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关键词： Subacute sclerosing panencephalitis   Measles   IL-12   IFN-gamma   Gene expression   Cytokines  

摘要： Background: Subacute sclerosing panencephalitis (SSPE) is a rare but fatal neurological syndrome resulting from persistent measles virus infection in the central nervous system. Despite the availability of a measles vaccine, SSPE continues to pose a significant health burden, and immunogenetic risk factors remain unclear. We aimed to study the role of the interleukin 12 (IL-12)/interferon-gamma (IFN-gamma) axis, known for it's significance in antiviral defense, in the development of SSPE. Methods: This cross-sectional case-control study recruited consecutive age and sex-matched SSPE cases (n = 51) and controls (n = 51). Gene expressions were quantified for IL-12B, IFNG, IL-12RB1, STAT4, IFNGR1, IFNGR2, STAT1, IRF8, and ISG15 genes using quantitative realtime PCR. Additionally, plasma levels of IL-12p40, IL12p70, and IFN-gamma were measured using the multiplex suspension array platform. Furthermore, single nucleotide polymorphisms (SNPs) in IL-12B, IL-12RB1, IFNG, IFNGR1, IFNGR2, and ISG15 genes were examined using TaqMan SNP genotyping assays. Statistical analyses compared gene expressions, cytokine levels, and alleles and genotypes frequencies between SSPE patients and controls. Results: Significant alterations in the expression of key IL-12 pathway-related genes were observed in SSPE patients compared to controls, including lower STAT4 (p = 0.0445) and higher IFNGR1 (p = 0.0005) and IRF8 (p = 0.0229). Elevated plasma levels of IL-12p70 (p = 0.0015) and IFN-gamma (p = 0.0381) were also observed in SSPE patients. Additionally, associations with SSPE were found for the rs3212227 SNP in IL-12B (p = 0.048), the rs1059293 SNP in IFNGR2 (p = 0.052), and the rs1921 SNP in ISG15 (p = 0.054) genes. Notably, gene-gene interactions among these genes exhibited associations with SSPE. Conclusion: This study provides novel insights into the dysregulation of the IL-12/IFN-gamma immune axis in SSPE and underscores the complex interplay between host genetics and viral infection in

关键词： genetic diversity   HLA   immunogenetics   Kazakhstan   linkage disequilibrium   polymorphisms  

摘要： Background: The human leukocyte antigen (HLA) system represents the most polymorphic segment within human DNA sequences and constitutes a core component of immune defense responses and in understanding population genetics. This research investigates the distribution of HLA class I and II polymorphisms across different ethnic groups in Kazakhstan, offering valuable insights into the genetic diversity and demographic evolution within this region. Methods: We performed an in-depth examination of HLA class I and II polymorphisms across diverse ethnic communities living in Kazakhstan, including Kazakhs, Russians, Uzbeks, Ukrainians, Germans, Tatars, and Koreans. Utilizing data from high-resolution HLA typing studies allowed us to assess allele frequencies alongside haplotype distributions while analyzing genetic interrelations between these populations. Additionally, we performed comparative assessments with global HLA databases to determine the genetic affiliations between these groups and their relationships with neighboring and more distant populations. Results: Our study revealed over 200 HLA alleles within the analyzed populations, and significant variations were observed in their allele and haplotype frequencies. Notably, the Kazakh group exhibited strong genetic ties to Asian and Siberian demographics;conversely, other ethnicities showed associations reflective of their historical roots. Notable alleles included HLA-A*02:01, B*07:02, C*07:02, DRB1*07:01, and DQB1*03:01, commonly observed across various groups. Linkage disequilibrium analysis revealed the presence of population-specific haplotypes, highlighting distinct genetic structures within these communities. Conclusions: The findings highlight the significant genetic diversity in Kazakhstan, influenced by its geographical location at the crossroads of Europe and Asia. These results are pertinent to immunogenetics, transplantation medicine, and personalized healthcare within Kazakhstan and adjacent regions. Fu

关键词： Idiopathic nephrotic syndrome   Steroid-sensitive nephrotic syndrome   Frequently relapsing   Steroid dependent   Human leukocyte antigen  

摘要： BackgroundManagement of patients with steroid-sensitive nephrotic syndrome (SSNS) is challenging because of frequent relapses. Causal variants in the human leukocyte antigen (HLA) class II region that are associated with relapse remain *** collected a cohort of East Asian individuals comprising 206 pediatric patients with SSNS and 435 healthy controls from Southwest China. Ninety children with steroid-sensitive nephrotic syndrome without relapse (SSNSWR) and 116 children with steroid-dependent and/or frequent relapse nephrotic syndrome (SDNS/FRNS) were genotyped using Sanger sequencing. We then measured the transcriptional level, allele expression imbalance (AEI) and functional proteins of HLA-DQA1 and HLA-DQB1 in different stages of SDNS/***1464545187 in ANKRD36 was associated with an approximately 1.69-fold greater risk for SSNSWR (P = 0.04;95% confidence interval [CI], 1.05-2.72). Clustered risk variants in HLA-DQA1 and HLA-DQB1 were significantly associated with SDNS/FRNS (rs1047989: P = 2.26E-07, odds ratio [OR] = 2.25, 1.65-3.05;rs9273471: P = 5.45E-05, OR = 1.84, 1.37-2.46;HLA-DQB1*06:02: P = 0.017, OR = 0.19, 0.04-0.77). The genotype distributions of rs1047989, 2:171713702, rs1049123, rs9273471, and HLA-DQB1*06:02 in patients with SSNS were significantly different from those in healthy controls. rs1047989 (HLA-DQA1) was significantly associated with a greater number of infections at relapse in SDNS/FRNS patients (P = 0.045, OR = 6.79, 95% CI: 1.29-168.52). Flow cytometry showed that the proportion of cells expressing HLA-DQA1+/DQB1+ (HLA-DQA1+, P = 0.0046;HLA-DQB1+, P = 0.0045) was lowest in the relapse stage. In addition, the mRNA levels of HLA-DQA1 and HLA-DQB1 were significantly greater in the relapse group than in the remission group (HLA-DQA1, P = 0.03;HLA-DQB1, P = 0.002). No significant AEIs were detected in the different stages of SDNS/FRNS. The rs1047989 variant is likely to affect the structure and stability of HLA-DQA

关键词： glutamate   mGluR5   Crassostrea gigas   hemocyte   IL-17 expression  

摘要： Metabotropic glutamate receptor 5 (mGluR5) is a critical regulator of immune responses within the neuroimmune system, influencing cytokine secretion and immune cell function. Although extensively studied in mammals, its role in regulating IL-17 in invertebrate immunity is poorly understood. This study examines CgmGluR5 expression and downstream signaling activation in Pacific oyster (Crassostrea gigas) hemocytes following glutamate (Glu) and Vibrio splendidus treatment. Glu treatment significantly induced the expression of CgmGluR5 and key signaling molecules, including PLC, DAG, IP3, Ca-2(+), and PKC, while enhancing mRNA levels of CgIL17-1, CgIL17-5, and CgCaspase3. Elevated Ca-2(+) content and CgIL17 expression in hemocytes were observed at 12 h post-Glu exposure, indicating CgmGluR5-mediated immune regulation through the phosphoinositide pathway. A 1.14-fold increase in the apoptosis rate was found in the Glu treatment group compared to the control group. Knockdown of CgmGluR5 suppressed CgIL17-1 and CgIL17-5 expression and reduced granulocyte proportions, reflecting its role in immune regulation. This study shows that CgmGluR5 mediates long-term immune regulation in oysters through the phosphoinositide pathway, providing new theoretical insights for aquaculture immune management.

关键词： 慢性骨髓增殖性肿瘤   调节性T细胞   细胞因子   免疫治疗  

摘要： 慢性骨髓增殖性肿瘤（myeloproliferative neoplasm，MPN）是肿瘤克隆和炎症相互作用的典型疾病模型，免疫微环境在其发生发展中发挥重要的调控作用。调节性T细胞（Regulatory T cells，Tregs）是免疫微环境中的重要组成部分，可受到IL-4、IL-10、IL-13和TGF-β等抗炎细胞因子以及肿瘤坏死因子-α、IL-2、IL-17、IFN-γ等促炎细胞因子的调控，同时也可分泌TGF-β、IL-10等多种细胞因子。目前Tregs在MPN中的具体作用机制尚不明确，本文综述了Tregs相关细胞因子在MPN中的表达及作用，并总结了目前MPN中靶向Tregs相关细胞因子的治疗方式，以期为Tregs及其相关细胞因子在MPN发病机制、临床应用等领域的研究提供思路。

关键词： evolutionary divergence   HBV   HCC   human leukocyte antigen   zygosity  

摘要： Background and Aims:The human leukocyte antigen (HLA) locus is implicated in HCC among chronic HBV carriers. We investigated associations of HLA variants, amino acid polymorphisms, zygosity, and evolutionary divergence with HBV-related HCC in Han Chinese and explored biological mechanisms. Approach and Results:We examined the associations of HLA variants (imputed 4-digit classical alleles and amino acid polymorphisms), zygosity, and evolutionary divergence with HBV-related HCC in a discovery set (706 HBV-related HCC cases, 6197 chronic HBV carriers in Taiwan). Significant signals were validated in an independent set (636 cases, 560 controls in Qidong, Mainland China). We used logistic regression adjusted for sex, age, and top 10 genetic principal components, with a Bonferroni correction for multiple testing (p<1.6x10(-4)). We evaluated predicted peptide-binding affinities and control of viral load, viral population diversity, and inflammatory markers for significant signals. HLA-DQB1*03:01 was most significantly associated with HBV-related HCC in discovery and validation sets (ORmeta-analysis=1.33, p(meta-analysis)=2.6x10(-8)). Three amino acids within the DQ beta 1 peptide-binding region, HLA-DQ beta 1Ala13, HLA-DQ beta 1Tyr26, and HLA-DQ beta 1Glu45, were positively associated with HCC. HLA-DQB1*03:01 was associated with lower binding affinity of HBV nucleocapsid antigen and higher HBV DNA load and serum soluble programmed cell death 1 (sPD-1) (p<0.05). HLA-DQB1 heterozygosity was inversely associated with HCC independent of HLA-DQB1*03:01 (p(meta-analysis)=3.3x10(-3)). Conclusions: HLA-DQB1*03:01 and its 3 key amino acids are associated with an increased HBV-related HCC risk. This association may be explained by the low binding affinity to HBV antigen, resulting in poor control of viral load and increased inflammation, as evidenced by sPD-1 levels.

关键词： Anti-TNF therapy   Autoinflammation   Innate immune cells   Systemic autoinflammatory diseases   TNF inhibitors: TNFR1   TNFR2  

摘要： Systemic autoinflammatory diseases (SAIDs) are rare conditions resulting from innate immune system dysregulation, culminating in repetitive bouts of systemic inflammation without the presence of external or self-antigens. Most SAIDs are associated with mutations in genes affecting the innate immune response. Tumor necrosis factor (TNF) is a central player in the pathogenesis of numerous chronic inflammatory disorders, and anti-TNF therapy is widely used in the clinical management of SAIDs. TNF inhibitors block the interaction of TNF with its two receptors, TNF receptor 1 (TNFR1) and TNF receptor 2 (TNFR2). These inhibitors primarily target soluble TNF (sTNF), which mainly binds to TNFR1, exerting anti-inflammatory effects. Interestingly, TNF inhibitors also affect transmembrane TNF (tmTNF), which engages TNFR2 to initiate reverse signaling. This reverse signaling can activate innate immune cells, prevent apoptosis, or paradoxically inhibit the production of pro-inflammatory cytokines. TNF inhibitors also promote the release of soluble TNFR2 (sTNFR2), which neutralizes circulating TNF. Some agents targeting TNFR2 can even act as agonists, triggering reverse signaling by binding to tmTNF. While effective, prolonged use of TNF inhibitors may cause significant side effects due to the widespread expression and pleiotropic functions of TNF receptors. More thoroughly understanding of the mechanisms underlying the action of TNF inhibitors is required to develop more effective and safer treatment for SAIDs. This article reviews current studies on the role of the innate immune system in SAID pathogenesis, the impact of anti-TNF therapy on innate immune cells, and perspectives on developing improved agents targeting TNF or its receptors.

关键词： COVID-19   acute respiratory distress syndrome   pulmonary fibrosis   surfactant protein-d   interleukin-10   angiotensin-converting enzyme-2  

摘要： Background Patients with severe COVID-19 can rapidly develop acute respiratory distress syndrome (ARDS), which further increases the risk of developing pulmonary fibrosis. The exact role of macrophage polarization and different cytokine production in the pathophysiology associated with COVID-19 induced ARDS or pulmonary fibrosis is unknown. It is necessary to identify potential biomarkers that can predict the progress of pulmonary fibrosis or other adverse *** We analyze the plasma samples obtained from healthy individuals and COVID-19 patients who were stratified according to the disease severity and fibrotic-like changes on chest computed tomography (CT) scans. Surfactant Protein D (SP-D), Matrix Metalloproteinase 8 (MMP8), Krebs von den lungen-6 (KL-6), Angiotensin-Converting Enzyme 2 (ACE2), and macrophage polarization-related biomarkers were determined by ELISA. Data were collected and evaluated using regression models and receiver operating characteristic (ROC) *** The plasma levels of SP-D, MMP8 in patients with ARDS were higher than those of non-ARDS patients. Patients with pulmonary fibrosis had higher plasma levels of SP-D compared to those without fibrotic changes. Among the biomarkers indicative of macrophage polarization, compared to non-ARDS patients, a significant increase in IL-10, Inducible nitric oxide synthase (iNOS), and Arginase-1 (Arg-1) were observed in ARDS patients, while Tumor necrosis factor-alpha (TNF-alpha) was decreased. The plasma level of IL-10 was also elevated in patients with fibrotic changes on CT, and was positively correlated with ACE2 and Arg-1. ROC curve results uncovered that SP-D showed higher efficacy in predicting pulmonary fibrosis and ARDS compared to other inflammatory markers. And IL-10 had similar predictive value with traditional inflammatory indicators such as CRP and *** SP-D and IL-10 exhibited certain predictive abilities for the development of ARDS and pulmonary fibrosis in

摘要： The glioblastoma tumor immune microenvironment (TIME) is an immunosuppressive barrier to therapy that encumbers glioblastoma responses to immune checkpoint inhibition (ICI). Immunosuppressive cytokines, pro-tumor myeloid cells, and exhausted T-cells are hallmarks of the glioblastoma TIME. Here we integrate spatial and single-cell analyses of patient-matched human glioblastoma samples before and after ICI with genetic, immunologic, single-cell, and pharmacologic studies in preclinical models to reveal that interleukin-6 (IL-6) inhibition reprograms the glioblastoma TIME to sensitize mouse glioblastoma to ICI and radiotherapy. Rare human glioblastoma patients who achieve clinical responses to ICI have lower pre-treatment IL-6 levels compared to glioblastomas who do not respond to ICI. Immune stimulatory gene therapy suppresses IL-6 tumor levels in preclinical murine models of glioblastoma. Furthermore, survival was longer in knockout mice with orthotopic SB28 glioblastoma relative to wild-type mice. IL-6 blockade with a neutralizing antibody transiently sensitizes mouse glioblastoma to anti-PD-1 by increasing MHCII+ monocytes, CD103+ migratory dendritic cells (DCs), CD11b+ conventional DCs, and effector CD8+ T cells, and decreasing immunosuppressive Tregs. To translate these findings to a combination treatment strategy for recurrent glioblastoma patients, we show that IL-6 blockade plus ICI durably sensitizes mouse glioblastoma to high-dose radiotherapy.

关键词： donor-specific HLA antibodies   pneumococcal vaccine   zoster vaccine   renal transplant   vaccination in kidney transplant   vaccines induced HLA antibodies  

摘要： Background In renal transplant waitlisted patients, vaccinations remain the standard of care for infection prevention. The vaccine and its adjuvant sensitizer can be potential sources for the induction of donor-specific antibodies (DSA) against human leukocyte antigens (HLA). These novel HLA antibodies can result in a positive flow cell crossmatch (FCXM), which can make a previously compatible live donor *** report We present an adult renal transplant waitlisted patient who has had multiple negative T-cell and B-cell FCXM with no detection of DSA at baseline. The patient then received a single dose of pneumococcal conjugate (PCV13) and a second dose of recombinant zoster vaccine (RZV). After these vaccinations, the patient's FCXM was positive for both T-cells and B-cells and the HLA class I antibodies (A1, 23, 24, 80;B44, 45, 76) showed a calculated panel reactive antibody (cPRA) of 51%. A1 and B44 DSA were detected which predicted incompatibility with the patient's planned live donor renal transplant. The patient had to enter the kidney-paired donation program instead and receive their transplantation after 16 *** RZV or PCV13 vaccines or their adjuvant components can potentially cause allosensitization in renal transplant waitlisted patients. The detection of DSA can result in reduced access to compatible transplants. With advances in HLA immunogenetics, better tools can monitor HLA-specific memory B-cells to provide crucial insights into the primary mechanism of action of HLA DSA antibody formation and suggest interventions to mitigate this memory B-cell activation.