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摘要： Combination chemotherapy and immunotherapy are effective against advanced gastric cancer (GC). However, T cell exhaustion in the tumor microenvironment may decrease the immune response and compromise the effectiveness of immunotherapy. Herein, we report the potential role of EBI3 in promoting T cell exhaustion and its mechanism in GC, showing high expression of EBI3 in GC. Correlation analysis between EBI3 expression level and clinical-pathological features indicated significant associations with Tumor stage, Nodal staging, pathologic stage, and degree of tumor differentiation. EBI3 expression levels correlated with a state of high CD8+ T cell exhaustion, as identified by transcriptome sequencing and mice orthotopic GC models. On exposure to EBI3, CD8+ T cells showed signs of cell exhaustion as reduced cytokine secretion and increased expression of inhibitory receptors in vitro/vivo studies. Mechanistically, EBI3 induced T cell exhaustion by promoting phosphorylation of STAT4, upregulating the transcription of downstream target genes CCL5 and IL-10. An anti-EBI3 heptapeptide (Val-Tyr-Leu-His-Trp-His-Asp) was developed, which competitively bound EBI3 and reversed the induction of T cell exhaustion. Taken together, we identified a T cell exhaustion mechanism in GC via the EBI3-STAT4-IL10/CCL5 axis and developed an anti-EBI3 heptapeptide with an antagonistic function. These findings provide a potential immunotherapeutic target and support the development of EBI3-based interventions to enhance immunotherapy efficacy in GC.

关键词： ILC2   cell therapy   islet transplantation   immune tolerance   type 1 diabetes (T1D)   BG   blood glucose   CAR   chimeric antigen receptor   GVHD   graft-versus-host disease   H&E   hemotoxylin and eosin   HLA   human leukocyte antigen   IEQ   islet equivalent   IFN   interferon   IL   interleukin   ILC   innate lymphoid cell   ILC2   group 2 innate lymphoid cell   IPGTT   intraperitoneal glucose-tolerance test   MHC   major histocompatability complex   NSG   nonobese diabetic-scidIL2Rgammanull   PBMC   peripheral blood mononuclear cell   PP   pancreatic progenitor   PSC   pluripotent stem cell   STZ   streptozotocin   T1D   type 1 diabetes   Treg   regulatory T cell  

摘要： Group 2 innate lymphoid cells (ILC2s) that produce interleukin (IL)-10 (IL-10 + ILC2s) have demonstrated regulatory and tissue-protective properties in murine studies, but preclinical studies are lacking that explore the potential of human IL-10 + ILC2s as a tolerance-promoting cell therapy for transplantation or autoimmunity. Here, we investigated whether human IL-10 + ILC2s could enhance islet function and prevent allograft rejection in humanized mouse models of islet transplantation. In vitro , human IL-10 + ILC2s did not display cytotoxicity toward allogeneic deceased-donor islets or stem cell–derived islet-like cells, and co-transplantation with IL-10 + ILC2s significantly improved glucose control post-transplantation. Allogeneic IL10 + ILC2s directly inhibited T cell–mediated cytotoxicity against islet-like cells in vitro and, in an antigen-specific transplant rejection model, prevented T cell–mediated rejection of deceased-donor islet grafts. Effects were greater with allogeneic IL-10 + ILC2s, as autologous cells did not inhibit T cell interferon-γ production or cytotoxic activity in vitro and were not sufficient to prevent islet rejection in vivo . Collectively, these studies provide proof-of-principle that human IL-10 + ILC2s have therapeutic potential for islet transplantation and type 1 diabetes and support their use as an allogeneic regulatory cell therapy.

关键词： 骨关节炎,脊柱   人类白细胞抗原B27   白细胞介素-17A   交互作用   易感性  

摘要： 目的分析人类白细胞抗原B27(HLA-B27)基因、白细胞介素-17A(IL-17A)水平对脊柱关节炎(SpA)易感性影响交互作用。方法将2020年2月至2022年3月就诊于邢台市人民医院的95例SpA病人纳入病例组,另选同期与SpA病人的性别、年龄相匹配的95例健康体检者作为健康组。采集所有受检者血清样本,流式细胞术法测定HLA-B27抗原表达情况,聚合酶链式反应-序列特异性引物法(PCR-SSP)测定HLA-B27基因分型,酶联免疫吸附测定检测血清IL-17A水平。对比病例组、健康组HLA-B27基因亚型、血清IL-17A水平,建立logistic回归交互作用模型,分析HLA-B27基因、IL-17A交互作用。绘制ROC曲线,分析HLA-B27基因协同血清IL-17A预测SpA发生的价值。结果病例组HLA-B27阳性率(76.84%)高于健康组(9.47%)(P<0.05),病例组HLA-B27基因亚型以HLA-B*2704、HLA-B*2705为主;AS组、JSpA组、PsA组、ReA组、USpA组的HLA-B27阳性率分别为88.10%、70.00%、60.00%、69.23%、70.00%,且五组HLA-B27基因亚型均以HLA-B*2704、HLA-B*2705为主;病例组血清IL-17A水平为57.46(11.81,92.85)ng/L,高于对照组的32.44(5.53,72.02)ng/L(P<0.05);HLA-B27阳性、阴性组SpA病人的性别、年龄、病程、发病至确诊时间及晚发型、幼年发病型占比相比,差异无统计学意义(P>0.05);HLA-B27阳性组血清IL-17A水平及SpA家族史占比均高于HLA-B27阴性组(P<0.05);logistic回归分析结果显示,SpA家族史[OR=4.90,95%CI:(1.06,22.70)]、IL-17A水平[OR=5.12,95%CI:(1.19,25.74)]是影响HLA-B27阳性的危险因素(P<0.05);logistic回归模型多因素分析显示,HLA-B27基因、血清IL-17A水平均是SpA发生的独立危险因素(P<0.05);logistic回归交互分析显示,HLA-B27基因、血清IL-17A水平交互项P<0.05,说明两者之间存在交互作用;绘制ROC曲线,结果发现,HLA-B27基因、IL-17A及二者协同预测SpA发生的AUC为分别为0.84,95%CI:(0.78,0.90);0.92,95%CI:(0.87,0.96);0.98,95%CI:(0.97,1.00)。结论SpA病人HLA-B27基因阳性率与血清IL-17A水平高,基因亚型HLA-B*2704、HLA-B*2705为主,HLA-B27基因协同血清IL-17A水平可有效预测SpA的发生。

关键词： Tumor progression   Autophagy modulation   Cancer cell survival   IL-6/STAT3 pathway   Proteasome  

摘要： Aims: This study aims to investigate the expression, clinical relevance, and functional roles of PSME2 in esophageal squamous cell carcinoma (ESCC). Materials and methods: The biomarkers for ESCC were identified through comprehensive analysis of publicly available mRNA transcriptome data obtained from TCGA and GEO databases. The mRNA and protein expression levels of PSME2 in ESCC were validated using two independent cohorts of ESCC samples. The proliferation, migration, invasion, and autophagy activity of ESCC cells were evaluated in vitro through the knockdown of PSME2 or PR171. The effects of the knockdown of PSME2, STAT3 inhibitor WP1066, and autophagy inhibitor chloroquine on the tumorigenic potential of ESCC cells were also assessed through an in vivo subcutaneous tumor model established in nude mice. Key findings: The result obtained indicates the upregulation of PSME2 in ESCC, suggesting poor prognosis. The result also shows that the knockdown of PSME2 and PR171 triggers the reduction in ESCC cell proliferation, migration, and invasion. Thus, it buttresses the fact that PSME2 knockdown induced autophagy through the IL6/ STAT3 pathway, leading to cell death resistance. The result also linked the suppression of tumor growth to the knockdown of PSME2 and WP1066 or chloroquine, suggesting that targeting these proteins may be a potential therapeutic strategy for inhibiting tumor progression. Significance: The study shows the promising role of PSME2 as a therapeutic target in ESCC management. The combined inhibition of PSME2 and activated pathways ensures effective suppression of tumor growth and proliferation, thus offering a novel strategy for better treatment outcomes in ESCC patients.

关键词： autoinflammatory disease   interleukin-1   interleukin-1 inhibition   recurrent pericarditis   rilonacept   csDMARD   conventional disease-modifying antirheumatic drug   ESC   European Society of Cardiology   NSAID   nonsteroidal anti-inflammatory drug   RP   recurrent pericarditis  

摘要： Background Recurrent pericarditis (RP) guidelines recommend second-line corticosteroids after aspirin/nonsteroidal anti-inflammatory drugs/colchicine, but complications of protracted use underscore the importance of corticosteroid-sparing strategies. Objectives Given clinical trial evidence supporting interleukin (IL)-1 pathway inhibition and US Food and Drug Administration approval of rilonacept in RP, the objective was to assess temporal trends in corticosteroid-sparing treatment of RP in a multicenter registry. Methods RESONANCE (REgiStry Of the NAtural history of recurreNt periCarditis in pEdiatric and adult patients; NCT04687358 ) combines retrospective and prospective data from clinical practice into a single observation period. Patients receiving treatment for idiopathic and postprocedural RP were included. Demographics and treatment intensifications were quantified. Results Of 313 patients with aspirin/nonsteroidal anti-inflammatory drugs/colchicine treatment (median disease duration 1.9 years; 1 preenrollment recurrence), 44% (n = 138) intensified treatment. Before rilonacept approval in RP, 71% (n = 10) of patients intensified to corticosteroids for second-line therapy, and 29% (n = 4) intensified to IL-1 pathway inhibition. After rilonacept approval, the proportion of patients intensifying to second-line IL-1 pathway inhibition increased to 64% by 2023 (n = 27; rilonacept: 57%, anakinra: 7%), whereas the proportion of patients intensifying to corticosteroids decreased to 33% (n = 14), P = 0.02. Approximately 59% (n = 35) of second-line corticosteroid initiators later transitioned to IL-1 pathway inhibition. In patients starting second-line IL-1 pathway inhibition, 5% (n = 3, rilonacept) and 25% (n = 4, anakinra) subsequently used corticosteroids for >30 days. Conclusions In RESONANCE, IL-1 pathway inhibition increasingly replaced corticosteroids as second-line therapy. Most patients starting corticosteroids transitioned to IL-1 pathway inhibition; few tra

摘要： Nearly 50 years after its discovery as a major genetic risk factor for spondyloarthritis (SpA), the precise contribution of HLA-B27 to disease development and progression remains only partially understood. Proposed mechanisms include aberrant antigen presentation, misfolding-induced endoplasmic reticulum stress and modulation of innate immune responses..

关键词： AIM2   Absent in melanoma 2   AO   acridine orange   ASC   Apoptosis-associated speck-like protein containing a CARD   ATP   Adenosine triphosphate   BMDMs   Bone marrow-derived macrophages   COX-2   Cyclooxygenase-2   CXCL1   C-X-C motif chemokine ligand-1   DAI   Disease activity index   DSS   Dextran sulfate sodium   FLA-ST   Flagellin from   Salmonella typhimurium   IBD   Inflammatory bowel disease   IL   Interleukin   LDH   Lactate Dehydrogenase   LPS   Lipopolysaccharide   MCP-1   Monocyte chemoattractant protein-1   M-CSF   Macrophage colony-stimulating factor   MDC   monodansylcadaverin   MDP   Muramyl dipeptide   MPO   myeloperoxidase   MSU   monosodium urate   MtDNA   Mitochondrial DNA   NLRC4   NLR family CARD domain-containing 4   NLRP3   NOD-, LRR- and pyrin domain-containing protein 3   ROS   reactive oxygen species   TNF-α   Tumor necrosis factor-α   Glycosylated cinnamaldehyde   NLRP3 inflammasome   Colitis   Peritonitis  

摘要： Cinnamaldehyde, a natural compound with diverse biological activities, has limited biomedical application due to its potential cytotoxicity. In this study, we synthesized a series of novel glycosylated cinnamaldehyde derivatives by varying both the sugar moiety and its attachment position on the aromatic ring. Preliminary screening for cytotoxicity and anti-inflammatory activity revealed that these structural modifications critically influenced bioactivity. Among the derivatives, compound 1a , bearing a β-D-galactosyl group at the para-position of the cinnamaldehyde phenyl ring, exhibited the most promising therapeutic potential. In contrast, replacing the β-D-galactosyl group with β-D-glucosyl ( 1b ) or α-D-mannosyl ( 1c ) residues resulted in loss of anti-inflammatory activity. Similarly, shifting the β-D-galactosyl group to the meta ( 1d ) or ortho ( 1e ) positions also abolished activity, highlighting the importance of both sugar identity and its positional attachment in determining function. Subsequent mechanistic studies focused on compound 1a and its effect on the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, a central mediator in inflammatory disorders. Compound 1a effectively suppressed NLRP3 inflammasome activation by reducing mitochondrial damage and disrupting inflammasome complex assembly in macrophages. Furthermore, 1a promoted Sirt1-mediated autophagy, which contributed to additional inhibition of inflammasome activation. Notably, 1a inhibited not only the NLRP3 inflammasome but also the NLRC4 inflammasome in macrophages. In vivo, oral administration of 1a significantly alleviated both dextran sulfate sodium (DSS)-induced colitis and monosodium urate (MSU)-induced peritonitis in mice, primarily through NLRP3 inflammasome suppression. Collectively, these findings identify compound 1a as a promising lead compound for the treatment of inflammasome-driven inflammatory diseases and underscore the therapeutic potential of rational g

关键词： Coronary artery   Fibrous cap thickness   Inflammation   Interleukin-6   Myocardial Infarction   Optical coherence tomography  

关键词： immunopeptidomics   EThcD   HLA ligandome   de novo   sequencing   Orbitrap Excedion Pro   CID   collision-induced dissociation   ETD   electron-transfer dissociation   EThcD   electron-transfer/higher-energy collision dissociation   HCD   higher-energy collision dissociation   HLA-I   human leukocyte antigen class I   IRM   ion routing multipole   LC-MS/MS   liquid chromatography coupled to tandem mass spectrometry   m/z   mass over charge   NCE   normalized collision energy   PSMs   peptide spectrum matches   PTM   posttranslational modifications   RF   radio frequency   SA   supplemental activation   z   charge  

摘要： Gaining a complete and unbiased understanding of the nontryptic peptide repertoire presented by human leukocyte antigen class I (HLA-I) complexes by LC-MS/MS is indispensable for therapy design for cancer, autoimmunity, and infectious diseases. A serious concern in HLA peptide analysis is that the routinely used collision-based fragmentation methods [collision-induced dissociation (CID)/higher-energy collision-induced dissociation (HCD)] do not always render sufficiently informative MS2 spectra, whereby gaps in the fragmentation sequence coverage prevent unambiguous assignments. Electron-transfer/higher-energy collision dissociation (EThcD) can be utilized to generate complementary ion series, i.e., b/y ions and c/z ions, resulting in richer, more informative MS2 spectra, thereby filling in the gaps. Here, we present data generated on a novel hybrid orbitrap mass spectrometer, facilitating fast and efficient hybrid fragmentation due to the implementation of EThcD in the ion routing multipole. We hypothesized that this would enable more comprehensive and less error-prone analysis of immunopeptidomes at minimal costs in duty cycle. First, we optimized ETD/EThcD methods using an elastase-digested cell lysate, as this contains peptides of similar length and charge distributions to immunopeptides. Next, we compared HCD and EThcD on immunopeptidomes originating from three cell lines with distinct HLA-I complexes that present peptides with varying physicochemical properties. We demonstrate that the new instrument not only enables efficient and fast ETD reactions but, when combined with collision-based supplemental activation, i.e. EThcD, also consistently increases the sequence coverage and identification of peptide sequences, otherwise missed by using solely HCD. We reveal several of the biochemical properties that make HLA peptides preferably identifiable by EThcD, with internal Arg residues being one of the most dominant determinants. Finally, we demonstrate the power o

关键词： Basal IFNλ Signaling   Epithelial Barrier Function   Hippo Signaling Pathway   Tight Junctions   cGAS-STING Pathway  

摘要： Type-III interferons (or IFNλs) play important roles in antiviral defense and intestinal epithelial barrier integrity. While interferon expression has been primarily studied in response to pathogens, basal interferon expression also occurs in pathogen-free environments. However, the mechanisms regulating basal IFN-λ expression and their functions have not yet been elucidated. Here, we show that basal IFN-λ2/3 expression is linked to the development of an intact cellular epithelium characterized by formation of tight junctions and establishment of barrier function. Our findings indicate that basal IFN-λ2/3 expression depends on cGAS-STING-mediated mitochondrial DNA detection, while it is inhibited by the Hippo mechanotransduction pathway at low cellular densities. Cells lacking basal IFN-λ2/3 expression fail to develop proper tight junctions and establish normal barrier function. Mechanistically, IFN-λ2/3 suppresses Claudin-2 expression, thereby promoting barrier formation as cells become confluent. These results demonstrate a previously unknown function of basal IFNλ expression in regulating epithelial cell junction formation and highlight their importance not only during pathogen challenges but also in maintaining epithelial cell function under steady-state conditions.