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关键词： polymyositis   dermatomyositis   vaccination   adverse events   HLA   GM/KM   juvenile dermatomyositis  

摘要： Introduction Vaccinations have had a transformative impact on public health, reducing the incidence of many infectious diseases and increasing survival. However, there remains uncertainty about the potential of vaccines to trigger autoimmune diseases such as the idiopathic inflammatory myopathies (IIM). Myositis after vaccination (MAV) is a rare clinical entity, but given immunogenetic associations with other adverse events, we explored genetic risk factors, particularly human leukocyte antigen (HLA) alleles and GM/KM immunoglobulin allotypes, that may predispose individuals to develop *** We examined clinical characteristics, vaccination history, autoantibodies, HLA alleles and GM/KM allotypes from 56 patients who developed MAV, 133 myositis cases with no documented vaccination within 6 months of onset (non-MAV), and 527 healthy controls from the pre-COVID-19 era. Genotyping for HLA and GM/KM allotypes was performed by standard assays. Differences in allele frequencies in race-matched groups were evaluated using chi-square tests, odds ratios (OR) and 95% confidence intervals (CI). Multivariate logistic regression adjusted for age, sex, and vaccination type. Statistical significance was defined as a Holms corrected p-value of less than *** No clinical or serologic differences were found between MAV and non-MAV patients. However, the HLA-DQA1*03:03 allele was a unique risk factor for MAV in Caucasians (OR=3.87, 95% CI=1.56-9.54, p=0.002), while the known myositis risk factor, HLA-DRB1*03:01, was a protective factor for MAV (OR=0.41, 95% CI=0,18-0.94, p= 0.033). GM2, GM13, and KM1 allotypes were more frequently observed in MAV patients than healthy controls, and other HLA alleles were risk or protective factors for specific vaccines given in patients who developed *** Immunogenetic factors may influence the likelihood of developing MAV. Further studies of larger, deeply phenotyped populations are needed to confirm these associations and cou

关键词： Anti-IL-6 receptor antibody   Microglia   Aquaporin-4   IL-6   NMOSD  

摘要： Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease characterized by periods of remission and relapse;severe relapses often lead to permanent neurological disability. Satralizumab, an anti--interleukin-6 receptor (anti-IL-6R) antibody, has been proven in previous studies to reduce the frequency and severity of relapses in patients with NMOSD. There are several reports on the mechanisms through which anti-IL-6R antibodies are thought to suppress relapse. However, the mechanisms underlying how anti-IL-6R antibodies reduce the severity of myelitis have not been elucidated. We investigated the effect of an anti-IL-6R antibody (MR16-1) on the severity of myelitis in an AQP4 peptide-immunized mice model. This mouse model exhibits NMOSD-like pathological characteristics and the production of anti-AQP4 autoantibodies. Unlike the previously reported experimental protocol where antibody and peptide are administered simultaneously, we tested delayed administration of MR16-1 (9 days after peptide immunization). We found that delayed MR16-1 administration suppressed the clinical score of AQP4 peptide-immunized mice experiencing myelitis. Mice treated with MR16-1 showed a greater percentage of CD11c+ microglia in the spinal cord, along with upregulated expression of phagocytosis-related genes. Blockade of IL-6R by anti-IL-6R antibodies may suppress the severity of myelitis by increasing CD11c+ microglia and enhancing phagocytic function in AQP4 peptide-immunized mice.

摘要： The accumulation of CD103+ CD8 tumor-resident memory T (TRM) cells is predictive of response to cancer immunotherapy. Here, we show that a therapeutic peptide vaccine controls tumor growth in wild-type mice, but not in CD103-knockout mice. CD8 tumor-infiltrating T lymphocytes include two major TRM subpopulations expressing either CD49a or CD103 integrin, with a subset co-expressing CD103 and Tcf-1. Vaccination induces a decrease in the percentage of Tcf-1+CD103+ TRM-like cells and expansion of CD49a+ TRM displaying an effector/exhausted profile. Tcf-1+CD103+ TRM-cell density increases in tumors from transgenic mice constitutively expressing active TGF-D-type-2-receptor and wild-type mice challenged with neutralizing anti-IL-12 antibodies. The stimulation of CD8 T cells with recombinant (r)TGF-D combined with anti-CD3 antibodies results in an increase in the proportion of Tcf-1+CD103+ cells, whereas rIL-12 decreases CD103 expression. These results highlight the opposite effects of TGF-D and IL-12 in the regulation of TRM-cell development and suggest that targeting Tcf-1+CD103+ CD8 TRM may improve immunotherapy efficacy.

关键词： tRNA   queuosine   RNA modifications   queuine   MHC-II  

摘要： Queuosine (Q) is a conserved tRNA modification in the wobble anticodon position of tRNAs that read codons of Tyr/His/Asn/Asp. Eukaryotic tRNA Q-modification requires the metabolite queuine - derived from diet or catabolism of the gut microbiome - and a host-genome encoded enzyme complex, QTRT1/QTRT2. tRNA Q-modification has been shown to regulate translational efficiency, but the response of the mammalian transcriptome and tRNAome to tRNA Q-modification in the context of cell proliferation has not been thoroughly investigated. Using cells that differ only in their tRNA Q-modification levels, we found that both human HEK293T cultures and the primary, murine bone marrow-derived dendritic cells (BMDCs) proliferate faster when tRNA Q-modification level is high. We carried out tRNA-seq and mRNA-seq to elucidate the molecular mechanisms underlying this phenotype, revealing distinct tRNA modification and transcriptome changes associated with altered proliferation. In both cell types, the m2 tRNA modification is positively correlated to Q-modification, consistent with its reported role in enhancing translational efficiency. We also find that elevated Q-modification levels result in transcriptome changes, but in a context-dependent manner. In HEK293T cells, upregulated genes are in catabolic processes and signaling pathway activation;whereas in BMDCs, upregulated genes are in immune response mediation, proliferation, and immunoglobulin diversification. Codon usage analysis of differentially expressed transcripts is consistent with Q-modification enhancing the translation of ribosomal proteins, which increases cell proliferation. We also find that tRNA Q-modification increases surface presentation of MHC-II in BMDCs. Our results provide insights into the broader implications of tRNA Q-modifications in regulating diverse biological functions. (c) 2025 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Biomass fuel   IL-17A   Neuroinflammation   Neurodegeneration   Lung-brain axis  

摘要： Biomass fuel (BMF) exposure is known to cause respiratory inflammation, but its impact on the central nervous system (CNS) and the mechanisms underlying this effect remain unclear. BMF combustion releases particulate matter (PM2.5), triggering systemic inflammation, which is linked to an increased risk of neurodegenerative diseases such as Parkinson's disease (PD). This study revealed that prolonged BMF exposure leads to dopaminergic neuron loss, increased alpha-synuclein (alpha-syn) phosphorylation, and neuroinflammation, resulting in motor and cognitive impairments in mice. Mechanistically, BMF activates the interleukin-17A (IL-17A) signalling pathway in the periphery, promoting Th cell infiltration across the blood-brain barrier, which stimulates astrocytes to release IL-17A and activates IL-17 receptor A (IL-17RA) on microglia. Transcriptomic and metabolomic analyses revealed that BMF exposure significantly disrupts immune and neurotransmitter pathways. Importantly, IL-17A knockout (IL-17A-/-) mice exhibit marked improvements in motor and cognitive functions and reduced neuroinflammation following BMF exposure. These findings identify IL-17A as a critical mediator of the lung-brain axis, orchestrating PD-related immune responses within both the CNS and peripheral nervous system. The IL-17A pathway represents a promising therapeutic target for PD and the related neuroinflammatory changes associated with environmental pollutant exposure.

关键词： Asthma   Immunology   Inflammation   Pulmonology  

摘要： The mechanisms of neutrophilic and mixed neutrophilic-eosinophilic asthma are poorly understood. We found that extracellular DNA and nucleosomes (Nucs) were elevated in the airways of patients with neutrophilic-eosinophilic asthma and correlated with bronchoalveolar lavage neutrophils. Bronchial tissue from neutrophilic-eosinophilic asthma had more DNA sensor-positive cells. Intranasally administered DNA did not induce airway hyperreactivity (AHR) or any pathology but induced AHR and neutrophilic-eosinophilic inflammation when coadministered with the allergen Alternaria (Alt). Nuc alone induced antiinflammatory/defensive genes, whereas the Nuc-Alt combination increased levels of TNF-alpha and innate cytokines. The Alt-Nuc phenotype was abolished in Cgas-/-, ALR-/-, Sting-/-, LysMCre:Stingfl/fl, IL7RCre:Ror alpha fl/fl, and Tnfr2-/- mice. Alt, unexpectedly, played an essential role in the Nuc-induced phenotype. It abrogated Nuc induction of antiinflammatory genes, facilitated Nuc uptake, induced type 2 innate lymphoid cells, which, in the presence of Nuc, produced high levels of TNF-alpha, and promoted neutrophilic infiltration. We established a paradigm whereby allergens inhibit the antiinflammatory effects of DNA/Nuc and facilitate STING-TNF-alpha-driven neutrophilic-eosinophilic inflammation in asthma.

关键词： span>RNA sequencinggene expressioncytokine burdenixekizumabguselkumababsabsolute valueBLbaselineBSAbody surface areaCDCluster of DifferentiationDEGdifferentially expressed geneFCfold changeFDRfalse discovery rateGSVAgene set variation analysisGUSguselkumabIFEimmunofixation electrophoresisIFNαinterferon αIFNγinterferon γILinterleukinIPAIngenuity Pathway AnalysisIXEixekizumabKRT17keratinKCkeratinocyteloglogarithmLSlesionLXRliver X receptorNCBINational Center for Biotechnology InformationNGSnext-generation sequencingPASIPsoriasis Area and Severity IndexPCprincipal componentPCAprincipal component analysisS100A7psoriasinPSTRpsoriasis disease transcriptomeRAGrecombination activating geneRNAseqRNA sequencingRXRretinoid X receptorsPGAstatic Physician’s Global Assessment of DiseaseTNFtumor necrosis factorTNFαtumor necrosis factor αTNFitumor necrosis factor inhibitorTRMtissue-resident memoryWweek  

关键词： epilepsy   cognition   trimetazidine   PTZ-kindling   neuroinflammation   oxidative stress   neurotransmitters  

摘要： Background Epilepsy is a chronic and complex brain disorder characterized by frequent seizures, cognitive impairments, neuroinflammation, oxidative stress, and imbalances in neurotransmitters. Developing an effective therapeutic intervention to target these pathological interventions remains a challenge. Trimetazidine (TMZ), the most commonly known anti-ischemic agent, has emerged as a promising candidate for its role in epilepsy due to its diverse mechanisms of action. This study investigates the neuroprotective, anticonvulsant, anti-inflammatory, antioxidant, and neuromodulatory effects of TMZ in managing *** Kindling was induced by administering Pentylenetetrazole (30 mg/kg, i.p) to Swiss albino mice on every alternate day;TMZ (5, 10, and 20 mg/k p.o) or sodium valproate (200 mg/kg p.o) was given for 5 weeks. Seizure severity was assessed on the Racine scale, and cognitive function and learning were evaluated using the elevated plus maze and the passive avoidance apparatus. Muscle strength was measured using the rotarod test. Neuroinflammatory biomarkers (IL-1 beta, IL-1R1, IL-6, NF-kappa B, TNF-alpha, HMGB-1, TLR-4), oxidative stress markers (MDA, GSH, SOD, catalase), and neurotransmitter (GABA, glutamate, dopamine, serotonin) levels were estimated in the hippocampus and cerebral cortex using commercially available sandwich ELISA *** TMZ, primarily at 10 and 20 mg/kg, significantly reduced seizure scores and improved the transfer latency, step-down latency, and motor abilities in the PTZ-kindled animals. It significantly reduced proinflammatory molecules IL-1 beta, IL-1R1, IL-6, NF-kappa B, TNF-alpha, HMGB-1, TLR-4. Additionally, it increased antioxidant enzyme activity (GSH, SOD, catalase) while lowering MDA levels and restoring GABA, dopamine, and serotonin levels, as well as suppressing glutamate levels, comparable to VPA at 200 mg/kg/day *** TMZ, at doses of 10 and 20 mg/kg p.o., demonstrated anticonvulsant and antioxidant ac

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 the 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 the lung. In mice, SCF synergized with IL-1(3/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 the 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： 心房颤动   β   肾上腺素受体   射频消融术   术后复发  

摘要： 目的 探讨β3肾上腺素受体(β3-AR)的表达水平对心房颤动（房颤）患者射频消融术后复发的预测价值。方法 选取2022年01月至2024年02月在昆山市第一人民医院心内科进行首次射频消融的房颤患者（房颤组，n=166）以及同期健康体检者（对照组，n=100）。依据随访结果，患者被划分为两个组别：未复发组124例，复发组42例。收集房颤患者的一般临床资料及相关实验室指标。采用荧光实时定量PCR法检测淋巴细胞β3-AR相对表达量。采用多因素Logistic回归分析房颤术后复发的危险因素；采用受试者工作特征（ROC）曲线分析β3-AR表达水平预测房颤复发的价值。结果 射频消融术后随访9个月，166例房颤患者复发42例，复发率为25.3%。与未复发组相比，复发组患者的LAD及sST2、IL-6水平显著升高，差异有统计学意义（P <0.05）。复发组β3-AR mRNA表达水平显著高于未复发组，差异有统计学意义（P <0.05）。多因素logistic回归分析显示，LAD、sST2、IL-6、β3-AR是房颤术后复发的独立危险因素（P＜0.05）。ROC显示，β3-AR表达水平预测房颤消融术后复发的ROC曲线下面积为0.884（CI95%：0.794～0.975；P <0.05）。结论 房颤患者术前高表达水平的β3-AR与射频消融术后复发有关，β3-AR可作为预测房颤复发潜在的生物学指标。