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关键词： HLA-A   HLA-B   HLA-C   NGS   novel allele  

摘要： Nine novel HLA alleles were detected during the HLA typing process.

关键词： HLA-DQB1*05:02:01:17 novel allele   Illumina   next-generation sequencing  

摘要： The HLA-DQB1*05:02:01:17 allele differs from HLA-DQB1*05:02:01:01 by a single nucleotide substitution in intron 3.

摘要： During (Mtb) infection, infected alveolar macrophages (AMs) initially up-regulate a NRF2 regulated cell-protective program, which is detrimental to host control and impedes AM activation, including MHC II expression. MHC II is critical for CD4+ T cell activation and host immunity during Mtb infection. We hypothesized that NRF2 regulates the MHC II pathway and AM antigen presentation to T cells. We found that NRF2 inhibits MHC II, but not MHC I, specifically in AMs, following Mtb infection and . NRF2 dampens and gene expression in uninfected AMs, and MHC II inhibition by NRF2 is retained following innate stimuli and IFNγ exposure. NRF2 expression in Mtb-infected AMs impedes their ability to activate ESAT6-specific CD4+ T cells. Thus, although NRF2 expression enhances cell-protective functions, it has the unexpected consequence of limiting innate-adaptive crosstalk, which can impair CD4+ T cell activation and host immunity during Mtb infection.

摘要： CD4+Foxp3+ regulatory T cells are essential for maintaining immune tolerance and preventing excessive inflammation, making them promising candidates for treating autoimmunity and GvHD. However, the translation of regulatory T cell therapy into clinical practice poses substantial challenges. Here, we show that adoptive regulatory T cell therapy increases IL-6 and TGF-beta-dependent pathogenic Th17 cell differentiation in murine models of inflammatory bowel disease and experimental autoimmune encephalomyelitis. Regulatory T cells increase the p-stat3/p-stat5 ratio in effector T cells by suppressing IL-2 secretion and competitively consuming IL-2, thereby promoting Th17 cell differentiation. Notably, IL-2 signaling deficiency not only promotes a Th17 cell-associated transcriptional program, but also enhances the pro-inflammatory properties of Th17 cells. Strikingly, therapeutic blockade of IL-6/STAT3 signaling pathway can reverse pathogenic Th17 cell differentiation and enhance the therapeutic effect of regulatory T cell therapy. Thus, our findings could potentially advance the clinical research progress of adoptive regulatory T cell therapy.

关键词： host-guest interaction   lysosomal escape   nanoparticle aggregation   rheumatoid arthritis   siRNA delivery  

摘要： The inefficient lysosomal escape of small interfering RNA (siRNA) from immune cells remains a major barrier to therapeutic efficacy. To address this challenge, an innovative pH-triggered aggregation nanoplatform for enhanced siRNA delivery is developed. By using adamantane (Ad)-modified hyperbranched poly-L-lysine (HBPL-Ad) as a backbone, this nanoplatform incorporated acetalated beta-cyclodextrin (beta-ACD) as a pH-sensitive "gatekeeper", together with siRNA to prepare physiologically stable aggregated nanoparticles (ANPs). Triggered by the acidic lysosomal microenvironment, the beta-ACD hydrolysis exposed beta-CD cavities to enable strong host-guest (beta-CD/Ad) binding. This binding caused nanoparticle aggregation and subsequent mild lysosomal membrane permeabilization (LMP), facilitating efficient siRNA escape independent of the proton sponge effect. The ANPs demonstrated superior cellular uptake and significantly enhanced TNF-alpha silencing across macrophages, dendritic cells, and Jurkat immune cells in vitro. Intraperitoneal administration of ANPs loaded with TNF-alpha siRNA in a collagen-induced arthritis (CIA) model achieved 93% mRNA reduction and 95% protein reduction in joint TNF-alpha levels, significantly outperforming Lipo2000 (56% mRNA and 60% protein reduction), effectively attenuating synovitis and cartilage erosion without detectable systemic toxicity. This work establishes pH-triggered programmable aggregation as a potent and transformative strategy for overcoming immune cell delivery barriers, offering a promising clinically viable platform for RNAi-based immunotherapy.

关键词： HLA-B27 status   rheumatic diseases   clinical differences   immunological markers   HLA-B*27-positive vs. -negative   inflammatory biomarkers  

摘要： Background/Objectives: Human leukocyte antigen B27 (HLA-B27) is a genetic marker strongly associated with various inflammatory rheumatic diseases, particularly those within the spondyloarthritis spectrum. Its presence influences disease onset, clinical severity, and therapeutic strategies. However, comparative data between HLA-B*27-positive and -negative patients, especially in Eastern European populations, remain limited. The study aimed to investigate the clinical, paraclinical, and psychosocial differences between HLA-B*27-positive and -negative individuals diagnosed with rheumatic diseases, in order to better understand the implications of HLA-B27 status on disease expression and patient quality of life. Methods: A cross-sectional, observational study was conducted between June 2023 and December 2024 at the Emergency Clinical Hospital for Children "Sf Ioan" in Galati, Romania, in collaboration with "Dunarea de Jos" University. Fifty adult patients with various rheumatic conditions were enrolled and stratified into HLA-B*27-positive (n = 22) and -negative (n = 28) groups. Data collection included clinical evaluations, laboratory biomarkers (CRP = C-reactive protein;ESR = erythrocyte sedimentation rate), and a structured quality-of-life questionnaire. Statistical analysis was performed using SPSS v27. Results: HLA-B*27-positive patients were significantly younger (mean age 46.00 vs. 55.07 years, p = 0.018) and had higher CRP levels (>1 mg/dL in 53.33% vs. 0%, p = 0.001). Ankylosing spondylitis was more prevalent in this group (22.73% vs. 3.57%, p = 0.039). Magnetic resonance imaging (MRI) was more frequently used (68.18% vs. 39.29%, p = 0.042), indicating greater suspicion of axial involvement. HLA-B27-positive patients also reported higher perceived stress (mean score 2.41 vs. 1.21, p < 0.001). Conclusions: HLA-B*27 positivity is associated with earlier disease onset, increased systemic inflammation, greater axial involvement, and higher psychological stress. The

关键词： HLA   italic>HLA-DRB4*01:03:38   novel allele   third-generation sequencing  

摘要： HLA-DRB4*01:03:38 differs from HLA-DRB4*01:03:01:01 by one nucleotide substitution at position 42 (G -> A) in exon 1.

关键词： COPD   adaptive immune response   structural changes   respiratory mechanics   IL-17 inhibitor  

摘要： Smoking remains the main risk factor for the development of chronic obstructive pulmonary disease (COPD). The inflammatory response mediated by innate and adaptive immune cells has been described in the development and progression of the disease, and the importance of Th17 cytokines has been observed. Studies have shown that blocking interleukin (IL)-17 can reduce inflammation in experimental models of lung injury. This study evaluated the effect of an IL-17 inhibitor in a cigarette smoke-induced COPD model in C57BL/6 mice. The effects of treatment with an IL-17 inhibitor were evaluated in an experimental model of COPD. Mice were exposed to cigarette smoke for 6 months, and treatment with IL-17 inhibitor was initiated in the fifth month. Four experimental groups were constituted: Control group-animals housed in a vivarium, receiving filtered room air;Control anti-IL-17 group-animals housed in a vivarium, receiving filtered room air and treatment with an anti-IL-17-neutralizing antibody;COPD group-animals exposed to cigarette smoke;and COPD anti-IL-17 group-animals exposed to cigarette smoke and treated with an anti-IL-17-neutralizing antibody. In the COPD groups, an increase in mean linear intercept was observed, along with a decrease in tissue elastance and tissue damping, confirming the COPD development. Administration of the IL-17-neutralizing antibody reversed these structural and functional alterations. Additionally, the COPD group exhibited an inflammatory response characterized by increased infiltration of polymorphonuclear and mononuclear cells and elevated numbers of IL-17- and IL-6-positive cells. These findings were consistent with the increased expression of IL-17 and IL-6 in lung homogenates, as assessed by ELISA. Treatment with the IL-17-neutralizing antibody effectively reversed this inflammatory response by reducing the expression of these inflammatory markers. These results were further supported by the evaluation of ROR gamma t gene expression, whi

关键词： bioinformatics   knee osteoarthritis   machine learning   TNF signaling pathway   WGCNA  

摘要： Knee osteoarthritis (KOA), a prevalent degenerative joint disease, involves complex inflammatory responses and signal pathway regulation in its pathogenesis. This study investigates the tumor necrosis factor signaling pathway's mechanistic role in KOA using diverse bioinformatics approaches. Initially, differential expression analysis identified 222 significant differentially expressed genes. Subsequent Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses indicated that these differentially expressed genes are mainly involved in inflammatory responses and cytokine signaling pathways. Weighted gene co-expression network analysis was then employed to identify the MEbrown module, which is closely associated with knee arthritis, and 20 key tumor necrosis factor signaling pathway-related genes were selected. Further analysis using LASSO regression and the Boruta algorithm screened out important genes, including MCL1, JUN, and GADD45B, whose superior performance in classification tasks was validated. Additionally, immune infiltration analysis revealed significant differences in immune cell distribution across knee arthritis samples, underscoring the critical role of inflammation regulation in disease progression. Overall, this study enhances the understanding of KOA pathogenesis and offers valuable insights for personalized treatment and, precision medicine.

关键词： HZD   PI3K/AKT   Psoriasis   TNF-α/IL-6   network pharmacology  

摘要： INTRODUCTION:Hua-Zhuo-Ning-Fu decoction (HZD) is a traditional Chinese medicine prescription that has been clinically used by Chinese medical master Wang Xinlu for treating psoriasis. However, the specific molecular mechanisms remain unclear. METHODS:To identify the effective compounds of HZD and psoriasis-related genes, we conducted comprehensive searches in public databases, including TCMSP, SwissTargetPrediction, Gene Cards, and OMIM. Based on the degree values, core genes of HZD against psoriasis were determined. Furthermore, the affinity energy between the active compounds of HZD and their core targets was validated via molecular docking. Finally, the anti-psoriasis effects and potential mechanisms of HZD were examined in M5-stimulated HaCaT cells in vitro and IMQ-induced psoriasis mice in vivo. RESULTS:Network pharmacological analysis of HZD for psoriasis treatment identified 43 active components and 243 targets. Topological and molecular docking analyses identified interleukin (IL)-6 and tumor necrosis factor-α (TNF-α) as core targets for its anti-psoriasis effects. Specifically, the docking energy of isovitexin with IL-6 was lower (-7.30 kcal/mol), and that of baicalin with TNF-α was lower (-6.70 kcal/mol). KEGG analysis revealed that the main pathway was the PI3K/AKT pathway. HZD inhibited cell viability, inflammation, and oxidative stress in M5- induced HaCaT cells. Animal experiments demonstrated that HZD alleviated psoriatic dermatitis, histopathological features, and inflammation in IMQ-induced mice with psoriatic plaques. Notably, HZD inhibited the expression of TNF-α and IL-6 and the activation of the PI3K/AKT pathway both in vivo and in vitro. DISCUSSION:Specific upstream/downstream regulators of the PI3K/AKT axis regulated by HZD still need to be explored. Further investigation is essential to clarify the functional relationship between the predicted targets and active components. CONCLUSION:In summary, HZD potentially mitigated inflammatory respons