Double-negative T cells ameliorate psoriasis by selectively inhibiting IL-17A-producing γδlow T cells.

BACKGROUND: Psoriasis is a chronic immune-mediated skin condition. Although biologic treatments are effective in controlling psoriasis, some patients do not respond or lose response to these therapies. Thus, new strategies for psoriasis treatment are still urgently needed. Double-negative T cells (DNT) play a significant immunoregulatory role in autoimmune diseases. In this study, we aimed to evaluate the protective effect of DNT in psoriasis and explore the underlying mechanism. METHODS: We conducted a single adoptive transfer of DNT into an imiquimod (IMQ)-induced psoriasis mouse model through tail vein injection. The skin inflammation and IL-17A producing γδ T cells were evaluated. RESULTS: DNT administration significantly reduced the inflammatory response in mouse skin, characterized by decreased skin folds, scales, and red patches. After DNT treatment, the secretion of IL-17A by RORc+ γδlow T cells in the skin was selectively suppressed, resulting in an amelioration of skin inflammation. Transcriptomic data suggested heightened expression of NKG2D ligands in γδlow T cells within the mouse model of psoriasis induced by IMQ. When blocking the NKG2D ligand and NKG2D (expressed by DNT) interaction, the cytotoxic efficacy of DNT against RORc+IL17A+ γδlow T cells was attenuated. Using Ccr5-/- DNT for treatment yielded evidence that DNT migrates into inflamed skin tissue and fails to protect IMQ-induced skin lesions. CONCLUSIONS: DNT could migrate to inflamed skin tissue through CCR5, selectively inhibit IL-17-producing γδlow T cells and finally ameliorate mouse psoriasis. Our study provides feasibility for using immune cell therapy for the prevention and treatment of psoriasis in the clinic.

Comparison of the efficacy and safety of picosecond Nd:YAG laser (1,064 nm), picosecond alexandrite laser (755 nm) and 2% hydroquinone cream in the treatment of melasma: A randomized, controlled, assessor-blinded trial.

Background: Increasing numbers of studies demonstrated that picosecond lasers (Picos) were effective and safe for melasma. However, A limited number of randomized controlled trials (RCTs) regarding Picos contribute to a modest level of evidence. Topical hydroquinone (HQ) remains to be the first-line therapy. Objective: To compare the efficacy and safety of non-fractional picosecond Nd:YAG laser (PSNYL), non-fractional picosecond alexandrite laser (PSAL), and 2% HQ cream in the treatment of melasma. Method: Sixty melasma patients with Fitzpatrick skin types (FST) III-IV were randomly assigned to the PSNY, PSAL, and HQ groups at a 1:1:1 ratio. Patients in PSNYL and PSAL groups received 3 laser sessions at 4-week intervals. The 2% HQ cream was applied twice daily for 12 weeks in patients of the HQ group. The primary outcome, the melasma area and severity index (MASI) score, was evaluated at weeks 0, 4, 8, 12, 16, 20, and 24. The patient assessment score by quartile rating scale was rated at weeks 12, 16, 20, and 24. Results: Fifty-nine (98.3%) subjects were included in the analysis. Each group showed significant change from baseline in MASI scores from week 4 to week 24. The MASI score in the PSNYL group showed the greatest reduction compared to the PSAL group (p = 0.016) and HQ group (p = 0.018). The PSAL group demonstrated comparable MASI improvement as the HQ group (p = 0.998). The PSNYL group had the highest patient assessment score, followed by the PSAL group and then the HQ group, although only the differences between PSNYL and HQ groups at weeks 12 and 16 were significant. Four patients (6.8%) experienced recurrence. Other unanticipated events were transient and subsided after 1 week to 6 months. Conclusion: The efficacy of non-fractional PSNYL was superior to that of non-fractional PSAL, which was not inferior to 2% HQ, thus non-fractional Picos providing an alternative for melasma patients with FSTs III-IV. The safety profiles of PSNYL, PSAL, and 2% HQ cream were similar. Clinical Trial Registration: https://www.chictr.org.cn/showprojen.aspx?proj=130994, ChiCTR2100050089.

D-Mannose Suppresses γδ T Cells and Alleviates Murine Psoriasis.

Psoriasis is a chronic skin disorder associated with multiple sequelae, such as psoriatic arthritis and cardiovascular diseases. Increasing evidence has shown that γδ T cells, as sources of IL-17A, play critical roles in psoriatic inflammations. However, there still lack effective ways to manipulate these pathogenic γδ T cells, which are less well studied than αß T cells. The present study aims to characterize the phenotype of γδ T cells and evaluate the impact of D-mannose (a C-2 epimer of glucose) on γδ T cell-mediated psoriasis. We found that skin-draining LN γδ T cells underwent robust proliferation and acquired an IL-17-producing phenotype during psoriasis. The transcriptomic profiles of these psoriatic γδ T cells had elevated glycolytic signatures. Importantly, D-mannose treatment suppressed the γδ T cell reaction and successfully alleviated the local and systematic inflammation induced by imiquimod. The decreased AKT/mTOR/HIF-1α signaling and glycolytic ability may contribute to the suppression of γδ T cells achieved by D-mannose. Our study increased understanding of γδ T cells in psoriasis and promoted D-mannose utilization as a potential clinical application for autoimmune diseases driven by γδ T cells.

Efficacy of photodynamic therapy for the treatment of Bowen's disease: An updated systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: This is a systematic review and meta-analysis on the effectiveness of Photodynamic Therapy (PDT) in Bowen's Disease (BD), with further summary of the data from all randomized controlled trials (RCTs). METHODS: Relevant data were extracted after conducting a literature search via PubMed, Embase, Scopus, the Cochrane Library, CNKI, and Wanfang databases, from inception until 31 July 2019. Meta-analyses of the data were performed using RevMan V.5.3. A total of 392 published RCTs related to the efficacy of PDT in BD treatment were identified. The papers were screened for duplicates and excluded based on title and abstract. Subsequently, 85 full-text articles were thoroughly reviewed and finally, data from 446 patients with 1147 skin lesions across 12 eligible studies were collated. RESULTS: Our findings revealed significant differences between the efficacies of PDT and other treatments, where a higher lesion reduction rate was observed after the first treatment session following PDT (P < 0.00001, Z = 4.98). PDT was found to be more effective than 5-fluorouracil (P < 0.00001, Z = 4.42) and cryotherapy (P = 0.008, Z = 2.67). However, there were no significant differences in recurrence rates following treatments with PDT, cryotherapy, and 5-fluorouracil. CONCLUSIONS: This systematic review and meta-analysis confirms and collates data from all RCTs pertaining to the efficacy of PDT for BD treatment. Our study has reiterated that PDT is more effective than 5-fluorouracil and cryotherapy for the treatment of BD.

Clinical characteristics and prognosis of acquired perforating dermatosis: A case report.

Acquired perforating dermatosis (APD) is an uncommon skin disease characterized by umbilicated hyperkeratotic lesions, and involves the transepidermal elimination of dermal components, including collagen and elastic fibers. The disease can affect patients with systemic disorders, especially those with chronic renal failure or diabetes mellitus. The current paper described four cases of patients with APD and investigated the clinical characteristics and prognosis of APD, as well as its possible link with systemic disorders. In each of the four cases, the patient had systemic disorders before the onset of APD, three had concomitant renal and thyroid disorders and one had hepatocirrhosis secondary to chronic hepatitis C. The results of the present study showed that APD occurred after the transient worsening of the original systemic disease. Furthermore, it was revealed that dermatosis symptoms were alleviated upon remission of the original systemic disorder, without specific dermatological treatment. Dermatosis symptoms improved in all four patients, indicating that the management of the associated systematic diseases was essential for the successful clinical outcomes of APD.

Long noncoding RNA LINC00520 prevents the progression of cutaneous squamous cell carcinoma through the inactivation of the PI3K/Akt signaling pathway by downregulating EGFR.

BACKGROUND: Long noncoding RNAs (lncRNAs) play pivotal roles in various malignant tumors. Epidermal growth factor receptor (EGFR) signaling is associated with the pathogenesis of cutaneous squamous cell carcinoma (cSCC). This study aimed to explore the role of LINC00520 in the development of cSCC via EGFR and phosphoinositide 3-kinase-protein kinase B (PI3K/Akt) signaling pathways. METHODS: A microarray analysis was applied to screen differentially expressed lncRNAs in cSCC samples. The A431 cSCC cell line was transfected and assigned different groups. The expression patterns of LINC00520, EGFR, and intermediates in the PI3K/Akt pathway were characterized using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting analysis. Cell proliferation, migration, and invasion were detected using the MTT assay, scratch test, and Transwell assay, respectively. Cell-based experiments and a tumorigenicity assay were conducted to assess the effect of LINC00520 on cSCC progression. This study was ended in September 2017. Comparisons between two groups were analyzed with t-test and comparisons among multiple groups were analyzed using one-way analysis of variance. The nonparametric Wilcoxon rank sum test was used to analyze skewed data. The enumerated data were analyzed using the chi-square test or Fisher exact test. RESULTS: Data from chip GSE66359 revealed depletion of LINC00520 in cSCC. Cells transfected with LINC00520 vector and LINC00520 vector + si-EGFR showed elevated LINC00520 level but decreased levels of the EGFR, PI3K, AKT, VEGF, MMP-2 and MMP-9 mRNAs and proteins, and inhibition of the growth, migration and adhesion of cSCC cells, while the si-LINC00520 group showed opposite trends (all P < 0.05). Compared with the LINC00520 vector group, the LINC00520 vector + si-EGFR group showed decreased levels of the EGFR, PI3K, AKT, VEGF, MMP-2 and MMP-9 mRNAs and proteins, and inhibition of the growth, migration and adhesion of cSCC cells, while the LINC00520 vector + EGFR vector group showed opposite results (all P < 0.05). CONCLUSION: Based on our results, LINC00520-targeted EGFR inhibition might result in the inactivation of the PI3K/Akt pathway, thus inhibiting cSCC development.

Daylight versus conventional photodynamic therapy for the treatment of actinic keratosis: A meta-analysis of randomized controlled trials.

Daylight photodynamic therapy (dPDT) is suggested to be effective for actinic keratosis (AK). We performed a meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of dPDT versus conventional photodynamic therapy (cPDT) in patients with AK. Relevant studies were identified through a systematic search of PubMed, Embase, and the Cochrane Library. A fixed or random effect model was applied, depending on the heterogeneity. Six RCTs with 369 patients with 5,556 AK lesions that were undergoing dPDT or cPDT with red light and methyl aminolevulinate (MAL) were included. Overall, the incidence of complete response (CR) was not significantly different between the two groups (risk ratio [RR]: 0.93, p = 0.07). Subgroup analyses indicated that dPDT was non-inferior to cPDT for CR in studies only included grade III AK lesions (RR: 0.97, p = 0.41), but less effective for CR in studies which also included grade III lesions (RR = 0.87, p < 0.001). Subsequent meta-analyses showed that dPDT was associated with a significantly reduced maximal pain score (mean difference = -4.51, p < 0.001) and a lower risk of adverse events (RR = 0.70, p < 0.001) as compared with cPDT. These results suggested although dPDT was better tolerated, the treatment efficacy of dPDT is non-inferior to cPDT with red light and MAL only in grade III AK lesions. The relative therapeutic efficacy of dPDT in AK of grade III lesions in comparison with cPDT should be further evaluated.

Ablative fractional carbon dioxide laser combined with intense pulsed light for the treatment of photoaging skin in Chinese population: A split-face study.

Intense pulsed light (IPL) is effective for the treatment of lentigines, telangiectasia, and generalized erythema, but is less effective in the removal of skin wrinkles. Fractional laser is effective on skin wrinkles and textural irregularities, but can induce postinflammatory hyperpigmentation (PIH), especially in Asians. This study evaluated the safety and efficacy of ablative fractional laser (AFL) in combination with IPL in the treatment of photoaging skin in Asians.This study included 28 Chinese women with Fitzpatrick skin type III and IV. The side of the face to be treated with IPL alone (3 times) or AFL in combination with IPL (2 IPL treatments and 1 AFL treatment) was randomly selected. Skin conditions including hydration, transepidermal water loss, elasticity, spots, ultraviolet spots, brown spots, wrinkle, texture, pore size and red areas, as well as adverse effects were evaluated before the treatment and at 30 days after the treatment.Compared with IPL treatment alone, AFL in combination with IPL significantly increased elasticity, decreased pore size, reduced skin wrinkles, and improved skin texture (P = .004, P = .039, P = .015, and P = .035, respectively). Both treatment protocols produced similar effects in relation to the improvement of photoaging-induced pigmentation. The combined therapy did not impair epidermal barrier function. No postoperative infection, hypopigmentation, or scarring occurred after IPL and AFL treatments. PIH occurred at 1 month after AFL treatment and disappeared at 30 days after completion of the combined therapy.AFL in combination with IPL is safe and effective for photoaging skin in Asians.

Successful treatment of erythema induratum with topical application of antituberculous drugs: A case report.

RATIONALE: Erythema induratum, a chronic recurrent lobular panniculitis with vasculitis, is strongly associated with Mycobacterium tuberculosis infection. The recommended drugs include isoniazid, rifampicin, and pyrazinamide, which are typically administered in combination (orally or intravenously). Till date, there are no reports about topical application of anti-tuberculous (anti-TB) drugs for treatment of erythema induratum. PATIENT CONCERNS: Herein, we present the case of a 73-year-old woman with recurrent ulceration, scarring and obvious pain in her lower legs. DIAGNOSES: She was diagnosed of erythema induratum. INTERVENTIONS: Topical anti-TB treatment (3.75% isoniazid twice a day) was necessitated by the development of severe gastrointestinal upset and significant reduction in platelets after oral treatment with isoniazid and rifampicin. OUTCOMES: The skin lesions showed improvement at one month and remitted mostly at two months. After 6 months, the skin lesions have subsided and no obvious side effects were observed. LESSONS: Our experience may help expand the therapeutic regimens for cutaneous tuberculosis, and provide physicians with alternative options for management of tuberculosis.

Retrospective Analysis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in 88 Chinese Patients.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases with high mortality rates. This study was designed to analyze the pathogenic factors, clinical manifestations, complications, treatment, and prognosis of SJS/TEN and to explore the differences between surviving and deceased patients. METHODS: SJS/TEN patients admitted to Beijing Friendship Hospital from January 2006 to December 2015 were included in the study. Patients' data were retrospectively analyzed. Comparative studies were performed on the survival group and the deceased group, and Fisher's exact probability test was used for statistical analysis. RESULTS: Among the 88 patients included, 40 (45.5%) were male with a mean age of 45 ± 18 years. Forty-eight (54.5%) had SJS, 34 (38.6%) had SJS/TEN, and 6 (6.8%) had TEN. Fifty-three (60.2%) cases were caused by medications, mainly antibiotics (n = 24) followed by traditional Chinese medicines (n = 7). Forty-two cases (47.7%) developed visceral damage. Eighty-two patients improved or recovered and were discharged from hospital, and six patients died. Comparative studies on the survival group and the deceased group showed that the presence of malignant tumor ( χ2 = 27.969,P < 0.001), connective tissue diseases ( χ2 = 9.187, P= 0.002), previous abnormal liver/kidney functions ( χ2 = 6.006, P= 0.014), heart rate >100 times/min ( χ2 = 6.347, P= 0.012), detached skin area >20% ( χ2 = 5.594, P= 0.018), concurrent mucosal involvement at the mouth, eyes, and external genitals ( χ2 = 4.945, P= 0.026), subsequent accompanying liver/kidney damage ( χ2 = 11.839, P= 0.001, and χ2 = 36.302,P < 0.001, respectively), and SCORTEN score >2 ( χ2 = 37.148,P < 0.001) increased the risk of death. CONCLUSIONS: SJS/TEN is mainly caused by medications, and nearly half of patients develop visceral damage. Multiple factors increase the mortality risk.

Drug Reaction with Eosinophilia and Systemic Symptoms: Retrospective Analysis of 104 Cases over One Decade.

BACKGROUND: Drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe, life-threatening disorder caused by drugs. In the present study, we tried to explore the types of DRESS-inducing drugs, incubation period, features of skin rashes, accompanying visceral damage, and effectiveness of glucocorticoid therapy so as to inform clinical practice. METHODS: Patients diagnosed with a drug-induced rash, dermatitis, and DRESS admitted to our hospital from January 2006 to December 2015 were included in the study. The diagnosis followed the criteria and scoring system set by the European Registry of Severe Cutaneous Adverse Reactions. Statistical analyses were carried out using SPSS version 17.0 (IBM, Armonk, NY, USA), and a value of P < 0.05 was considered statistically significant. RESULTS: Among 104 patients, 38 were male and 66 female (aged 18-83 years). The latent period was 13 (interquartile range [IQR]: 10-17) days. The most common allergy-inducing drugs were antibiotics (n = 37, 35.6%), followed by antiepileptic drugs and traditional Chinese medicines (TCMs). Eighty-two cases (78.8%) had rash with area >50% body surface area (BSA). Liver damage occurred in 90% of cases. Patients were divided into oral antihistamine group and glucocorticoid/immunosuppressive agent/intravenous immunoglobulin (IVIG) group. Sex, age, incubation period, duration of hospital stay, and the number of patients with body temperature ≥38.5°C were not significantly different between the two groups. However, the number of patients meeting the criteria of "definite" and "probable" (χ2 = 5.852, P = 0.016), with an eosinophilic granulocyte count of ≥1.5 × 109/L (χ2 = 7.129, P = 0.008), and with rash area of >50% BSA (χ2 = 4.750, P = 0.029), was significantly different. CONCLUSIONS: Antibiotics were associated with allergic reactions, but TCMs also had an important role. Allergy resulting from repeat use of the same drug was more severe with a shorter incubation period. The most typical rash was widespread erythematous papules. Liver damage accounted for >90% of cases.

Ultraviolet B light-induced apoptosis in human keratinocytes enriched with epidermal stem cells and normal keratinocytes.

BACKGROUND: The stem-cell compartment is the primary target for the accumulation of oncogenic mutations. Overexposure to solar ultraviolet radiation is responsible for the development and progression of > 90% of skin cancers. Ultraviolet B (UVB) light-induced keratinocyte apoptosis is a strong preventive mechanism against carcinogenesis. The aim of this study was to isolate keratinocytes enriched with putative human epidermal stem cells and to investigate their apoptotic induction by UVB. METHODS: Keratinocytes enriched with putative human epidermal stem cells were isolated by adherence to collagen IV and the expressions of ß1-integrin and p63 were investigated. Keratinocytes enriched with putative human epidermal stem cells and normal keratinocytes were irradiated with UVB at 0 - 80 mJ/cm(2). The apoptotic response was investigated with phase-contrast microscopy, Hoechst 33342 staining, flow cytometry of annexin V/PI, and procaspase-3 Western blotting. RESULTS: Keratinocyte enriched with stem cells expressed high levels of p63 protein and ß1-integrin and low level of pan-keratin (C11). In comparison to non-irradiated cells, significant apoptosis of keratinocyte enriched with stem cells was found with 40 and 80 mJ/cm(2) UVB. However, significant apoptosis of normal keratinocytes was only found for 80 mJ/cm(2) UVB. CONCLUSIONS: Human epidermal stem cells can undergo apoptosis in response to UVB radiation and are more susceptible than other keratinocytes. The method could be used in vitro studies of human epidermal stem cells.

[Effects of intense pulse light on the mRNA expression of type I procollagen in human fibroblasts].

OBJECTIVE: To investigate the effects of intense pulse light (IPL) on the mRNA expression of type I procollagen in human fibroblasts. METHODS: Four healthy female subjects aged 19 - 41, underwent IPL on the back skin 3 times with an interval of 2 weeks. Before the IPL and after 1, 2, and 3 times of treatment samples of back skin were obtained to undergo real time quantitative PCR to detect the mRNA expression of type I procollagen. RESULTS: The mRNA expression level of type I procollagen after one time of IPL treatment was [(4.7 +/- 1.0) x 10(-4)], not significantly different from that before treatment [(2.1 +/- 0.7) x 10(-4), P = 0.100]. The mRNA expression levels of type I procollagen after treatment for 2 times and 3 -time were (7.9 +/- 1.7) x 10(-4) and (11.1 +/- 2.4) x 10(-4) respectively, both significantly higher than that before treatment (both P < 0.05). CONCLUSION: Promoting the mRNA transcription of type I procollagen in dermal fibroblasts, IPL therapy is effective in dermal remodeling and wrinkle removing.