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关键词： autism spectrum disorder   interleukin-17A   IL-17RA   cerebral cortex  

摘要： Background: T-helper 17 (Th17) cells are a subset of CD4+ T cells that produce interleukin (IL)-17A. Recent studies showed that an increase in circulating IL-17A causes cognitive dysfunction, although it is unknown how increased systemic IL-17A affects brain function. Aims & Objectives: Using transgenic mice overexpressing ROR gamma t, a transcription factor essential for differentiation of Th17 cells (ROR gamma t Tg mice), we examined changes in the brain caused by chronically increased IL-17A resulting from excessive activation of Th17 cells. Methods: To investigate the effect of IL-17 on neuronal and glial cells in the brain, we made use of mutant mice overexpressing ROR gamma t (ROR gamma t Tg mice). Results ROR gamma t Tg mice exhibited elevated Rorc and IL-17A mRNA expression in the colon, as well as a chronic increase in circulating IL-17A. We found that the immunoreactivity of Iba1 and density of microglia were lower in the dentate gyrus of ROR gamma t Tg mice compared with wild-type mice. However, GFAP+ astrocytes were unchanged in the hippocampi of ROR gamma t Tg mice. Levels of synaptic proteins were not significantly different between ROR gamma t Tg and wild-type mouse brains. In addition, novel object location test results indicated no difference in preference between these mice. Discussion & Conclusion: Our findings indicate that a continuous increase of IL-17A in response to ROR gamma t overexpression resulted in decreased microglia activity in the dentate gyrus, but had only a subtle effect on murine hippocampal functions.

关键词： 鸡传染性喉气管炎病毒   杂交瘤细胞技术   单克隆抗体   gD蛋白  

摘要： 为了制备识别鸡传染性喉气管炎病毒（ILTV）gD蛋白的单克隆抗体，本研究以ILTV作为免疫原，采用杂交瘤技术制备融合细胞，再用酶联免疫吸附（ELISA）与间接免疫荧光（IFA）技术筛选能分泌特异性识别ILTVgD蛋白抗体的杂交瘤细胞，并对所分泌的单抗进行特性研究。间接ELISA与IFA试验结果表明，本研究成功筛选到两株能分泌识别ILTVgD蛋白的杂交瘤细胞。细胞微量中和试验结果表明，两株杂交瘤细胞分泌的抗体均能中和ILTV。抗体亚型鉴定均为IgG1，轻链为 κ 链。ILTV gD蛋白单克隆抗体的制备与特性研究为ILTV gD中和表位的筛选与ILTV血清抗体检测方法的建立提供了基础。

关键词： Clostridioides difficile   diet   fibers   group 3 innate lymphoid cells   gut microbiota   interleukin-22   intestinal epithelial cells   intraepithelial lymphocytes   MHC-II   short-chain fatty acids  

摘要： Here, we explore the relationship between dietary fibers, colonic epithelium major histocompatibility complex class II (MHC-II) expression, and immune cell interactions in regulating susceptibility to Clostridioides difficile infection (CDI). We find that a low-fiber diet increases MHC-II expression in the colonic epithelium, which, in turn, worsens CDI by promoting the development of pathogenic CD4⁺ intraepithelial lymphocytes (IELs). The influence of dietary fibers on MHC-II expression is mediated by its metabolic product, acetate, and its receptor, free fatty acid receptor 2 (FFAR2). While acetate activation of FFAR2 on epithelial cells helps resist CDI, it does not directly regulate MHC-II expression. Instead, MHC-II is regulated by FFAR2 in type 3 innate lymphoid cells (ILC3s). Acetate enhances interleukin-22 (IL-22) production by ILC3s, which then suppresses MHC-II expression on the colonic epithelium. In conclusion, a low-fiber diet reduces acetate-induced IL-22 production by ILC3s, leading to increased MHC-II on the colonic epithelium. This change affects recovery from CDI by expanding the population of pathogenic CD4⁺ IELs. © 2025 The Authors

关键词： social defeat stress exposure as juveniles   microglia   glutamatergic neurotransmission  

摘要： Background Exposure to psychosocial stress (e.g. bullying) in juveniles is one of risk factors as development of stress-related psychiatric disorders, especially with treatment-resistant, later in life. Exposures to repeated psychosocial stress activates microglia, which are important players as they contribute by either exacerbating or dampening the events that lead to neuroinflammation and neuronal damage. An abnormality of the glutamatergic neurotransmissions is a common event in the pathophysiology of these diseases. However, it is unclear whether exposure to psychosocial stress as juveniles is affected to brain immunity and glutamatergic systems.

关键词： cancer immunology   STING   interferon lambda   NSCLC   CRISPR/Cas9  

摘要： Introduction The importance of the cGAS-STING pathway and type I interferon (IFN) in anti-tumor immunity has been widely studied. However, there is limited knowledge about the role of type III IFNs in cancer settings. Type III IFNs, comprising IFN lambda 1-4, are opposite to type I IFN only expressed by a few cell types, including epithelial cells, and the receptor subunit IFNLR1, is equally only expressed on limited types of *** Gene and protein expression of the cGAS-STING signaling pathway was characterized in a series of non-small cell lung cancer (NSCLC) cell lines. Herring-testis DNA stimulation and chemotherapy drugs (doxorubicin and cisplatin) were used to activate the cGAS-STING pathway, and the level of activation was determined by measuring changes in the transcriptomic profile as well as type I and III IFNs by ELISA. Re-expression of IFNLR1 on cancer cell lines was achieved using CRISPR activation (CRISPRa) followed by evaluating chemotherapy-induced apoptosis using flow cytometry *** STING was not broadly expressed across the NSCLC cell lines. Those cancer cell lines expressing all relevant factors supporting the cGAS-STING pathway secreted IFN lambda following STING activation whereas only few of them expressed IFN beta. Treatment with chemotherapy drugs likewise preferentially induced IFN lambda, which was abrogated in CRISPR-Cas9 STING knock-out cells. Expression of IFNLR1 was found downregulated in the cancer cell lines compared to the benign epithelial cell line Nuli-1. Rescuing IFNLR1 expression by CRISPRa in multiple cancer cell lines sensitization them to IFN lambda-stimulation and resulted in significant reduction in cell *** Downregulation of IFNLR1 can be an immune evasion mechanism developed by cancer cells to avoid responding to endogenous type III IFNs. Thus, rescuing IFNLR1 expression in NSCLC in conjunction to chemotherapy may potentially be harnessed to elevate the anti-tumoral responses.

关键词： multi-electrode array   neuron networks   human iPSC derived neurons   inflammation   cytokine   long-COVID   TNF-alpha   IL-6  

摘要： Cognitive impairment is one of the many symptoms reported by individuals suffering from long-COVID and other post-viral infection disorders such as myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). A common factor among these conditions is a sustained immune response and increased levels of inflammatory cytokines. Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) are two such cytokines that are elevated in patients diagnosed with long-COVID and ME/CFS. In this study, we characterized the changes in neural functionality, secreted cytokine profiles, and gene expression in co-cultures of human iPSC-derived neurons and primary astrocytes in response to prolonged exposure to TNF-alpha and IL-6. We found that exposure to TNF-alpha produced both a concentration-independent and concentration-dependent response in neural activity. Burst duration was significantly reduced within a few days of exposure regardless of concentration (1 pg/mL - 100 ng/mL) but returned to baseline after 7 days. Treatment with low concentrations of TNF-alpha (e.g., 1 and 25 pg/mL) did not lead to changes in the secreted cytokine profile or gene expression but still resulted in significant changes to electrophysiological features such as interspike interval and burst duration. Conversely, treatment with high concentrations of TNF-alpha (e.g., 10 and 100 ng/mL) led to reduced spiking activity, which may be correlated to changes in neural health, gene expression, and increases in inflammatory cytokine secretion (e.g., IL-1 beta, IL-4, and CXCL-10) that were observed at higher TNF-alpha concentrations. Prolonged exposure to IL-6 led to changes in bursting features, with significant reduction in the number of spikes in bursts across a wide range of treatment concentrations (i.e., 1 pg/mL-10 ng/mL). In combination, the addition of IL-6 appears to counteract the changes to neural function induced by low concentrations of TNF-alpha, while at high concentrations of TNF-alpha the add

关键词： Kidney transplantation   HLA   Eplet   dnDSA   AMR  

摘要： De novo donor-specific antibody (dnDSA) generation is the most important marker of antibody-mediated rejection (AMR). However, not all dnDSAs induce AMR. The effects of mismatched eplets on dnDSA production and the occurrence AMR remain controversial. We analyzed 64 cases of dnDSA positive kidney transplantation that occurred between 2017 and 2021 at our center to reveal the relationships between mismatched eplet and dnDSA generation and the characteristics of antibody-specific and AMR associated mismatched eplets. Among the 64 dnDSA positive cases, 114 dnDSA were produced. Both the average production time and medium fluorescence index (MFI) value of human leukocyte antigen (HLA) II dnDSA were higher than those of HLA I (time, p = 0.024;MFI, p = 0.032). More HLA II dnDSAs were generated in the AMR group (p < 0.001). The frequency of HLA II dnDSAs was higher in cases of longer antibody generation time, higher MFI, and AMR( p < 0.05). The differences in the numbers of mismatched HLA I and II eplets were statistically significant between the rejection and no rejection groups (p = 0.030). dnDSA-specific and AMR associated mismatched eplets were strongly correlated (p < 0.0001). The dominant mismatched eplets included 41 T, 163R, 25Q, 78 V, 47QL and 55PP. dnDSA-specific eplets accounted for majority of the total mismatched eplets of donors and recipients. The amino acids with increased proportions of dnDSA-specific eplets were mainly non-polarity amino acids (p < 0.0001). AMR-associated mismatched eplets accounted for majority of the dnDSA-specific mismatched eplets. Arginine, histidine, glutamine, glutamate, lysine and asparagine levels increased significantly in the rejection group compared with the no rejection group (p < 0.001). The amino acids with increased proportions of AMR-associated mismatched eplets were all polar (p < 0.0001) and mainly positively charged (p < 0.0001). The polarity and charge of amino acids in mismatched eplets may be the key factors affectin

关键词： alcohol dependence   delirium tremens   TNFR1   TNF   CCL11  

摘要： Background Inflammatory factor TNF-alpha has been implicated in the pathophysiology of alcohol withdrawal syndrome (AWS) and craving phenomenon in relation to alcohol dependence (AD) [1]. Its binding to TNF receptor 1 (TNFR1) has also been reported to be involved in the apoptosis pathway [2] and to lead to neuronal cell death. Delirium tremens (DT) is a serious subtype of AWS and associated with high mortality if inadequately treated. Little is known about the role of the soluble form TNFR1 (sTNFR1) in patients with AD and its relationship with DT.

摘要： Here, we explore the relationship between dietary fibers, colonic epithelium major histocompatibility complex class II (MHC-II) expression, and immune cell interactions in regulating susceptibility to Clostridioides difficile infection (CDI). We find that a low-fiber diet increases MHC-II expression in the colonic epithelium, which, in turn, worsens CDI by promoting the development of pathogenic CD4+ intraepithelial lymphocytes (IELs). The influence of dietary fibers on MHC-II expression is mediated by its metabolic product, acetate, and its receptor, free fatty acid receptor 2 (FFAR2). While acetate activation of FFAR2 on epithelial cells helps resist CDI, it does not directly regulate MHC-II expression. Instead, MHC-II is regulated by FFAR2 in type 3 innate lymphoid cells (ILC3s). Acetate enhances interleukin-22 (IL-22) production by ILC3s, which then suppresses MHC-II expression on the colonic epithelium. In conclusion, a low-fiber diet reduces acetate- induced IL-22 production by ILC3s, leading to increased MHC-II on the colonic epithelium. This change affects recovery from CDI by expanding the population of pathogenic CD4+ IELs.

关键词： MK2   inflammatory bowel disease   Th1   Th17   inflammation   fibrosis  

摘要： Background CD4+ T cells contribute to chronic inflammation and fibrosis in inflammatory bowel disease (IBD), but the cellular mechanisms remain elusive. We have found that the mitogen-activated protein kinase 2 (MK2) pathway plays a major role in inflammation and overall pathology in IBD. Thus, here, we examined the role of MK2 in regulating CD4+ T cell responses in IBD *** Interleukin-10 (IL-10) knockout (KO) mice treated with MK2 inhibitors (MK2i) and CD4-specific MK2 knockdown mice treated with chronic dextran sodium sulfate (DSS) treatments were used to examine inflammation and fibrosis by multiplex array, gene expression, flow cytometry, and histology. Human tissues were treated with MK2i to examine Th1 and Th17 *** IL-10 KO mice treated with MK2i therapeutically showed significantly reduced interferon gamma (IFN gamma) and interleukin-17A (IL-17A) and a significantly reduced number of IFN gamma+ and IL-17A+ producing CD4+ T cells by flow cytometry. To investigate the direct role of MK2 in CD4+ T cells during IBD, we utilized CD4-specific MK2 knockdown mice in chronic DSS colitis. A decrease in colonic inflammation, IFN gamma and IL-17, pro-fibrotic genes, and extracellular matrix deposition was observed in mice with MK2 knockdown in CD4+ T cells compared to control mice. Additionally, IL-17A and IFN gamma directly regulated the expression of fibrosis genes in colon *** IL-10 KO mice treated with MK2i therapeutically showed significantly reduced interferon gamma (IFN gamma) and interleukin-17A (IL-17A) and a significantly reduced number of IFN gamma+ and IL-17A+ producing CD4+ T cells by flow cytometry. To investigate the direct role of MK2 in CD4+ T cells during IBD, we utilized CD4-specific MK2 knockdown mice in chronic DSS colitis. A decrease in colonic inflammation, IFN gamma and IL-17, pro-fibrotic genes, and extracellular matrix deposition was observed in mice with MK2 knockdown in CD4+ T cells compared to control mice.