicate that vitiligo amplified the risk of several autoimmune diseases, including rheumatoid arthritis (OR 1.17; 95 % CI 1.08-1.27), psoriasis (OR 1.10; 95 % CI 1.04-1.17), type 1 diabetes (OR 1.41; 95 % CI 1.23-1.63), pernicious anemia (OR 1.23; 95 % CI 1.12-1.36), autoimmune hypothyroidism (OR 1.19; 95 % CI 1.11-1.26), alopecia areata (OR 1.22; 95 % CI 1.10-1.35), and autoimmune Addison's disease (OR 1.22; 95 % CI 1.12-1.33). Additionally, our analysis identified correlations with vitiligo for 14 known (nine risk, five protective) and seven uncharacterized serum metabolites. After adjusting for genetically predicted levels of histidine and pyruvate, the associations between vitiligo and these diseases were attenuated. CONCLUSIONS: We substantiated vitiligo's influence on susceptibility to seven autoimmune diseases and conducted a thorough investigation of serum metabolites correlated with vitiligo. Histidine and pyruvate are potential mediators of vitiligo associated with autoimmune diseases.By combining metabolomics with genomics, we provide new perspectives on the etiology of vitiligo and its immune comorbidities.

m6A RNA methylation: The latent string-puller in fibrosis.

Fibrosis is a pathological phenomenon characterized by the aberrant accumulation of extracellular matrix (ECM) in tissues. Fibrosis is a universally age-related disease involving that many organs and is the final stage of many chronic inflammatory diseases, which often threaten the patient's health. Undoubtedly, fibrosis has become a serious economic and health burden worldwide, However, the pathogenesis of fibrosis is complex. Further, the key molecules still remain to be unraveled. Hence, so far, there have been no effective treatments designed against the key targets of fibrosis. The methylation modification on the nitrogen atom at position 6 of adenine (m6A) is the most common mRNA modification in mammals. There is increasing evidence that m6A is actively involved in the pathogenesis of fibrosis. This review aims to highlight m6A-associated mechanisms and functions in several organic fibrosis, which implies that m6A is universal and critical for fibrosis and summarize the outlook of m6A in the treatment of fibrosis. This may light up the unknown aspects of this condition for researchers interested to explore fibrosis further.

Further insight into systemic sclerosis from the vasculopathy perspective.

Systemic sclerosis (SSc) is an autoimmune disease characterized by immune dysfunction, vascular system dysfunction, and tissue fibrosis. Vascular injury, vascular remodeling, and endothelial dysfunction are the hallmark pathological changes of the disease. In the early stages of SSc development, endothelial cell injury and apoptosis can lead to vascular and perivascular inflammation, oxidative stress, and tissue hypoxia, which can cause clinical manifestations in various organs from the skin to the parenchymal organs. Early diagnosis and rational treatment can improve patient survival and quality of life. Ancillary examinations such as nailfold capillaroscopy as well as optical coherence tomography can help early detect vascular injury in SSc patients. Studies targeting the mechanisms of vascular lesions will provide new perspectives for treatment of SSc.

The evaluation of IgG4 and IgG expression in cutaneous Rosai-Dorfman disease.

OBJECTIVE: The authors investigated the expression of IgG4 and IgG in cutaneous Rosai-Dorfman Disease (CRDD) to further improve the understanding of this disease. METHODS: The authors retrospectively reviewed the clinicopathological features of 23 CRDD patients. The authors diagnosed CRDD by the presence of emperipolesis and immunohistochemical (IHC) staining of histiocytes consisting of S-100(+)/CD68(+)/CD1a(-) cells. The expressions of IgG and IgG4 in cutaneous specimens were assessed by IHC (EnVision) and quantitatively calculated by a medical image analysis system. RESULTS: All 23 patients, including 14 males and 9 females, were confirmed to have CRDD. Their ages ranged from 17 to 68 years (mean 47.91 ± 14.16). The most frequently affected skin regions were the face, followed by the trunk, ears, neck, limbs, and genitals. In 16 of these cases, the disease presented as a single lesion. IHC staining of sections showed that IgG was positive (≥ 10 cells/High-Power Field [HPF]) in 22 cases, while IgG4 was positive (≥ 10 cells/HPF) in 18 cases. Moreover, the IgG4/IgG proportion ranged from 1.7% to 85.7% (mean 29.50 ± 24.67%, median 18.4%) in the 18 cases. STUDY LIMITATIONS: In the majority of studies, as well as in the current study, the design. RDD is a rare disease, so the sample size is small. In the next studies to come, the authors will expand the sample for multi-center verification and in-depth study. CONCLUSION: The positive rates of IgG4 and IgG and the IgG4/IgG ratio assessed through IHC staining may be important in understanding the pathogenesis of CRDD.

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.

The evaluation of IgG4 and IgG expression in cutaneous Rosai-Dorfman disease

Abstract Objective The authors investigated the expression of IgG4 and IgG in cutaneous Rosai-Dorfman Disease (CRDD) to further improve the understanding of this disease. Methods The authors retrospectively reviewed the clinicopathological features of 23 CRDD patients. The authors diagnosed CRDD by the presence of emperipolesis and immunohistochemical (IHC) staining of histiocytes consisting of S-100(+)/CD68(+)/CD1a(-) cells. The expressions of IgG and IgG4 in cutaneous specimens were assessed by IHC (EnVision) and quantitatively calculated by a medical image analysis system. Results All 23 patients, including 14 males and 9 females, were confirmed to have CRDD. Their ages ranged from 17 to 68 years (mean 47.91 ± 14.16). The most frequently affected skin regions were the face, followed by the trunk, ears, neck, limbs, and genitals. In 16 of these cases, the disease presented as a single lesion. IHC staining of sections showed that IgG was positive (≥ 10 cells/High-Power Field [HPF]) in 22 cases, while IgG4 was positive (≥ 10 cells/HPF) in 18 cases. Moreover, the IgG4/IgG proportion ranged from 1.7% to 85.7% (mean 29.50 ± 24.67%, median 18.4%) in the 18 cases. Study limitations In the majority of studies, as well as in the current study, the design. RDD is a rare disease, so the sample size is small. In the next studies to come, the authors will expand the sample for multi-center verification and in-depth study. Conclusion The positive rates of IgG4 and IgG and the IgG4/IgG ratio assessed through IHC staining may be important in understanding the pathogenesis of CRDD.

Intimate intertwining of the pathogenesis of hypoxia and systemic sclerosis: A transcriptome integration analysis.

Objectives: Systemic sclerosis (SSc) is an autoimmune disease caused by various pathogenic factors, including hypoxia. Hypoxia stimulates the production of the extracellular matrix to promote fibrosis. However, the integrated function and the underlying mechanism of hypoxia in SSc are unclear. Methods: In the present study, we used Agilent SurePrint G3 Human Gene Expression v3 for the transcriptional sequencing of fibroblasts with and without hypoxia to detect differentially expressed genes (DEGs) in hypoxia. We analyzed the results with the transcriptome data of SSc lesions (GSE95065) to select the co-DEGs. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses were performed on the basis of the co-DEGs using the R package ClusterProfiler, which showed that hypoxia and cross talk of hypoxia with other pathogenic factors are involved in the pathogenesis of SSc. Furthermore, we constructed a protein-protein interaction (PPI) network of co-DEGs and screened two significant functional expression modules. Results: We identified nine hub genes (ALDH1A1, EGF, NOX4, LYN, DNTT, PTGS2, TKT, ACAA2, and ALDH3A1). These genes affect the pentose phosphate pathway, oxidative stress, and lipolysis. Conclusion: Our study provides insights into the mechanisms underlying the effects of hypoxia on SSc pathogenesis, which will help to better understand SSc pathogenesis and develop new therapeutic strategies for SSc.

Bullous lichen sclerosus-generalized morphea overlap syndrome improved by tofacitinib.

We here report a case of a middle-aged man with an unusual case of bullous lichen sclerosus complicated with generalized morphea. He showed initial recurrent flaccid bullae, followed by ivory-white sclerotic plaques and extensive skin sclerosis, with additional walking disorder caused by knee-joint contracture, and ulcers on the lower extremities and back. The patient had no visceral involvement. After oral hydroxychloroquine and oral corticosteroids failed, the patient was given tofacitinib, which resolved his ulcers after 4 weeks and ameliorated his knee-joint contracture and skin sclerosis within 4 months. Owing to the occurrence of diffuse large B-cell lymphoma, he stopped using tofacitinib, and the ulcer and walking disorder reappeared. This is rare case of bullous lichen sclerosus-generalized morphea overlap syndrome. The patient recovered well after treatment with tofacitinib. His symptoms recurred after discontinuation of tofacitinib.

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.

Esomeprazole alleviates fibrosis in systemic sclerosis by modulating AhR/Smad2/3 signaling.

Systemic sclerosis (SSc) is a connective tissue disease with the involvement of complex signaling pathways, such as TGF-ß/Smad2/3. SSc can lead to severe multiple organ fibrosis, but no effective therapy is currently available because of its unclear pathogenesis. Exploring new treatments is the focus of recent research on SSc. Recent studies have implied a potential antifibrotic role of esomeprazole (ESO), but with currently unidentified mechanisms. Signaling of AhR, a ligand-dependent transcription factor, has been described as a key controller of fibrosis, tumorigenesis, and immune balance. Recently, it has been reported that ESO may be an exogenous agonist of AhR signaling, while no previous study has revealed the effects of ESO on SSc and its underlying mechanisms. In this study, we demonstrate that ESO suppresses the migration of SSc dermal fibroblasts, downregulates profibrotic markers, including COLIA1, α-SMA CTGF and MMP1, and limits collagen production potentially via the activation of AhR signaling. More importantly, ESO could block Smad2/3 phosphorylation concurrently with the reduction in collagen via AhR signaling. Moreover, our results from the bleomycin (BLM)-induced SSc model in skin and lung shows that ESO ameliorates fibrosis in vivo, which in keeping with our in vitro results. We conclude that ESO is a potential therapeutic drug for SSc fibrosis.

Nonsense Suppression Therapy: An Emerging Treatment for Hereditary Skin Diseases.

Nonsense mutations cause the premature termination of protein translation via premature termination codons (PTCs), leading to the synthesis of incomplete functional proteins and causing large numbers of genetic disorders. The emergence of nonsense suppression therapy is considered to be an effective method for the treatment of hereditary diseases, but its application in hereditary skin diseases is relatively limited. This review summarizes the current research status of nonsense suppression therapy for hereditary skin diseases, and discusses the potential opportunities and challenges of applying new technologies related to nonsense suppression therapy to dermatology. Further research is needed into the possible use of nonsense suppression therapy as a strategy for the safer and specific treatment of hereditary skin diseases.

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.

Successful management of giant condyloma acuminatum of vulva with the combination of surgery and photodynamic therapy: Report of two cases.

Patients with condylomata acuminata of the vulva usually have increased difficulty to achieve complete response to treatment and also have a higher risk for disease recurrence. Treatment for this disease varies, including surgical excision, cryotherapy, electrocautery, CO2 laser therapy, topical therapy, and photodynamic therapy (PDT), but none of these alone provides a satisfactory outcome, especially for giant condyloma acuminatum (GCA). We reported two cases of GCA successfully cured with surgical removal, electrocautery and photodynamic therapy.

Safety and efficacy of Rituximab in systemic sclerosis: A systematic review and meta-analysis.

PURPOSE: Rituximab is widely prescribed to treat systemic sclerosis (SSc) by the depletion of pathogenic B cells. Nonetheless, the clinical benefit of Rituximab in SSc remains contentious. This meta-analysis was conducted to systematically evaluate the safety and efficacy profile of Rituximab in SSc patients. PATIENTS AND METHODS: We performed a systematic online query in PubMed, Cochrane, and Web of Science. The available studies on the use of Rituximab in SSc patients were comprehensively reviewed and investigated. RESULTS: In total, 14 studies, including 597 participants, were analyzed. Pooled results showed the long-term improvement in the modified Rodnan skin score (mRSS) for skin function (ΔmRSS: 7.00 at 6 months, 9.70 at 12 months, and 10.93 at 24 months), while forced vital capacity (FVC) (ΔFVC: -0.69 at 6 months, -2.62 at 12 months, and -0.67 at 24 months) and diffusing capacity of the lungs for carbon monoxide (DLCO) (ΔDLCO: -2.39 at 6 months, -3.28 at 12 months, and -0.79 at 24 months) for lung function remained stable in SSc patients after Rituximab treatment. The rate of Rituximab-related adverse events was 12% in the pooled results. CONCLUSION: The pooled results of this meta-analysis indicated that Rituximab is well tolerated, and it is able to improve cutaneous function and stabilize pulmonary function in SSc patients.

Oncolytic virotherapy, alone or in combination with immune checkpoint inhibitors, for advanced melanoma: A systematic review and meta-analysis.

BACKGROUND: Advanced melanoma, one of the most lethal forms of skin cancer, remains a difficult condition to treat, despite the substantial scientific progression in cancer treatment. Oncolytic virotherapy (OV), either alone or combined with immune checkpoint inhibitors (ICIs), has often been administrated in an attempt to cure this malignancy. However, the clinical outcomes dramatically vary among different reports. METHODS: In this study, we performed a meta-analysis to evaluate the clinical efficacy and safety profile of OV, combined with ICIs in some cases, in advanced melanoma patients. The original clinical studies were identified based on the online query in PubMed, Cochrane, and Web of Science before December 30, 2018. RESULTS: A total of 18 publications involving 1472 patients were included for the final meta-analysis. The data concerning objective response rate (ORR) and incidence rate of severe immune-related adverse events (irAEs) were extracted accordingly from the text or supplementary materials. The results illustrated that a single treatment of OV could generate a 25% ORR for advanced melanoma, and the ORR could be improved to 45% if combined with ICIs. Further analysis demonstrated that the introduction of ICIs in OV could increase the incidence rate of severe irAEs (AE ≥ 3) from 12% to 39%. However, the rate attributed to OV remains at 12% in the combination group. CONCLUSION: The clinical efficacy of OV can be significantly improved by ICIs even though more onerous burden will be exerted simultaneously on the safety profile.

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.

Dissecting cellulitis of the scalp successfully treated with ALA-PDT: Case report.

A case of recalcitrant dissecting cellulitis of the scalp (DCS) in a 23-year-old male patient was treated with 4 times of topical ALA-PDT at intervals of 10-15 days. The patient responded well without any unbearable adverse effects and presented satisfactory effects. Before applying this therapy, the patient and his doctors had tried other methods, specifically glucocorticoids, intradermal injection, and even surgical treatment, but none of them had presented satisfactory effects. This suggests that topical ALA-PDT could be an effective and safe alternative for DCS patients who are refractory to other standard therapies.