Melatonin Attenuates Imiquimod-Induced Psoriasis-Like Inflammation and Restores the Th17/Treg Immune Balance.

Psoriasis is a common immune-mediated skin disease characterized by abnormally reactive inflammation and epidermal hyperplasia. Previous studies have shown melatonin (MLT) has powerful anti-inflammatory effects. The mechanisms that MLT regulates psoriasis-associated skin inflammation remain unclear. Here, in imiquimod-induced psoriasis-like mice, MLT supplementation reduced skin inflammation and corrected the Th17/Treg cell imbalance. Network pharmacology and proteome sequencing analyses revealed that MLT attenuates the inflammatory response in the skin of psoriatic mice by inhibiting the PI3K/Akt signaling pathway. Overall, the data suggest that MLT has a protective effect against psoriasis-like inflammation.

An empirical study on 'how to retain rural teachers with emphasis on hygiene or motivation factors': A case of Western China.

How to retain prominent teachers is a fundamental problem for rural education in less developed countries. However, the critical institutional factors affecting teachers' turnover intention still need to be better understood. According to Herzberg's motivation-hygiene theory, this study examines the effects of hygiene factors (rural incentive policy, personnel policy, and teacher pay) and motivation factors (advancement, work itself, and achievement) on rural teachers' turnover intention. Based on a sample of 973 rural teachers, the results from structural equation modeling (SEM) showed that both hygiene factors and motivation factors can significantly reduce the turnover intention of rural teachers. Meanwhile, the effect of motivation factors is greater than that of hygiene factors. It was also confirmed that marital status, age, and teaching subject have a significant moderation effect on the relationship between motivation/hygiene factor and turnover intention, whereas gender has no significant moderation effect. Theoretical and practical implications for attracting and retaining rural teachers are discussed.

Successful treatment of epidermolysis bullosa pruriginosa by dupilumab.

Epidermolysis bullosa pruriginosa (EBP) is a rare variant of dystrophic epidermolysis bullosa caused by COL7A1 gene mutation. Intense pruritus and nodular prurigo-like lesions are the main features of the disease. To date, the treatment strategies for this condition are not well established. Recent studies have indicated that type 2 inflammation plays a role in the pathophysiology of EBP, suggesting Th2 cytokines could be potential therapeutic targets. In this prospective case series study, we reported three patients with EBP, diagnosed by clinical manifestations, histopathological evaluations, and genetic sequencing, two of whom were treated with dupilumab for 20 weeks. Results showed that the clinical symptoms, pruritus, and quality of life of the patients were significantly improved, as measured by the Epidermolysis Bullosa Disease Activity and Scarring Index, the Visual Analog Scale, and the Children's Dermatology Life Quality Index. Serum immunoglobulin E levels also fell gradually over the 20-week treatment period. Immunotyping of Th1/2/17 cell subsets in peripheral blood by flow cytometry revealed a higher Th2 but parallel Th1 and Th17 cell subsets in patients compared to healthy controls, and a significant decrease in Th2 and an increase in Th17 cells after dupilumab administration. Of note, after 20 weeks of dupilumab treatment, the expression of type VII collagen in the basement membrane of the skin lesion of the patients significantly increased, which was evidenced by immunofluorescence analysis. No treatment-related adverse events were documented. Taken together, targeting type 2 inflammation with dupilumab may be an effective and safe treatment option for EBP.

Dupilumab improves clinical symptoms in children with Netherton syndrome by suppressing Th2-mediated inflammation.

Background: Netherton syndrome is a rare, life-threatening autosomal recessive genetic disorder with no effective treatment yet. Skin barrier dysfunction caused by SPINK5 gene mutations is a hallmark of the disease. Antigen penetration through the defective skin and nonspecific inflammation provide a pro-T helper 2 (Th2) immune microenvironment in the disease. Therefore, Th2 cytokines are considered to be candidate therapeutic targets. Objective: To evaluate the clinical responses of patients with Netherton syndrome to dupilumab, an IL-4Rα antagonist, and identify changes in the Th1/2/17 pathway activity, skin barrier defect protein LEKTI expression after treatment. Methods: Four children with severe Netherton syndrome (aged 2 y to 4 y and 6 m) who were treated with dupilumab from January to June 2022 were evaluated at baseline, and at 4, 8, 12, 16, and 20 weeks after the start of dupilumab administration. Treatment response was assessed using the Eczema Area and Severity Index (EASI), the Numerical Rating Scale (NRS), the Dermatology Life Quality Index (CDLQI), and the Dermatitis Family Impact-questionnaire (DFI). Blood eosinophil counts, serum IgE levels and inflammatory cytokines were measured. The immunotyping of Th1/2/17 cells was performed by flow cytometry and cytokine expressions in T cell subsets were analyzed by single-cell RNA sequencing. In addition, expression of the LEKTI in skin lesions was evaluated by immunohistochemical analysis. Results: All four patients experienced clinical improvement, with significantly reduced EASI scores (by 75.0-83.9%) and NRS (by 87.5-90.0%) from baseline to 20 weeks of treatment. Improved quality of life scores were also seen for all patients, as measured by CDLQI and DFI. Serum IgE levels also fell by 75.6-86.9%. The serum Th2 cytokines IL-4, IL-5 and IL-13 were found at low level, with no significant changes during the treatment. However, Th2 cytokines expressed by T cells, especially IL-4, decreased at single-cell level after treatment (P = 0.029). The baseline percentage of Th2 cells (among total CD3+CD4+ T cells) was significantly higher in patients than that in healthy controls (HC) (P < 0.0001); this percentage fell from 8.25% ± 0.75% to 4.02% ± 0.62% after 20 weeks dupilumab treatment. There was no noticeable change in LEKTI protein expression in skin lesions pre- and post-treatment. Two patients reported mild ocular adverse effects, but there were no severe adverse events. Conclusion: Dupilumab may be an effective and safe treatment option in a subset of pediatric patients with Netherton syndrome, especially in improving itch and the quality of life. These effects were achieved in part by suppression of the Th2-mediated inflammation.

IL-21 Rescues the Defect of IL-10-Producing Regulatory B Cells and Improves Allergic Asthma in DOCK8 Deficient Mice.

Mutations in human DOCK8 cause a combined immunodeficiency syndrome characterized by allergic diseases such as asthma and food allergy. However, the underlying mechanism is unclear. Regulatory B (Breg) cells that produce IL-10 exert potent immunosuppressive functions in patients with allergic and autoimmune disorders. DOCK8-deficient B cells show diminished responses to TLR9 signaling, suggesting a possible defect in IL-10-producing Breg cells in those with DOCK8 deficiency, which may contribute to allergies. Here, we isolated peripheral blood mononuclear cells from DOCK8-deficient patients and generated a Dock8 KO mouse model to study the effect of DOCK8 deficiency on Breg cells. DOCK8-deficient patients and Dock8 KO mice harbored quantitative and qualitative defects in IL-10-producing Breg cells; these defects were caused by abnormal Dock8-/- CD4+ T cells. We found that recombinant murine (rm)IL-21 restored the function of Bregs both in vitro and in Dock8 KO mice, leading to reduced inflammatory cell infiltration of the lungs in a murine asthma model. Overall, the results provide new insight into the potential design of Breg-based or IL-21-based therapeutic strategies for allergic diseases, including asthma associated with DOCK8 deficiency.

Crosstalk Between Circulating Follicular T Helper Cells and Regulatory B Cells in Children With Extrinsic Atopic Dermatitis.

Atopic dermatitis (AD) in early childhood is often the initial manifestation of allergic disease associated with high IgE. Accumulating evidences show that follicular helper T (Tfh) cells play a critical role in promoting B cell differentiation and IgE production, human regulatory B (Breg) cells participate in immunomodulatory processes and inhibition of allergic inflammation. However, the roles and interactions between IL-10-producing Breg cells and Tfh cells in childhood AD are unclear. In this study, we found that the percentage of CD19+IL-10+ Breg cells in children with extrinsic AD was significantly lower than that in age-matched healthy controls, and that it correlated negatively with enhanced CD4+CXCR5+PD-1+ICOS+ circulating Tfh cell responses and increased disease activity; however, there was no significant correlation with serum total IgE levels. A co-culture system revealed that Breg cells from patients with extrinsic AD cannot effectively inhibit differentiation of Tfh cells in an IL-10 dependent manner. Abnormal pSTAT3 signaling induced via Toll-like receptors (TLR), but not the B-cell receptor (BCR) signaling, might contribute to the defect of Breg cells in AD. Taken together, these observations demonstrate an important role for IL-10-producing Breg cells in inhibiting Tfh cell differentiation, and suggest that they may participate in the pathogenesis of AD.

Characterization of a Cohort of Patients With LIG4 Deficiency Reveals the Founder Effect of p.R278L, Unique to the Chinese Population.

DNA ligase IV (LIG4) deficiency is an extremely rare autosomal recessive primary immunodeficiency disease caused by mutations in LIG4. Patients suffer from a broad spectrum of clinical problems, including microcephaly, growth retardation, developmental delay, dysmorphic facial features, combined immunodeficiency, and a predisposition to autoimmune diseases and malignancy. In this study, the clinical, molecular, and immunological characteristics of 15 Chinese patients with LIG4 deficiency are summarized in detail. p.R278L (c.833G>T) is a unique mutation site present in the majority of Chinese cases. We conducted pedigree and haplotype analyses to examine the founder effect of this mutation site in China. This suggests that implementation of protocols for genetic diagnosis and for genetic counseling of affected pedigrees is essential. Also, the search might help determine the migration pathways of populations with Asian ancestry.

IL-21 alleviates allergic asthma in DOCK8-knockout mice.

Patients with DOCK8 deficiency are at increased susceptibility to develop allergic diseases such as food allergy and asthma. Here, we aimed to analyze the pathogenesis of asthma in DOCK8-deficient patients. In our mouse model, DOCK8-knockout (KO) mice sensitized with low-dose OVA were challenged with 1.5% OVA to induce allergic asthma. As compared to that in WT mice, remarkable airway hyperresponsiveness was observed in KO mice. Increased inflammatory cells and eosinophils infiltrated in airway lumen in KO mice especially around bronchi. KO mice showed higher levels of serum IgE and OVA-specific IgE and significantly elevated IgE-producing B cells in blood and in spleen. Surprisingly, nasal administration with rmIL-21 significantly reduced the airway hyperresponsiveness, inflammatory infiltration, as well as the serum IgE and IgE-producing B cells. DOCK8-knockout mice are susceptible to low-dose OVA induced allergic airway inflammation and airway hyperresponsiveness. Supplementary nasal administration of rmIL-21 alleviates allergic asthma in this mouse model.

Intraperitoneal injection of IL-4/IFN-γ modulates the proportions of microglial phenotypes and improves epilepsy outcomes in a pilocarpine model of acquired epilepsy.

Recent studies have reported microglia that are activated in the central nervous system (CNS) in patients with temporal lobe epilepsy and animal models of epilepsy. However, limited data are available on the dynamic changes of the proportions of various phenotypes of microglia throughout epileptogenesis and whether IL-4/IFN-γ administration can modulate the proportions of microglial phenotypes to affect the outcome of epilepsy. The current study examined this issue using a mouse model of pilocarpine-induced epilepsy. Flow cytometry showed that classically activated microglia (M1) and alternatively activated microglia (M2) underwent variations throughout the stages of epileptogenesis. The altered trends in the microglia-associated cytokines IL-1ß, IL-4, and IL-10 paralleled the changes in phenotype proportions. We found that intraperitoneal injections of IL-4 and IFN-γ, which have been reported to modulate the phenotypes of microglia in vitro, also affected the proportion of microglia in vivo. In addition, correctly timing the modulation of the proportion of microglia improved the outcomes of epilepsy based on the reduced frequency, duration, and severity of spontaneous recurrent seizures (SRS) and increased the performances of the mice in the Morris water maze. This study is the first to report altering the proportion of microglial phenotypes in pilocarpine-induced epileptogenesis. Intraperitoneal injection of IL-4/IFN-γ could be used to modulate the proportions of the types of microglia, and epilepsy outcomes could be improved by correctly timing this modulation of phenotypes.

Molecular and immunological characterization of DNA ligase IV deficiency.

DNA ligase IV (LIG4) deficiency is an extremely rare autosomal recessive primary immunodeficiency disease caused by the LIG4 mutation. To date, fewer than 30 cases of patients have been reported worldwide. No reversion mutations have been previously identified in LIG4. This study enrolled seven Chinese patients with LIG4 deficiency who presented with combined immunodeficiency, microcephaly, and growth retardation. One patient (P1) acquired non-Hodgkin lymphoma. Four patients had impaired T cell proliferation function and skewed T cell receptor diversity. Five novel mutations in LIG4 and a potential hotspot mutation (c.833G>T; p.R278L) in the Chinese population were identified. TA cloning analysis of T cells, NK cells, granulocytes, and oral mucosa cells in P6 revealed wild-type clones and clones that contained both maternally and paternally inherited mutations, indicating possible somatic reversion which need further investigation since no functional or protein assays were possible for all the patients died and no cell lines were available.