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关键词： anti-IL4/IL13 antibody   atopic dermatitis   conjunctivitis  

摘要： OBJECTIVE:To evaluate the differential expression of RNA in blood monocytes in patients with Juvenile idiopathic arthritis (JIA) treated with TNF antagonists (TNFi), and to explore the effect and mechanism of gene expression on the efficacy of JIA. METHODS:A total of 29 children with JIA treated with methotrexate (MTX) and TNFi in Guangzhou Women and Children's Medical Center of Guangzhou Medical University from April 2021 to November 2023 were enrolled. After 6 months, the children were divided into two groups according to the treatment effect, i.e., 13 cases in the ineffective group and 16 cases in the effective group, the peripheral blood of the children was collected, the blood mononuclear cells were isolated for transcriptome sequencing, the differentially expressed genes between the groups were analyzed, the signaling pathways and metabolic pathways related to the efficacy of TNFi were analyzed by GO and KEGG enrichment, and the mechanism related to the efficacy of TNFi was explored. This study was approved by Medical Ethics Committee of the Guangzhou Women and Children's Medical Center of Guangzhou Medical University (Ethics No.: 2023-330B00). RESULTS:There was a statistically significant difference in the gender and age distribution between the two groups of children (P < 0.05), while no statistically significant differences were observed in disease duration, rheumatoid antibody levels, or JIA subtypes (P > 0.05). After sequencing data quality control and comparison of reference genomes, a total of 18 523 protein-coding genes were identified in all children's samples. A total of 705 differentially expressed genes (DEGs) were identified between the effective group and the invalid group through differential analysis, of which 579 were up-regulated in the effective group and 126 in the inactive group. GO function and KEGG pathway enrichment analysis showed that DEG was significantly enriched in 55 GO entries and 32 KEGG metabolic pathways, which were mainly rel

关键词： fibro-adipogenic progenitor cells (FAPs)   muscle satellite cells (MuSCs)   interleukin-6 (IL-6)   heme oxygenase-1 (HO-1)   oxidative stress   myogenic differentiation  

摘要： Fibro-adipogenic progenitor cells (FAPs) support muscle tissue homeostasis, regulate muscle growth, injury repair, and fibrosis, and activate muscle progenitor cell differentiation to promote regeneration. We aimed to investigate the effects of co-culturing FAPs with muscle satellite cells (MuSCs) on myogenic differentiation. Proteomic profiling of co-culture supernatants identified significant DCX, IMP2A, NUDT16L1, SLC38A2, and IL-6 upregulation. Comparative transcriptomics of mono-cultured versus co-cultured MuSCs revealed differential expression of oxidative stress-related genes (HMOX1, ALOX5, GSTM3, TRPM2, PADI1, and CTSL). Pathway enrichment analyses highlighted cell cycle regulation, TNF signaling, and ferroptosis. Gene ontology analysis of MuSCs indicated significant gene enrichment in myosin-related components. Combined transcriptomic and proteomic analyses demonstrated HO-1 downregulation at the transcriptional and translational levels, with altered pathways being predominantly related to myosin filament, muscle system process, and muscle contraction cellular components. HO-1 knockdown reduced intracellular iron accumulation in MuSCs, suppressing iron-dependent autophagy. This alleviated oxidative stress and promoted myogenic differentiation. Exogenous IL-6 (0.1 ng/mL) downregulated HO-1 expression, initiating an identical regulatory cascade, while HO-1 overexpression reversed the IL-6-mediated reduction in the expression of the autophagy markers LC3 and ATG5, suppressing myogenic enhancement. This establishes the co-culture-induced IL-6/HO-1 axis as a core regulator of iron-dependent oxidative stress and autophagy during myogenic differentiation.

关键词： DRB1*15:03 positive   DRB5 negative   linkage disequilibrium   putative haplotypes  

摘要： The HLA class II region contains nine DRB genes: DRB1, DRB3, DRB4 and DRB5 express functional gene products, whereas DRB2, DRB6, DRB7, DRB8 and DRB9 are pseudogenes. In this study, we assessed the frequency and diversity of two functional genes, DRB1 and DRB5;in particular, HLA-DRB1*15:03 with absence of the associated HLA-DRB5*01:01 allele (DRB1*15:03 positive DRB5*01:01 negative). We aimed to determine the frequency of DRB1*15:03 positive DRB5*01:01 negative in this cohort and to define any putative full or partial haplotypes that may show this genotype pattern. We performed HLA typing by NGS using One Lambda AllType or CareDx AlloSeq Tx17 on 6268 solid organ transplant (SOT) samples using DNA extracted from either buccal swabs or whole blood. The absence of HLA-DRB5 was confirmed by One Lambda LABType rSSOP. Confirmation of DRB1*15 homozygotes was performed by CareDx Copy Number (RUO) tool. In the present cohort, 554 (8.8%) individuals were identified as HLA-DRB1*15:03 positive. Of those, 48 individuals (8.7% of HLA-DRB1*15:03 positive) did not have the associated DRB5*01:01 allele present. We believe that this percentage could be as high as 11.2% when considering DRB1*15:XX homozygotes. Although linkage disequilibrium analysis showed strong LD between DRB1*15:03 and DRB5*01:01 (D ' = 0.89), supporting their co-inheritance on the same haplotype block, a moderate correlation coefficient (r2 = 0.302) implied that DRB5*01:01 is not always present in all DRB1*15:03 carriers. Extended haplotypes associated with this phenomenon were constructed and characterised. Certain HLA-A, B, DRB1 haplotypes were strongly predictive of absent DRB5. To our knowledge, this is the largest cohort ascertaining the diversity and frequency of the HLA-DRB1*15:03 apparent haplotypes. Our results show a considerable proportion of DRB1*15:03 positive individuals lack the DRB5 gene. The results of this study are useful for unrelated donor research, transplantation, anthropological and disease

关键词： TNF-alpha   308 G > A   Migraine risk   Jammu population   Migraine with aura   Migraine without aura   Pro-inflammatory cytokines  

摘要： Migraine is a complex neurological disorder characterized by recurrent unilateral headaches. Its pathophysiology has been associated with inflammatory processes, with TNF-alpha, a pro-inflammatory cytokine, being one such factor implicated in various neurological conditions, including migraine. This study aimed to evaluate the association between the TNF-alpha -308 G > A polymorphism and migraine risk by integrating both a case-control investigation and a meta-analysis to enhance statistical power and reliability. The investigation commenced with a case-control study in the Jammu region of North India, conducted in accordance with STROBE guidelines. To enhance statistical power and reliability, a meta-analysis of independent studies was performed, followed by Trial Sequential Analysis to verify sample size adequacy. First, the case-control study showed that there was no significant association between -308 G > A and overall migraine risk across various genetic models (allele: 0.80 [0.58-1.11], p = 0.193) in the Jammu population. Although the migraine with aura subgroup showed marginal significance in the allelic model (p = 0.02), this association was not supported after adjustment (p = 0.14). Similarly, the meta-analysis revealed no significant association between the polymorphism and overall migraine (allele: 1.21 [0.92-1.58], p = 0.16) or its two clinical subtypes, migraine with aura and without aura. However, when stratified by ethnicity, a significant association was identified in African populations, while no such association was observed in Asian or Caucasian groups. This study underscores the importance of combining case-control data with meta-analysis to strengthen genetic association findings. Future research should focus on larger, multi-ethnic cohorts to validate these findings and improve generalizability.

关键词： MHC-I   antigen presentation   tumor immune escape   cepharanthine   autophagy  

摘要： Major histocompatibility complex class I (MHC-I)-mediated antigen presentation plays a pivotal role in anti-tumor immunity by enabling CD8+ T cells to recognize and eliminate malignant cells. In melanoma, modulation of this pathway is critical for improving the efficacy of immunotherapies. Our study demonstrates that the natural compound Cepharanthine (CEP) exhibits notable antitumor activity by enhancing MHC-I-mediated antigen presentation. CEP treatment upregulated MHC-I expression (both membrane-bound and total levels) in melanoma cells in a concentration-dependent manner, thereby improving antigen-presenting capacity. Interestingly, when autophagy was pharmacologically blocked using Bafilomycin A1, co-treatment with CEP did not lead to further elevation of MHC-I expression, suggesting that CEP's effect is mediated through disruption of the autophagic pathway. Mechanistically, CEP induced autophagosome accumulation, as evidenced by an increase in GFP-LC3 puncta. Fluorescence imaging further confirmed that CEP selectively impaired lysosomal acidification without affecting autophagosome-lysosome fusion, thereby inhibiting late-stage autophagic flux. Furthermore, CEP treatment promoted CD8+ T cell infiltration into tumor tissues and enhanced the antitumor efficacy of anti-PD-1 therapy, resulting in greater tumor suppression compared to either treatment alone. The study elucidates how CEP's selective lysosomal inhibition creates a tumor microenvironment more susceptible to immune surveillance, primarily through preserved MHC-I surface expression and subsequent T cell recognition. This work highlights CEP as a promising immunomodulatory agent and provides a potential strategy for improving the outcomes of immune checkpoint blockade therapy.

关键词： Acute anterior uveitis   ankylosing spondylitis   HLA-B27   spontaneous hyphema  

摘要： PurposeTo report a rare case of spontaneous hyphema associated with human leukocyte antigen (HLA) -B27 positive acute anterior uveitis (AAU) and discuss its possible pathophysiological mechanisms and *** case report of a 27-year-old Chinese man presented as acute anterior uveitis in the right eye (OD).ResultsA 27-year-old male presented with acute onset of pain, photophobia, and blurred vision in OD without a history of trauma. Ophthalmic examination revealed severe anterior uveitis in OD with 2 mm of spontaneous hyphema. Laboratory investigations confirmed HLA-B27 positivity, and radiographic findings established a diagnosis of ankylosing spondylitis (AS). The patient was treated with topical corticosteroids, cycloplegics, systemic corticosteroids, and tranexamic acid. He demonstrated significant clinical improvement with resolution of hyphema and reduction of anterior chamber inflammation by day *** hyphema is an unusual complication of HLA-B27 positive AAU, likely resulting from severe inflammation-induced vasculitis. Early recognition and aggressive management with topical and systemic anti-inflammatory therapy can lead to favorable outcomes. This case highlights the importance of evaluating underlying systemic conditions in patients presenting with atypical anterior segment findings.

关键词： Aqueous humor   interleukin-6   pentraxin 3   uveitis  

摘要： Purpose: Evidence exists that pentraxin 3 (PTX3) is involved in the pathogenesis of autoimmune diseases. The aim of this study was to analyze the levels of PTX3 in aqueous humor (AH) samples from patients with specific autoimmune uveitic entities. In addition, we correlated PTX3 levels with the levels of proinflammatory cytokines and chemokines and the clinical disease activity. Methods: AH samples from patients with active uveitis associated with human leukocyte antigen (HLA)-B27-related inflammation (n = 12), Beh & ccedil;et's disease (BD) (n = 13), Vogt-Koyanagi-Harada (VKH) disease (n = 12), sarcoidosis (n = 8) and control subjects (n = 9) were measured with the use of multiplex assays. Results: When considering all uveitis patients as one group (n = 45), PTX3 levels were significantly increased compared to controls (p = 0.002). When comparing the four individual disease groups to controls, PTX3 levels were significantly higher in only HLA-B27-associated uveitis (p < 0.001). PTX3 levels were significantly higher in patients with HLA-B27-associated uveitis than in patients with BD (p = 0.034) and VKH disease (p < 0.001). PTX3 levels had a significant correlation with clinical disease activity (r = 0.480;p = 0.001) and strong positive correlations with aqueous humor levels of interferon-gamma (r = 0.749;p < 0.001), interleukin (IL)-1 ss (r = 0.804;p < 0.001), IL-6 (r = 707;p < 0.001), CCL20 (r = 0.691;p < 0.001) and CXCL8 (r = 0.775;p < 0.001). Conclusions: PTX3 is an inflammatory marker and might exert a pathogenic role in HLA-B27-associated uveitis.

摘要： Islet-resident macrophages contribute to hypoxia-induced islet cell death during pancreatic islet transplantation. However, their specific role during this process remains elusive. Here, we report that interleukin-1 alpha (IL-1 alpha) and IL-1 beta are released by islet-resident macrophages, resulting in the suppression of insulin secretion. This may be due to a decreased inflammation-driven expression of pancreatic and duodenal homeobox 1 (PDX-1) and MafA in beta cells. Islet-resident macrophages release significantly less IL-1 alpha when compared to IL-1 beta. However, both cytokines inhibit insulin expression and secretion to a comparable extent. We identified heparan sulfate on the islet surface, which acts as a "molecular glue" potentiating the inhibitory action of IL-1 alpha on insulin expression via specific binding to IL-1 receptor (IL-1R). In vivo analyses revealed that the loss of IL-1 signaling in isolated islets accelerates their revascularization and, thus, enhances their endocrine function. These findings indicate that heparan sulfate fine-tuned IL-1 signaling crucially determines the outcome of islet transplantation.