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关键词： psoriasis   secukinumab   perianal abscess   Crohn's disease   drug-related adverse reactions  

摘要： Secukinumab, a monoclonal antibody targeting interleukin-17A, is effective for treating moderate-to-severe plaque psoriasis but may induce paradoxical inflammatory bowel disease, particularly Crohn's disease. We describe a 41-year-old male with a history of psoriasis who developed new-onset Crohn's disease accompanied by a perianal abscess after prolonged secukinumab treatment. The patient experienced increased bowel movements and postoperative fever, and colonoscopy revealed diffuse colonic inflammation and deep ulcerations;histopathology confirmed chronic active enteritis with epithelioid granulomas. Infectious causes and other differential diagnoses were excluded. Treatment with corticosteroids and mesalamine led to symptom resolution and normalization of inflammatory markers. This case illustrates a rare but important adverse effect of IL-17A inhibition and emphasizes the dual role of IL-17A in promoting skin inflammation while maintaining intestinal homeostasis. Careful evaluation of gastrointestinal history and close monitoring during therapy are essential to prevent and manage potential intestinal complications.

关键词： Autoimmune disease   Gamma Delta T cell   IL-17A   Inflammation   Psoriasis  

摘要： BackgroundPsoriasis, an inflammatory autoimmune disease, arises from intricate interactions between the immune system and epithelium. Recent reports have suggested new roles for gamma delta (gamma delta) T-cells in addition to immune surveillance, however, it remains to be determined whether the mechanisms identified in psoriasis murine models have a similar role in humans. The aim of the present study was to investigate the relationship between IL-17 A mRNA expression levels and gamma delta T-cell frequency in human psoriatic lesions, and to clarify the potential role of gamma delta T-cells in psoriasis *** study involved 20 patients diagnosed with psoriasis and 16 control subjects. Expression of the IL-17 A gene was measured in formalin-fixed paraffin-embedded (FFPE) tissues by RT-PCR method. TCR gamma delta+ immunofluorescence staining was performed to measure the distribution of gamma delta T-cells in the same *** psoriatic lesion biopsies, TCR gamma delta+ T-cell percentage was found higher than the control samples. Additionally, psoriasis patients exhibited elevated levels of IL-17 A gene expression. In addition, this study showed a weak negative correlation between the proportion of gamma delta T-cells and IL-17 A mRNA expression in psoriatic skin *** weak negative correlation between IL-17 A mRNA levels and gamma delta T-cell presence in human psoriasis lesions highlighting the novel effector functions of these cells in psoriasis pathogenesis.

关键词： AA   amino acid   Abx   antibiotics   ADP   adenosine diphosphate   AHR   aryl hydrocarbon receptor   AMP   adenosine monophosphate   ATP   adenosine triphosphate   CD   Crohn’s disease   CITE   cellular indexing of transcriptomes and epitopes   DEG   differentially expressed genes   DN   double negative   ECAR   extracellular acidification rate   GFP   green fluorescent protein   GO   gene ontogeny   IBD   inflammatory bowel disease   IEL   intraepithelial lymphocyte   IFNAR   interferon alpha receptor   IL   interleukin   IL-15RC   IL-15 receptor complex   MHC   major histocompatibility complex   NK   natural killer   OCR   oxygen consumption rate   OXPHOS   oxidative phosphorylation   PRR   pattern recognition receptor   SCENITH   TM   Single Cell ENergetIc metabolism by profiling Translation inhibition   SRC   spare respiratory capacity   TCR   T cell receptor   UC   ulcerative colitis   WT   wildtype  

摘要： Intraepithelial lymphocytes expressing the γδ T cell receptor (γδ IEL) provide continuous surveillance of the intestinal epithelium. We report that mice harboring a microbiota-specific hyperproliferative γδ IEL (γδ HYP ) phenotype also upregulate the expression of the ectonucleotidase CD39, a marker of regulatory γδ T cells. Enhanced TCR and IL-15 signaling correlates with a progression from a naïve-like CD39 neg γδ IEL to a more mature, tissue-adapted CD39 hi IEL population. We found that TCR γδ activation drives CD122-mediated CD39 upregulation on γδ HYP IELs and increased mucosal IL-15 further amplifies CD39 expression in these cells. Further investigation revealed that CD39 induction requires sustained exposure to the γδ HYP -associated microbiota. Moreover, CD39 hi γδ IELs exhibit a reduced capacity to produce pro-inflammatory cytokine, which may explain the lack of histopathology in γδ HYP mice. Overall, our study identifies a previously unappreciated mechanism by which an altered microbiota amplifies CD39 expression on γδ HYP IELs, leading to the expansion of γδ IELs with regulatory potential.

关键词： Oral ulcer   Mucositis   Invasomes   Microneedle patches   Sodium alginate   And Healing  

摘要： Oral ulcerative mucositis (OUM) is a common painful disease that affects oral functions, such as eating or speaking leading to a low quality of life. This study aims to develop a novel strategy for relieving pain associated with OUM by using local anesthetics. Here, a hybrid dissolving microneedle patch integrated with lidocaine (Lido)-encapsulated invasomes (modified liposomes containing terpenes as penetration enhancers) depots are introduced for sustained Lido delivery, reduced dosing frequency, and improved patient compliance. Different Lido-loaded invasomes formulations were developed using design expert (R) software to study the effects of different type terpenes (Limonene, Cineole, Camphor) and their concentration using a thin-film hydration approach. Dissolving microneedle (MN) patches made of sodium alginate (SA), Glycerol and polyvinyl alcohol (PVA) via the casting method. Optimized invasomes formulations containing cineole exhibited excellent stability, a high entrapment efficiency of 83.5%, and a nanoscale size of approximately 295 nm. The incorporation of SA/PVA with 1% glycerin MNs resulted in effective mucosal penetration, rapid dissolution within 10 min, and significant mechanical strength. Research conducted in-vitro and ex-vivo demonstrated enhanced permeation and a significant increase in lidocaine release, achieving 95% within 24 h. In-vivo evaluations demonstrated substantial pain relief, reduced inflammation (evidenced by decreased TNF-alpha and NF-kappa B levels), enhanced anti-inflammatory IL-10 expression, and modulation of angiogenesis via VEGF downregulation, leading to accelerated mouth healing with complete epithelial restoration. This hybrid system significantly improves drug delivery and patient comfort by aiding in biocompatibility, Mucoadhesion, and healing. This innovative system transcends traditional anesthetic administration, providing a painless and targeted therapeutic platform that improves OUM management.

关键词： IL-33   支气管哮喘   气道重塑   剂量反应  

摘要： 目的：分析白细胞介素-33(interleukin-33,IL-33)在不同程度支气管哮喘患者中的变化及其与气道重塑的剂量-反应关系。方法：回顾性分析2022年5月至2024年5月于本院接受治疗的150例支气管哮喘患者的临床资料，根据疾病程度将所有患者分为重度组（81例）、中度组（46例）和轻度组（23例）。根据气道面积/总横截面积比值（airway area to total crosssectional area ratio,WA）将所有患者分为气道重塑组（WA≥60%,57例）和非气道重塑（WA<60%,93例）。比较不同疾病程度支气管哮喘患者的临床资料及IL-33变化。分析IL-33水平与支气管哮喘患者气道重塑指标的相关性。广义可加模型分析疾病程度与相关因素的关系。采用多因素Logistic回归分析确定支气管哮喘患者气道重塑的独立风险预测因子。通过限制性立方样条模型评估IL-33水平与气道重塑的剂量-反应关系。采用受试工作者特征曲线分析IL-33水平对气道重塑的预测价值。结果：重度哮喘患者的IL-33、基质金属蛋白酶-9(matrix metalloproteinase-9,MMP-9)、转化生长因子-β1(transforming growth factor-β1,TGF-β1)水平明显升高，金属蛋白抑制剂-1(tissue inhibitor of metalloprotein inhibitors-1,TIMP-1)水平明显降低（P<0.05）。IL-33水平MMP-9、TGF-β1呈正相关，与TIMP-1呈负相关（P<0.05）。多因素Logistic回归分析结果显示，呼吸道感染、吸烟、嗜酸性粒细胞计数>1.55%、TIMP-1≤112.09μg/L、MMP-9>7.34 ng/mL、TGF-β1>3.77 ng/mL、白细胞介素-17>16.03 ng/L、IL-33>790.02 ng/L、重度哮喘均为影响支气管哮喘患者气道重塑的独立危险因素（P<0.05）。限制性立方样条模型结果显示，IL-33水平与气道重塑的关联强度呈非线性剂量反应关系（P<0.05）。IL-33水平对气道重塑具有一定的预测价值（曲线下面积=0.767）。结论：重度哮喘患者的IL-33水平明显升高，且IL-33水平是支气管哮喘患者气道重塑的重要影响因素，与患者气道重塑呈非线性剂量-反应关系。

关键词： 子宫内膜异位症   温阳化瘀消癥汤   穴位针刺   转化生长因子-β   白细胞介素-17  

摘要： 目的 研究温阳化瘀消癥汤联合穴位针刺治疗子宫内膜异位症（EMT）的疗效，探究对患者子宫动脉血流和血清转化生长因子-β（TGF-β）、白细胞介素-17(IL-17)水平的影响。方法 收集2022年3月至2024年4月在我院接受治疗的EMT患者80例，根据不同的治疗方法，将80例EMT患者分为联合组（n=48，温阳化瘀消癥汤联合穴位针刺）和针刺组（n=32，穴位针刺），比较两组方法治疗效果、中医证候积分、子宫动脉血流动力学指标、血清细胞因子水平、疼痛视觉模拟量表（VAS）评分及不良反应发生率。结果 治疗后，联合组的临床有效率高于针刺组（P<0.05）；治疗后，两组主证经行腹痛、腰骶不适、非经期腹痛、性交痛及次症腰酸腿软积分均明显降低（P<0.05），且联合组低于针刺组（P<0.05）；两组患者左右侧子宫动脉最大血流速度均增大，且联合组大于针刺组，搏动指数、阻力指数均降低（P<0.05），且联合组低于针刺组（P<0.05）；两组血清转化生长因子-β、白细胞介素-17水平均明显降低（P<0.05），且联合组低于针刺组（P<0.05）；两组患者VAS评分均下降，且联合组低于针刺组（P<0.05）；两组不良反应发生率无显著差异（P＞0.05）。结论 温阳化瘀消癥汤联合穴位针刺治疗EMT可调节患者血清IL-17、TGF-β水平，从而减少EMT的病变，改善患者子宫血流，疗效良好，安全可靠。

关键词： plakins   epiplakin   psoriasis   atopic dermatitis   scRNAseq  

摘要： Proteins of the plakin family are predominantly expressed in the epidermis and play a crucial role in cytoskeletal assembly by crosslinking intracellular structural components with cell-cell junctions and the plasma membrane. While most plakins are critical for maintaining epidermal integrity, the role of epiplakin (EPPK1) in inflammatory skin disorders has not been thoroughly investigated. We therefore used single-cell RNA sequencing (scRNAseq) analysis, immunofluorescence, and ex vivo cytokine treatment of human skin explants to investigate EPPK1 regulation in psoriasis. ScRNAseq analysis of psoriatic and healthy skin revealed that EPPK1 was the only member of the plakin family showing specific downregulation in the epidermis of psoriatic lesions. This finding was corroborated at the protein level by immunostaining of human psoriasis samples showing a specific downregulation of EPPK1 in the suprabasal granular layer of psoriatic epidermis. Transcriptomic profiling of Eppk1-/- murine epidermis revealed reduced expression of genes involved in epithelial adhesion and lipid metabolism, partially overlapping with the psoriatic keratinocyte signature, suggesting that EPPK1 loss may predispose the skin to barrier dysfunction under inflammatory stress. Investigation of the mechanism underlying the EPPK1 regulation in psoriasis revealed that interferon-gamma (IFN-gamma) was the main cytokine involved in its downregulation in human ex vivo skin. Collectively, our findings demonstrate a specific IFN-gamma-dependent downregulation of EPPK1 in psoriasis, suggesting that lack of EPPK1 might contribute to the epithelial defects observed in this inflammatory skin condition.

关键词： Asthma   Immunology   Inflammation   Innate immunity  

摘要： Group 3 innate lymphoid cells (ILC3s) have emerged as an important player in the pathogenesis of neutrophilic asthma. However, the regulatory mechanism supporting ILC3 responses in lung remains largely unclear. Here, we demonstrated that stem cell factor (SCF) expression is significantly increased and positively correlated with IL-17A and MPO expression in asthmatic patients. Notably, we identified ILC3 as a major IL-17A-producing responder to SCF in lung. In mice, SCF synergized with IL-1β/IL-23 to enhance pulmonary ILC3 activation and neutrophilic inflammation. Mechanistically, SCF promoted ILC3 proliferation and cytokine production. Transcriptomic analysis revealed that SCF treatment upregulated the genes related to proliferation and Th17 differentiation, associated with increased AKT and STAT3 signaling. In contrast, deficiency of SCF receptor, c-Kit, reduced ILC3 proliferation and IL-17A production, resulting in the amelioration of airway hyperreactivity (AHR) and neutrophilic inflammation in mouse neutrophilic asthma model. Furthermore, genetic deletion of SCF in fibroblasts revealed fibroblasts as the primary source of SCF for ILC3 activation in lung. Moreover, administration of imatinib, a c-Kit inhibitor, alleviated LPS, air pollution or ovalbumin/LPS-induced AHR and neutrophilic inflammation. Our findings elucidated a positive modulatory role of SCF/c-Kit signaling in ILC3 responses during neutrophilic inflammation, offering a potential therapeutic target for neutrophilic asthma.

关键词： TNF-alpha   insulin   CDAI   antioxidants   obesity   gene-diet interaction  

摘要： Background/objectives: The interplay between genetic factors and nutritional patterns is critical in understanding metabolic health. This analysis evaluated the potential reciprocal relationships between the TNF-alpha -308 G/A gene polymorphism, the Composite Dietary Antioxidant Index (CDAI), and insulin-related variables in Spanish adults with obesity. Methods: A cross-sectional analysis was conducted in 292 adults with obesity. Anthropometric, biochemical, and dietary variables were assessed. TNF-alpha -308 G/A genotyping was performed. Associations and potential interactions between CDAI and genotype on insulin and homeostatic model assessment for insulin resistance (HOMA-IR) were examined using multivariate regression and two-way ANOVA. Results: Higher CDAI scores were significantly associated with lower insulin levels (p < 0.001) and HOMA-IR (p < 0.001), regardless of genotype. Carriers of the A allele (GA/AA) showed a non-significant trend toward higher insulin levels (p = 0.087) and a steeper decrease in insulin levels with increasing CDAI, with a significant interaction observed between TNF-alpha genotype and CDAI (interaction p = 0.003). Multivariate analyses confirmed that CDAI and TNF-alpha genotype were independently associated with insulin and HOMA-IR levels. However, interaction terms were not consistently significant across all models. Conclusions: These findings emphasize the potential of antioxidant-rich diets to help modulate the influence of pro-inflammatory genotypes on insulin resistance, highlighting the relevance of integrating genetic and dietary factors in managing obesity-related metabolic risks. Further studies are warranted to confirm these preliminary findings and to better understand the mechanisms underlying gene-diet interactions in metabolic regulation.

关键词： Heritability   Genetic correlation   GWAS   Diverse populations   HLA  

摘要： The human leukocyte antigen (HLA) region is a critical genetic locus associated with diverse complex traits, yet its intricate genetic architecture poses significant challenges to elucidation. Leveraging recent advances in regional heritability estimation and extensive datasets from the Million Veteran Program (MVP), we conducted a comprehensive investigation of the HLA region's genetic architecture. This involved heritability estimation and genetic correlation analyses within the HLA region across European Americans (EAs) and African Americans (AAs). Our analyses demonstrated that in EAs, the HLA region exhibited significantly greater local heritability than other genomic regions of comparable length for lipid metabolic traits (triglycerides [TG], total cholesterol [TC], high-density lipoprotein [HDL], low-density lipoprotein [LDL]), anthropometric measures (body mass index [BMI]), and suicide-related traits (suicidal ideation without suicide attempts [IDE] and suicidal thoughts and behaviors [SITB]) (false discovery rate [FDR]-adjusted empirical p-values < 0.05). Notably, this enrichment was not observed in AAs. Genetic correlation analyses revealed disparities between local HLA and genome-wide findings. EAs exhibited 16 significant local HLA correlations and 32 genome-wide correlations. Conversely, AAs displayed more significant local genetic correlations within the HLA region (14 pairs) than genome-wide (3 pairs), with two pairs (IDE-SITB, LDL-TC) concordantly significant. These findings underscore the HLA region's substantial contribution to the variance of these lipid metabolic traits, BMI, and suicide-related traits. Further investigation into the genetic mechanisms by which HLA-mediated pathways influence these phenotypes is crucial for elucidating the complex role of this region, particularly concerning lipid metabolism and suicidal behaviors.