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摘要： CD4 T cell autoreactivity against citrullinated (cit) self-epitopes presented by HLA-DRB1 is associated with rheumatoid arthritis (RA) pathogenesis. We understand the molecular bases of T cell receptor (TCR) recognition of cit-fibrinogen, cit-vimentin, and cit-α-enolase epitopes, and the role of citrulline in shaping TCR repertoire usage. Nevertheless, how TCRs recognise other cit-epitopes, including tenascin-C (TNC) and how alternative citrullination positions may modulate the T cell recognition remains unclear. Here, we examined TNC peptide, which contains citrullination at position P-1 and P2, to study the underlying TCR-HLA-DRB1*04:01- TNC molecular interactions. Crystal structure of HLA-DRB1*04:01 at 2.4 Å resolution revealed a conserved peptide binding register to the established HLA-DRB1*04:01-peptide structures, where both citrullines protruded upwards. Next, we determined the crystal structure of a RA patient-derived TRAV35/TRBV10-2 (PB) TCR in complex with HLA-DRB1*04:01 at 3.2 Å resolution. The CDR3α loop (VGNTN) of PB TCR formed a secondary helical conformation at the N-terminus of the peptide binding cleft, allowing extensive interactions between the P-1 and P2 citrullines of TNC peptide. Surface plasmon resonance, tetramer staining, and CD69 activation assays revealed that the PB TCR did not cross-react to other RA autoantigens, and the P-1-Cit, P2-Cit, and P5-Tyr of TNC are the key determinants underlining the strict specificity of the PB TCR. Collectively, we provide molecular insight of citrullination in modulating TCR recognition.

关键词： Multiple sclerosis   IFNG rs2069727 T/C   Interferon-gamma   MicroRNA   Biomarker  

摘要： Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder, with relapsing-remitting MS (RRMS) being the most common subtype. Interferon-gamma (IFN-gamma) plays a dual role in MS pathogenesis. MicroRNAs (miRNAs) have emerged as potential diagnostic biomarkers. This study examined the effect of relative expression of hsa-miR-24-3p and hsa-miR-181d-3p, plasma IFN-gamma levels, and the IFNG rs2069727 T/C variant on MS risk, evaluating their interrelationships and diagnostic potential. This case-control study comprised two overlapping groups-a genetic polymorphism group (330 RRMS, 330 healthy controls (HCs)) and a miRNA group (25 glatiramer acetate (GA)-treated RRMS patients, 25 treatment-na & iuml;ve RRMS patients, and 25 HCs)- collected at the Ankara Bilkent City Hospital Neurology Polyclinic. The IFNG rs2069727 T/C variant did not display a statistically significant disparity between RRMS patients and HCs. Significantly elevated hsa-miR-24-3p and hsa-miR-181d-3p relative expression levels were observed in GA-treated and treatment-na & iuml;ve RRMS patients compared to HCs. Conversely, age-adjusted plasma IFN-gamma concentrations were markedly lower in GA-treated and treatment-na & iuml;ve RRMS patients versus HCs. Individuals with low plasma IFN-gamma levels (<= 1.311 pg/mL) demonstrated significantly elevated hsa-miR-24-3p relative expression compared to the high IFN-gamma group (> 1.311 pg/mL). Conversely, subjects with low hsa-miR-181d-3p levels (<= 2.90) exhibited significantly higher plasma IFN-gamma concentrations relative to those with high hsa-miR-181d-3p levels (> 2.90). In the GA-treated group, EDSS negatively correlated with age-adjusted plasma IFN-gamma. This study identified age-adjusted plasma IFN-gamma, hsa-miR-24-3p, and hsa-miR-181d-3p expression as potential blood-based biomarkers for RRMS diagnosis and analyzed them alongside disability scores. The miRNAs in this study can be further evaluated as prospective therapeutic targets.

关键词： coronary thrombus   NETs   STEMI   inflammation   IL-6R   PAD4  

摘要： Inflammation contributes to myocardial injury in ST-elevation myocardial infarction (STEMI). Interleukin-6 receptor (IL-6R) inhibition has been shown to mitigate myocardial injury and reduce levels of the prothrombotic and inflammatory mediator, neutrophil extracellular traps (NETs). The enzyme peptidylarginine deiminase 4 (PAD4) is central in NET formation. We hypothesized that PAD4 links IL-6R activation and NET formation. Methods: We conducted thrombus aspiration and peripheral blood sampling in 33 STEMI patients. In thrombi and leukocytes, we quantified the mRNA of IL-6, IL-6R, and PAD4. In peripheral blood, the protein levels of IL-6, IL-6R, PAD4, dsDNA, H3Cit, MPO-DNA, and troponin T were quantified. Results: In thrombi and circulating leukocytes, PAD4 mRNA was associated with IL-6R mRNA (thrombi: beta = 0.34, 95% CI [0.16-0.53], p = 0.001, circulating leukocytes: beta = 0.92, 95% CI [0.07-1.77], p = 0.036). There were no correlations between PAD4 and IL-6 in thrombi and leukocytes. The protein levels of IL-6R were associated with the NET marker H3Cit (rs = 0.40, p = 0.02). In thrombi, PAD4 mRNA was associated with high levels of troponin T (beta = 1.15 95% CI [0.27-2.04], p = 0.013). Conclusion: We demonstrate an association between PAD4, IL-6R, and troponin release in STEMI patients. Our findings indicate a PAD4-mediated connection between IL-6R and NET formation and highlight PAD4 as a potential treatment target for mitigating inflammation and myocardial injury in STEMI.

摘要： Cardiovascular disease is the main cause of death in patients with ankylosing spondylitis (AS). Previous studies showed high serum levels of IL- 33 in AS patients and suggested that it may play a role in disease development. However, the possible role of IL- 33/sST- 2 in atherosclerosis in AS has not been investigated. To assess serum levels of IL- 33 and sST- 2 and to assess their association with carotid intima-media thickness (CIMT) and disease activity in a group of Egyptian patients with AS. Serum levels of IL- 33 and sST- 2 were statistically higher in AS patients compared to controls (median, 451.75 vs 37.42, p = 0.000) and (median, 5.71 vs 0.74, p = 0.000) respectively. IL- 33 and sST- 2 levels positively correlated with Bath Ankylosing Spondylitis Disease Activity Index (r = 0.445, p = 0.004) and (r = 0.421, p = 0.007) respectively, and Ankylosing Spondylitis Disease Activity Score with CRP (r = 0.684, p = 0.000) and (r = 0.452, p = 0.003) respectively. There was a positive correlation between serum IL- 33/sST- 2 and CIMT. The high serum levels of IL- 33 and sST- 2 in AS patients and their positive correlation with CIMT and AS disease activity suggest that IL- 33/ST2 axis-induced inflammation may be a major factor in the development of cardiovascular disease in AS patients.

关键词： Anti-inflammatory   Human health   Network Pharmacology   Rubiaceae   UPLC-Q-TOF-MS   Sore throat relief  

摘要： Psychotria rubra Herbal Tea (PRHT) is a traditional Chinese folk medicine used to treat in-flammation induced by respiratory infections. Its specific mechanisms of action, however, remain unclear. The study combined ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS), network pharmacology, and in vitro cell experiments to systematically analyze the chemical composition and validate the biological activity of PRHT. Protein-protein interaction (PPI) network analysis and molecular docking were used to identify key targets and mechanisms. PRHT was found to contain 128 active compounds, including alkaloids, amino acids and their derivatives, and flavonoids. Key targets such as STAT3, IL-6, and TP53 were identified through PPI network analysis. PRHT exhibited significant anti-inflammatory effects by modulating the STAT3/IL-6/TNF-alpha signaling pathway. Experimental results demonstrated that PRHT inhibited the release of inflammatory cytokines in a dose-dependent manner. Molecular docking confirmed strong interactions between PRHT components and core targets. The study reveals that PRHT exerts anti-inflammatory effects by regulating the STAT3/IL-6/TNF-alpha signaling pathway, contributing to inflammation balance and tis-sue repair. These findings provide scientific evidence for the development of PRHT as a functional anti-inflammatory agent and offer new insights into treatment strategies for respiratory infections.

摘要： Donor-specific T cell responses, particularly against human leukocyte antigen (HLA)-DQ antigens, are critical in transplant immunology as they influence graft survival and rejection. This study investigated HLA-DQ-specific CD4 T cell responses in naive individuals using HLA-DQ monomers, representing common donor HLA-DQ antigens (DQ2.5, DQ5, DQ6, DQ8), as defined alloantigen sources to enrich and detect HLA-DQ-specific T cells. Using a repeated stimulation protocol with HLA-DQ monomers, we achieved an enrichment of HLA-DQ-specific CD4 T cells, evidenced by proliferation and activation marker upregulation. Additionally, epitope prediction identified 15-mer HLA-DQ peptides capable of binding to self-HLA-DRB1 alleles. TCR sequencing demonstrated an enriched, oligoclonal repertoire of HLA-DQ-specific CD4 T cells post-stimulation, with specific TCR clonotypes expanding in response to HLA-DQ monomer stimulation. Together, our study presents an method for enriching HLA-DQ-specific CD4 T cells using HLA-DQ monomers as an alloantigen source, thereby improving the detection of alloreactive, donor-specific T cells in naive individuals with the potential to mediate immune responses, including graft rejection and donor-specific antibody (DSA) production.

摘要： Accumulating evidence from rodent and human studies indicates that the activity of thermogenic adipocytes positively correlates with optimal metabolic function. In this issue of the JCI, Yesian et al. uncover a paracrine signaling pathway from type 2 innate lymphoid cells to preadipocytes via IL-13 that increases beige adipogenesis through a PPARγ-dependent pathway. Mice with deletion of Il13ra1 demonstrated glucose dysregulation, and variants near the human IL13RA1 locus were associated with body weight and diabetic status. It is tempting to speculate that targeting IL-13 holds therapeutic potential for improving metabolic fitness in humans.

关键词： 直肠癌   癌胚抗原   细胞角质素片段19   铁蛋白   中性粒细胞/淋巴细胞  

摘要： 目的探讨直肠良、恶性肿瘤间肿瘤标志物与中性粒细胞/淋巴细胞(Neutrophil to lymphocyte ratio,NLR)差异,找出对直肠癌早期诊断有意义的指标。方法选择直肠癌患者126例,直肠良性肿瘤患者92例。收集相关肿瘤标志物癌胚抗原(Carcinoembryonic antigen,CEA)、细胞角质素片段19(Cytokerantin-fragment-19,CYFRA21-1)、铁蛋白(Ferritin,Ferr)、糖类抗原199(Carbohydrate antigen199,CA199)、糖类抗原724(Carbohydrate antigen724,CA724)水平及术前NLR水平,分析各指标在两组间的差异,对有差异的指标建立二元Logistic回归模型,绘制受试者操作特征曲线(Receiver Operating Characteristic,ROC),并对各指标进行相关性分析。结果恶性组患者中年龄、CEA、CYFRA21-1、NLR水平显著高于良性组,恶性组患者Ferr水平显著低于良性组(P<0.05)。CEA、CYFRA21-1、NLR为直肠癌危险性因素,3者比值比(Odds Ratio,OR)分别为1.255(95%CI:1.088~1.446,P=0.002)、1.602(95%CI:1.143~2.245,P=0.006)、1.739(95%CI:1.003~3.015,P=0.049)。Ferr为直肠癌保护性因素,OR为0.996(95%CI:0.993~0.998,P=0.001)。CEA、CYFRA21-1、Ferr、NLR对直肠癌预测概率分别为74.1%、69.2%、72.7%、65.0%,4者联合的预测概率为83.7%。其中,4者联合检测的灵敏度为0.776,特异度为0.773。NLR/CEA、NLR/CYFRA21-1间存在正相关关系(P<0.05),其余无统计学意义(P>0.05)。结论CEA、CYFRA21-1、Ferr、NLR水平在直肠良、恶性肿瘤间存在差异,4者联合检测对直肠癌早期诊断具有一定临床价值。

关键词： 危重病   结核   肺   中性粒细胞减少   淋巴细胞   预后  

摘要： 目的:评估中性粒细胞与淋巴细胞比值(neutrophil to lymphocyte ratio,NLR)及血清降钙素原(procalcitonin,PCT)对重症医学科(ICU)重症肺结核患者预后的价值。方法:回顾性分析2021年1月至2023年12月河北省胸科医院ICU收治的重症肺结核患者144例,依据患者入ICU 28 d的生存状态分为生存组(67例)与死亡组(77例),收集患者的基本临床资料和入ICU 24 h内NLR、血清PCT等化验检查结果进行组间比较,分析上述指标单独及联合检测对ICU重症肺结核患者预后的预测效能。结果:死亡组患者NLR及血清PCT水平分别为12.76(9.49,23.44)和4.18(2.64,5.66)ng/ml,均高于生存组[分别为8.13(6.24,15.06)和2.31(1.09,3.52)ng/ml],差异均有统计学意义(Z值分别为-5.501和-5.343,P值均<0.001)。在单独预测ICU重症肺结核患者预后方面,NLR的受试者工作特征曲线下面积(AUC)为0.766,敏感度为75.3%,特异度为70.1%;PCT预测的AUC为0.759,敏感度为77.9%,特异度为65.7%;二者联合预测的AUC为0.833,敏感度为81.8%,特异度为73.1%。结论:相较于单独检测,联合NLR与血清PCT检测对评估ICU重症肺结核患者的预后价值更高,可以为临床诊治提供参考。