课程文献中心 更多>>

关键词： atopic dermatitis   basophils   benralizumab   CD125   eosinophils   mast cells  

摘要： Background Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by tissue eosinophilia and itch. We evaluated the effect of eosinophil depletion with benralizumab on markers of inflammation in the skin of patients with AD. Methods After a 4-week washout from oral anti-inflammatory medications 20 patients with moderate to severe AD completed a randomized, double-blind, placebo-controlled parallel-group study comparing 3 doses q4wk 30 mg subcutaneous benralizumab to placebo. Lesional and unaffected skin biopsies were collected before and after 28 and 65 days of treatment, respectively, for quantification of eosinophils and IL-5R alpha-bearing cells in papillary dermis. Histological measurements of epidermal thickness, spongiosis, neutrophilic and lymphocytic infiltration, as well as clinical scores EASI, SCORAD, IGA, DLQI, and POEM were conducted throughout the study. Outcomes were compared between placebo and benralizumab treatment groups using a Mann-Whitney U-test. Results Benralizumab, compared to placebo, reduced IL-5R alpha+ cells and MBP+ EG2+ eosinophils in lesions and unaffected skin (p < 0.05). In skin lesions, benralizumab reduced MBP+ eosinophils and basophils but had no effect on eosinophil progenitor (EoP;CD34+ IL-5R alpha+) or mast cell numbers. There was no change in other skin histological measurements or IGA scoring of the observational lesion, nor improvement in clinical scores. Conclusion Benralizumab treatment significantly inhibited accumulation of MBP+ eosinophils and basophils in lesional skin of patients with moderate to severe AD. However, a lack of improvement in histological and clinical outcomes suggests that other inflammatory pathways are central to the pathobiology of severe atopic dermatitis.

关键词： angiolymphoid hyperplasia   dupilumab   eosinophils  

关键词： dorsal root ganglion   interleukin-1β   interleukin-6   macrophage   neurogenic inflammation   psoriasis  

摘要： Neuroimmunological mechanisms are essential for maintaining bodily homeostasis. Abnormal activation of these mechanisms is significantly linked to various skin disorders and constitutes a significant component in the development of these diseases. However, the involvement of neuroimmunological interactions in psoriasis pathogenesis is not yet fully understood. In this study, we identify the peripheral nervous system as a significant source of interleukin-6 (IL-6), which contributes to skin inflammation and acts as a key regulator in the onset and progression of psoriasis. Through single-cell sequencing analysis of mouse dorsal root ganglia (DRG) tissue, we identified a specific group of neurons that secrete IL-6. These neurons exhibited elevated levels of IL-6 expression following treatment with imiquimod (IMQ). Additionally, we observed a reciprocal regulatory relationship between the peripheral nervous system and immune cells. Neuronal activity is tightly controlled by surrounding macrophages. The expression of IL-6 is regulated by the secreted IL-1β upon M1 polarization, and dependent on MAPK signaling. Consequently, IL-6 is secreted from neurons into the skin, exacerbating the development and progression of psoriasis. This study reveals the mechanisms by which sensory neurons regulate psoriasis through IL-6, further clarifying the neuropsychiatric factors involved in the pathogenesis of psoriasis. It offers new insights for the clinical treatment of psoriasis.

关键词： CD69   graft-versus-leukemia   haploidentical hematopoietic stem cell transplantation   IL15   NK cell   pediatric acute leukemia  

摘要： A Phase I/II clinical trial was conducted in pediatric patients with high-risk malignancies to assess the safety and efficacy of NK cell infusion post-haplo-HSCT. Patients received either alloreactive NK cells from KIR/HLA-mismatched donors or IL-15-stimulated NK cells from KIR/HLA-matched donors, across three dose-escalating cohorts. The IL15-NK cell infusion product demonstrated enhanced activating receptor expression and functional capacity. Increased NKG2D expression was observed in NK cells from patients receiving IL15-NK cells. One-year follow-up showed accelerated immune reconstitution in both the allo-NK and IL15-NK cell arms. IL15-NK recipients exhibited a pro-inflammatory cytokine profile (IL-2, IL-4, IL-6, IFN-γ). Elevated CD69 expression was associated with a higher risk of transplant-related complications.

摘要： The gut microbiota and its associated micro-ecosystem are closely related to the onset and development of ulcerative colitis (UC). It is known that Corynebacterium glutamicum (C. glutamicum) helps rebuild gut eubiosis from diabetes dysbiosis;however, its effects on UC remain unknown. This study aims to investigate the therapeutic effects and mechanisms of C. glutamicum on UC. In this study, C. glutamicum was encapsulated with thiolated hyaluronic acid (HA-SH) to form a hydrogel, termed as CG-HA-SH. The adhesion and distribution of CG-HA-SH in the intestine were evaluated, along with its therapeutic effects on UC mice, including its impact on the gut microbiota. Additionally, changes in short-chain fatty acids (SCFAs) in the intestines of UC mice were analyzed, and RNA sequencing (RNA-Seq) was employed to investigate the mechanisms by which C. glutamicum alleviated inflammation. HA-SH enhanced the resistance of C. glutamicum in gastric and intestinal fluids, providing approximately 12 hours of adhesion at colitis inflammation sites. C. glutamicum reduced the levels of pro-inflammatory factors such as IL-1 beta (by 97.31%) and TNF-alpha (by 90.10%) while increasing anti-inflammatory IL-10 levels (by 197.59%) in the colon. It also increased the abundance of E. fissicatena, Muribaculum, and butyrate and enhanced intestinal tight junctions (OCC, by 318.93%) and the mucus barrier (MUC2, by 515.93%). The mRNA levels of cIAP1/2 decreased by 4.33-fold, and their protein expression levels were reduced by 36.97% correspondingly. The enrichment of the TNF pathway was the most significant. Therefore, C. glutamicum exhibited remarkable efficacy in alleviating inflammation and reshaping dysbiotic gut microbiota by downregulating the cIAP1/2-mediated TNF signaling pathway and NF-kappa B signaling pathway. cIAP1 and cIAP2 might serve as effective therapeutic targets.

关键词： DPB1*1491:01   HLA-DPB1   NGS   transplantation  

摘要： HLA-DPB1*1491:01 differs from HLA-DPB1*05:01:01:01 by a non-synonymous nucleotide substitution in Exon 2.

关键词： CPOE reminders   HLA-B*15:02   carbamazepine   pharmacogenomics  

摘要： Carbamazepine (CBZ) is associated with severe cutaneous adverse reactions in individuals carrying the HLA-B*15:02 allele, which is prevalent in Asian populations. Genetic screening before the initiation of CBZ is recommended, yet screening is not always undertaken. To determine the effect of implementing computerized physician order entry (CPOE) reminders on the screening rates of HLA-B*15:02 before CBZ prescription. We conducted a retrospective analysis of 1611 patients who were prescribed CBZ between 2012 and 2023 in a regional hospital in Taiwan. The intervention involved integrating automated HLA-B*15:02 screening reminders into the CPOE system in outpatient settings. Patients were divided into an outpatient (intervention) group and an inpatient (control) group, and their data were analyzed before and after the intervention. Screening rates were compared using Fisher's exact test, and subgroup analyses were conducted on the basis of age group and physician specialty. After the intervention, the outpatient group exhibited an increase in screening rate from 23.7% to 55.6% ( < 0.001). However, no significant change was observed in the inpatient group. Subgroup analysis revealed major improvements among neurologists and patients aged 41-80 years in outpatient settings. Implementing CPOE reminders substantially improves rates of screening for HLA-B*15:02 in outpatient settings, indicating the effectiveness of informatic interventions in enhancing adherence to pharmacogenomic guidelines. Extending such interventions to inpatient settings may further mitigate the risk of CBZ-induced severe cutaneous adverse reactions.

摘要： Psoriasis is a chronic inflammatory skin disease, with the IL-17 pathway being a key contributor. Ym1, a positionally cloned inflammation regulatory gene linked to various disorders, has an unclear effect on skin inflammation. In this study, the role of Ym1 was investigated in both mannan and imiquimod-induced psoriasis-like dermatitis models, using Ym1-deficient congenic mice. Natural polymorphism of Ym1 influenced the development of skin inflammation, dependent on macrophages, since adoptive transferring of Ym1-deficient macrophages alleviated disease, whereas recombinant Ym1 worsened it. Particularly, Ym1 congenic mice exhibited decreased IL-17 production in innate immune cells, and depletion of gamma delta T cells mitigated disease and lowered skin IL-17 levels. Additionally, RNA-seq analysis revealed Ym1-regulated keratinization in lesional skin. Recombination Ym1 directly influenced the inflammatory response and proliferation of mouse primary keratinocytes. Collectively, we conclude that Ym1 regulates gamma delta T cell-derived IL-17 production and keratinocyte functionality, and thereby contributes to skin inflammation in mice.