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关键词： biologics   drug-induced   inflammatory bowel disease   juvenile arthritis   paradoxical psoriasis   psoriasiform dermatitis   psoriasis   TNF inhibitor-induced psoriasis   tumor necrosis factor-alpha inhibitor  

摘要： Tumor necrosis factor-alpha inhibitors (TNFi) are used to treat various autoimmune diseases but can induce paradoxical psoriasiform dermatitis (PD) in a subset of patients. This retrospective chart review aimed to identify risk factors impacting PD severity in 70 pediatric patients at a single center. Forty patients (57.1%) discontinued their initial TNFi: 12/40 (30.0%) switched to another TNFi, with 4/12 (33.3%) experiencing PD recurrence, while 25/40 (62.5%) switched medication classes. Female sex was associated with increased use of high-potency topical steroids (p = 0.01), suggesting more severe disease. Juvenile idiopathic arthritis (p = 0.02), older age (p < 0.01), and concomitant immunomodulator use (p = 0.04) were associated with a longer latency period before PD development.

关键词： NF-κB signaling pathway   Pancreatic acinar cells   SLC25A19   mitochondrial thiamin pyrophosphate uptake   pro-inflammatory cytokines  

摘要： We investigated the effect(s) of pro-inflammatory cytokines on carrier-mediated thiamin pyrophosphate (TPP) uptake by pancreatic acinar cells (PACs) mitochondria using mouse-derived PAC 266-6 cells and human primary PACs as models. First, we assessed the level of expression of the mitochondrial TPP transporter (MTPPT) mRNA in pancreatic tissue of patients with chronic pancreatitis and found the level to be significantly lower than that in normal control subjects. We then examined the effects of exposing PACs to IL-1β, IL-6, and TNF-α on mitochondrial TPP uptake and observed significant inhibition by all these pro-inflammatory cytokines. Focusing on IL-1β (since it showed a more severe effect), we found this pro-inflammatory cytokine to also cause a significant inhibition in MTPPT protein and mRNA expression, as well as in activity of the promoter. Effect on the latter, appeared to be mediated via a decrease in the binding affinity of NF-Y (a nuclear factor that drives promoter activity) as well as via epigenetic mechanism/histone-modification were significant reduction in levels of enrichment of the activator markers H3K4-trimethylation and H3K9-acetylation, and an increase in level of enrichment of the repressor marker H3K27-trimethylation were observed. Finally, evidence was obtained suggesting a role for the intracellular NF-κB signaling pathway in mediating the effects of IL-1β on PAC mitochondrial TPP uptake process. These results show that exposure of PACs to IL-1β causes inhibition in mitochondrial TPP uptake, and that this effect is exerted at the level of transcription and is mediated via the NF-κB signaling pathway.

摘要： In the original publication [...].

关键词： full-length sequence   HLA-DQB1*05:305   next generation sequencing  

摘要： We report the confirmation and extension of the HLA-DQB1*05:305 allele detected in a Chinese individual.

关键词： Sepsis   Intestinal inflammation   Nur77   Paneth cell   Necroptosis   ER homeostasis   Ascl2   Achaete-scute family bHLH transcription factor 2   ASV   Amplicon sequence variant   AMP   Antimicrobial peptide   AMFR   Autocrine motility factor receptor   BTP   Bioactive triple peptide   CLP   Cecal ligation and puncture   Csn-B   Cytosporone B   Ctrl   Control   DAPI   4′,6-diamidino-2-phenylindole   Dll4   Delta like canonical Notch ligand 4   DNA   deoxyribonucleic acid   DSS   dextran sulfate sodium   DPBS   Dulbecco’s phosphate-buffered saline   ER   Endoplasmic reticulum   ELISA   Enzyme-Linked Immunosorbent Assay   EGF   Epidermal growth factor   FAM134B   Family with sequence similarity 134 member B   GAPDH   Glyceraldehyde-3-phosphate dehydrogenase   H&E   Hematoxylin and eosin   HC   Healthy control   HMGB1   High mobility group box 1   IP   immunoprecipitation   IL   Interleukin   ISC   Intestinal stem cell   Lgr5   Leucine rich repeat containing G protein-coupled receptor 5   LPS   Lipopolysaccharide   LC3   Microtubule-associated protein 1 light chain 3   NLRP3   NLR family pyrin domain containing 3   NR4A1   Nuclear receptor subfamily 4 group A member 1   Olfm4   Olfactomedin 4   PCR   Polymerase chain reaction   PVDF   Polyvinylidene fluoride   PKCα   Protein kinase C alpha   qPCR   Quantitative real-time PCR   RIP3   Receptor-interacting protein kinase 3   RNA   Ribonucleic acid   TUNEL   Terminal deoxynucleotidyl transferase dUTP Nick End Labeling   TNF   Tumor necrosis factor   WT   Wild type   Wnt3   Wnt family member 3  

摘要： Introduction Sepsis, a systemic inflammatory syndrome, is frequently associated with intestinal dysfunction, which in turn exacerbates disease severity. Intestinal epithelial Paneth cells exhibit increased susceptibility to necroptosis upon inflammatory stimulation. Nuclear receptor Nur77 has been implicated in multiple programmed cell death pathways. However, the precise role of Nur77 in regulating Paneth cell necroptosis during sepsis remains unclear. Objectives This study elucidates the role and underlying molecular mechanisms of nuclear receptor Nur77 in regulating Paneth cell necroptosis during sepsis. Methods We employed both systemic and Paneth cell-specific Nur77 knockout mouse models. Paneth cell necroptosis was assessed using TUNEL staining, immunofluorescence, and transmission electron microscopy. Endoplasmic reticulum (ER) homeostasis was evaluated based on ultrastructural integrity, ER-phagy, and ER stress. Protein modification and protein–protein interaction were validated by structure prediction and immunoprecipitation. Results Systemic or Paneth cell-specific Nur77 knockout exacerbated intestinal inflammation by enhancing Paneth cell necroptosis during sepsis. Nur77 deficiency in Paneth cells altered ileal microbiota rather than intestinal stem cell niche after LPS challenge. Nur77 deficiency-induced Paneth cell necroptosis was attributed to impaired ER homeostasis caused by defective ER-phagy. Mechanistically, LPS induced Nur77-PKCα interaction and their subsequent translocation to the ER, which promoted AMFR phosphorylation, FAM134B ubiquitination and subsequently ER-phagy. Treatment with Nur77 agonists (BTP and Csn-B) alleviated intestinal inflammation and restored Paneth cell homeostasis in sepsis mice. Conclusion This study demonstrates that Paneth cell necroptosis plays a critical role in intestinal inflammation. Our work also identifies Nur77 as a potential therapeutic target to protect Paneth cells and maintain intestinal homeostasis during s

关键词： Atopic dermatitis   Th9 cells   PU.1 transcription factor   IL-9   Immunological profiling   Biomarkers  

摘要： Atopic dermatitis (AD) is a chronic inflammatory skin disease resulting from complex interactions between genetic, environmental, and immunological factors, particularly the dysregulation of T helper (Th) cell subsets. While Th2 responses have been central to AD research, evidence highlights the role of Th9 cells and their signature cytokine, interleukin-9 (IL-9), in allergic inflammation. However, the involvement of the Th9/IL-9 axis in AD remains insufficiently characterized. This study investigates the role of the Th9/IL-9 axis in AD through an integrated clinical, immunological, and molecular approach. The study comprised a total of 89 subjects, consisting of 54 AD cases and 35 healthy controls. Disease severity and allergen sensitivity were assessed using SCORAD scores and skin prick testing, respectively. PU-1 mRNA was quantified using real-time PCR. Th9 cell frequency was determined through flow cytometry, vitamin D levels were measured by chemiluminescence, and total IgE and IL-9 levels were estimated using ELISA. AD patients demonstrated a significant increase in circulating Th9 cell frequency (11.5 +/- 0.3% vs. 5.0 +/- 0.5%, p < 0.0001), PU.1 mRNA expression with an average 2.5-fold upregulation (p < 0.001), and elevated serum IL-9 concentrations (18.6 +/- 6.3 pg/mL vs. 8.3 +/- 1.9 pg/mL, p < 0.0001) compared to healthy controls. Stratified analysis revealed significant associations of PU.1 mRNA and IL-9 levels with rural residence, vitamin D deficiency, and peripheral eosinophilia (p < 0.05). Allergen sensitivity, as determined by skin prick testing, was positive in 50% of AD patients, and 66.7% exhibited elevated total serum IgE levels. Our findings underscore the involvement of the Th9/PU.1/IL-9 axis in the immunopathogenesis of AD. The observed upregulation of Th9 cell frequency, PU.1 expression, and IL-9 levels suggests a contributory role of Th9-mediated pathways in disease development and severity. These results provide a foundation for future studi

关键词： 木瓜总三萜   类风湿性关节炎   炎症反应   细胞因子   TLR4/NF-κB/NLRP3信号通路  

摘要： 研究木瓜总三萜（TCS）对脂多糖（LPS）和三磷酸腺苷（ATP）诱导的MH7A细胞以及弗氏完全佐剂（CFA）诱导的佐剂性关节炎（AA）大鼠的抗关节炎作用及其机制。在体外，采用MTT检测细胞活力；采用Transwell法检测细胞迁移；比色法和ELISA法检测细胞上清液中乳酸脱氢酶（LDH）、环氧合酶-1（COX-1）、COX-2、白细胞介素-4（IL-4）、IL-1β、IL-6、IL-10、IL-18、前列腺素E2（PGE2）、肿瘤坏死因子-α（TNF-α）含量；采用免疫荧光检测NOD样受体蛋白3（NLRP3）、凋亡相关斑点样蛋白（ASC）、半胱氨酸天冬氨酸蛋白酶(caspase) -1共定位。在体内，检测AA大鼠足肿胀程度和关节炎指数；苏木精-伊红染色观察踝关节组织形态学、计算关节组织学评分；比色法和ELISA法检测AA大鼠踝关节滑膜组织中LDH、COX-1、COX-2、IL-4、IL-1β、IL-6、IL-10、IL-18、PGE2、TNF-α含量；实时荧光定量PCR法测定MH7A细胞和踝关节滑膜组织中ASC、caspase-1、COX-1、COX-2、髓样分化因子88（MyD88）、NLRP3、PGE2、Toll样受体4（TLR4）mRNA表达；Western blot法测定MH7A细胞和踝关节滑膜组织中ASC、caspase-1、胞浆NF-κB p65、MyD88、NLRP3、胞核NF-κB p65、pro-caspase-1、pro-IL-18、pro-IL-1β、TLR4蛋白表达。结果显示，TCS可显著抑制LPS和ATP诱导的MH7A细胞迁移，降低AA大鼠足肿胀度、关节指数评分，减轻踝关节滑膜水肿和炎性细胞浸润，减少骨侵蚀、软骨破坏和血管翳形成，降低关节炎症、血管翳、软骨和骨损伤的关节组织学评分；降低MH7A细胞上清液和关节滑膜组织中COX-2、IL-6、IL-18、IL-1β、LDH、PGE2、TNF-α含量，升高上清液和关节滑膜组织中的COX-1、IL-4、IL-10水平；下调LPS和ATP诱导的MH7A细胞和AA大鼠踝关节滑膜组织中ASC、caspase-1、COX-2、MyD88、NLRP3、PGE2、TLR4 mRNA和ASC、caspase-1、MyD88、NLRP3、胞核NF-κB p65、pro-caspase-1、pro-IL-18、pro-IL-1β、TLR4蛋白表达，抑制MH7A细胞内NLRP3、ASC和caspase-1共定位，上调LPS和ATP诱导的MH7A细胞和AA大鼠踝关节滑膜组织中COX-1 mRNA和胞浆NF-κB p65蛋白表达。以上结果表明，TCS对LPS和ATP诱导的MH7A细胞和CFA诱导的AA大鼠具有较好的抗类风湿性关节炎作用，其机制与抑制TLR4/NF-κB/NLRP3通路激活、减少炎症反应密切相关。

关键词： HLA-DPA1*02:01:01:36 novel allele   Illumina   next-generation sequencing  

摘要： The HLA-DPA1*02:01:01:36 allele differs from HLA-DPA1*02:01:01:02 by a single nucleotide substitution in intron 2.

摘要： Peripheral immune dysregulation is frequently reported in autism spectrum disorder (ASD);however, the underlying molecular mechanisms remain unclear. We recruited a well-defined cohort of young Arab children with ASD, aged 2-4 years, along with matched controls in Qatar. Using a multimodal approach, we integrated transcriptomic, proteomic, and single-cell RNA-seq data analyses from this cohort. Targeted transcriptomic profiling identified differential expression of 50 immune-related genes in the circulating PBMCs of children with ASD, three of which (JAK3, CUL2, and CARD11) negatively correlated with ASD symptom severity. These gene signatures were validated in independent studies using blood and brain tissues from individuals with ASD. Enrichment analysis revealed involvement of these genes in immune function, particularly through TNF signaling pathway. Proteomic analysis highlighted disrupted TNF signaling and upregulated levels of TNFSF10 (TRAIL), TNFSF11 (RANKL), and TNFSF12 (TWEAK) in plasma of individuals with ASD. Single-cell RNA-seq revealed that B cells, CD4 T cells, and NK cells potentially contributed to these upregulations in ASD. Dysregulated TRAIL, RANKL, and TWEAK signaling pathways were specifically observed in CD8 T cells, CD4 T cells, and NK cells of individuals with ASD. These findings provide new insights into immune dysregulation mechanisms in ASD and highlight potential therapeutic targets.

关键词： KHDRBS1   Caerin peptide   Pyroptosis   IL-18   HeLa cell   Cervical cancer  

摘要： Cervical cancer remains a significant global health challenge, particularly in developing countries where access to HPV vaccination is limited. We previously demonstrated that caerin 1.1/1.9 (F1F3) peptides inhibit tumour growth in vitro and in vivo by inducing pyroptosis, followed by apoptosis and immune activation. In this study, we elucidate the molecular mechanisms underlying F1F3-induced pyroptosis in HeLa cells. Our results show that F1F3 triggers pyroptosis independently of GSDME, as evidenced by comparable IL-18 and LDH release in both wild type and GSDME knockout cells. Cross-linking mass spectrometry identified the interaction of F1 to KHDRBS1 and F3 to DDX5, respectively. Knockout of either KHDRBS1 or DDX5 enhanced HeLa cell sensitivity to F1F3 and significantly elevated IL-18 secretion. Notably, KHDRBS1-deficint tumours displayed accelerated growth yet responded more robustly to F1F3 treatment, suggesting a context-dependent tumour-suppressive role of KHDRBS1. These findings uncover a previously uncharacterised pathway regulated by KHDRBS1-DDX5 and demonstrate that F1F3 can effectively interfere with this axis to induce anti-tumour immune responses, highlighting their potential as novel therapeutic agents for cervical cancer.