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关键词： Interleukin-6 (IL-6)   Neutrophil extracellular traps (NETs)   T follicular helper (Tfh) cell   Toll-like receptor 9 (TLR9)  

摘要： ObjectiveAlthough neutrophil extracellular traps (NETs) are recognized as key contributors to rheumatoid arthritis (RA) progression, their immunomodulatory effects on T follicular helper (Tfh) cell differentiation remain enigmatic. Based on the effect of NETs on RA fibroblast-like synoviocytes (RA-FLSs), our study is aimed at investigating the effect of NETs on Tfh cell differentiation in ***, western blotting, and flow cytometry were used to investigate whether NETs mediated the inflammatory phenotype transformation of synovium fibroblasts to produce IL-6 and promote Tfh cell differentiation through TLR9/MyD88/NF-kappa B pathway. The expressions of Cit H3, MPO, TLR9, and Bcl-6 in the synovial tissues of the trauma control group and the RA group were analyzed by *** findings indicated that the plasma concentrations of IL-6 and MPO-DNA in RA patients were positively correlated with the level of IL-21 in lymphocytes and the proportion of circulating T follicular helper cells in peripheral blood. Further analysis revealed that NETs mediate the release of IL-6 from RA-FLSs through the TLR9/MyD88/NF-kappa B pathway, thereby inducing the differentiation of CD4 + T cells into Tfh cells and promoting the development of adaptive immunity in *** study demonstrated that NETs promoted Tfh cell differentiation by inducing IL-6 production by synovial fibroblasts through the TLR9/MyD88/NF-kappa B pathway. Targeting TLR9 may be a potential target for the treatment of RA. Key Points center dot NETs promoted Tfh cell differentiation by inducing IL-6 production by synovial fibroblasts through the TLR9/MyD88/NF-kappa B *** dot Targeting TLR9 may be a potential target for the treatment of RA.

关键词： cytokines   gene expression profiling   helper-inducer T-lymphocytes   Interleukin-10   neuroimmunomodulation   prurigo nodularis  

关键词： Hypoimmune iPSCs   B2M knockout   Endothelial differentiation  

摘要： Background: Induced pluripotent stem cells (iPSCs) represent a promising source for regenerative therapies, yet allogeneic transplantation is limited by immune rejection. While strategies for generating hypoimmune iPSCs have been proposed, their efficacy after differentiation into lineage-specific cell types remains underexplored. Methods: A human iPSC line (36A) from peripheral blood mononuclear cells using a Sendai virus-based reprogramming protocol. Hypoimmune properties were conferred via CRISPR-Cpf1-mediated B2M knockout, combined with lentiviral overexpression of HLA-E and CD47. Immune evasion was validated using NK cell cytotoxicity assays. Endothelial differentiation was induced using a defined, stepwise protocol, and in vivo functionality was evaluated in humanized NSG mice. Results: The hypoimmune iPSCs retained pluripotency, exhibited stable karyotype, and demonstrated > 99% expression of HLA-E/CD47. NK cell-mediated lysis was significantly reduced in edited cells, although IFN-gamma levels remained elevated. Upon differentiation, the hypoimmune iPSCs yielded > 98% CD31(+)CD144(+) endothelial cells, which showed enhanced survival in vivo compared to wild-type controls. Conclusion: Multiplex gene editing successfully conferred durable immune evasion in both undifferentiated and endothelial-differentiated iPSCs. These findings support the clinical potential of hypoimmune iPSC-derived cell therapies for allogeneic transplantation without immunosuppression.

关键词： T-cells  

摘要： Interleukin-2 (IL-2) regulates immune homeostasis by fine-tuning the balance between effector and regulatory T (Treg) cells. To identify regulators of IL-2 signaling, we performed genome-wide CRISPR-knockout screening in IL-2-dependent cells derived from a patient with adult T cell leukemia (ATL) and found enrichment of single guide RNAs targeting PRDM1, which encodes B lymphocyte-induced maturation protein 1 (BLIMP1). BLIMP1 inhibits IL-2 production by T cells;however, its role in IL-2 signaling remains unknown. Here, we show that overexpressing Prdm1 down-regulated IL-2 signaling, whereas Prdm1-deficiency enhanced IL-2 signaling in mouse CD4+ T cells and Treg cells with augmented IL-2 signaling in T cells from influenza-infected mice and during adoptive T cell transfer-induced colitis. Deleting PRDM1 in human CD4+ T cells and Treg cells also increased IL-2 signaling. Furthermore, CD4+ T cells from patients with ATL expressed less BLIMP1 and had enhanced IL-2 signaling, whereas overexpressing PRDM1 in ATL cells suppressed IL-2 signaling. Thus, BLIMP1 inhibits IL-2 signaling during normal and pathophysiological responses, suggesting that manipulating BLIMP1 could have therapeutic potential.

关键词： HIV   mouse model   graft-versus-host disease   peripheral blood mononuclear cells   T-helper cells  

摘要： The main challenge after engraftment of human tissues to mice is the development of graft-versus-host disease. It often occurs in an acute form, which reduces the time frame for observations. This is especially important to take into account when planning long-term studies of chronic diseases such as HIV infection. In addition, in mice, even with a similar genotype but different origin, the interaction between the graft and the recipient's organism can manifest itself differently. We engrafted human immune cells in three different concentrations into immunodeficient NOD/Shi-Prkdcscid Il2rgem1/Cyagen mice. Then, the initial points of development of a severe graft-versus-host reaction and the maximum possible time window for humane observation were determined. The study included regular complete blood count and the monitoring of the dynamics of the concentration of human cells in the blood of mice. In addition, the effect of grafts on the activation of the recipient's immune system was assessed. Finally, necropsy and histological and immunohistochemical examinations of the organs were performed to determine the localization of human cells. In this way, critical factors determining the success of human immune system reconstitution in mice were identified.

摘要： In acute myeloid leukemia (AML), elevated IL-6 levels in the bone marrow (BM) are linked to poor prognosis. However, the mechanisms driving this elevation and its role in chemoresistance remain unclear. Using the Prrx1-Cre system, we selectively deleted Il6 in BM mesenchymal stromal cells (MSCs) and established an AML mouse model. Our results show that MSCs are a major source of IL-6 in AML BM. Importantly, Il6 deletion in MSCs reduced oxidative phosphorylation (OXPHOS) activity in AML cells, slowed disease progression, and enhanced the chemosensitivity to cytarabine (Ara-C). Similarly, the OXPHOS inhibitor IACS-010759 improved chemosensitivity in AML mice. Exogenous recombinant IL-6 reversed the chemosensitivity gains from Il6 deletion, confirming its role in chemoresistance. We further demonstrated that Il6 absence in MSCs inhibits mitochondria transfer to AML cells, dampening OXPHOS and enhancing Ara-C efficacy. In summary, our study underscores the critical role of Il6 from MSCs in AML progression and chemoresistance. Targeting IL-6 in MSCs may offer a promising therapeutic strategy for AML. NCT06486350

摘要： Inflammation is a hallmark of immune responses. Its mechanistic underpinnings in mammals are well-defined: pro-inflammatory cytokines of the interleukin 1 (IL-1) superfamily establish and support microenvironments that promote immune cell activities. Despite a growing number of reports on inflammatory processes and components of the IL-1 signaling axis in several invertebrate lineages, orthologs of these central cytokines have not been detected outside of the jawed vertebrates. Here, protein structure prediction algorithms were applied to identify genes encoding a family of IL-1 proteins with homologs throughout Eumetazoa (termed "IL-1anc" to reflect their ancestral evolutionary origin). Using (sea lamprey) and (purple sea urchin) as model systems, we demonstrate that IL-1anc proteins share important features with mammalian IL-1α/IL-1β including expression patterns, protein localization, and processing. Together, our data indicate that the IL-1 superfamily and associated circuitry represent a foundational module of animal immunity that far predates the jawed vertebrates.

摘要： Type I interferons are secreted in response to various stimuli and are used as a treatment for many diseases, including infections with the hepatitis B virus (HBV) and its satellite virus, hepatitis delta (HDV). HDV significantly aggravates HBV-mediated liver damage and is - in contrast to HBV - a strong inducer of interferon responses, including IFN-beta. As the role of IFN- beta in liver metabolism is so far ill explored, we studied its impact on hepatocyte metabolism in HDV-infected cultures. Transcriptome analysis, isotope tracing and functional tests on differentiated, HDV-infected hepatocytes showed reduction of mitochondrial TCA cycle and respiratory activity and increases in serine, asparagine and glutathione synthesis. Furthermore, the stress-response factor ATF4 was activated by IFN-beta via yet unidentified non-canonical mechanisms and mediated resistance to oxidants. IFN-beta furthermore reduced the expression and activity of liver differentiation markers. Thus, IFN-beta-mediated dedifferentiation and stress-resistance may contribute to HDV-associated liver pathology.

关键词： autoimmune diseases   inflammation   protein-protein interactions   small molecules   TNF alpha  

摘要： Most diseases are accompanied by an inflammatory response, making effective pharmacological control highly desirable. Tumor necrosis factor alpha (TNF alpha) is a key cytokine driving inflammatory and autoimmune diseases, such as rheumatoid arthritis and inflammatory bowel disease. Although biological TNF alpha inhibitors revolutionized treatment, they have drawbacks including lacking blood-brain barrier penetration, parenteral administration, and immunogenicity. Recent studies highlight the potential of small-molecule approaches to target TNF alpha by stabilizing an asymmetrical, receptor-incompetent trimer conformation. Balinatunfib (also known as SAR441566) is an orally available small molecule designed to exploit this mechanism, thereby preventing TNF alpha from effectively binding to its receptors. In preclinical models, balinatunfib reduces inflammation comparably to biologic therapies, yet avoids the complexities of large protein therapeutics. This allosteric strategy involves capturing a sampled but distorted state of TNF alpha, thereby blocking receptor clustering and downstream proinflammatory signaling. The oral route of administration confers practical advantages in terms of patient compliance and could facilitate drug access to sites traditionally less amenable to biologics, such as the central nervous system. By demonstrating that small molecules can achieve high-affinity, conformation-based inhibition of TNF alpha, balinatunfib, and related compounds may result in a new area of orally administered therapies that advance the management of TNF alpha-mediated diseases.

关键词： 猪流行性腹泻病毒   N蛋白   时间分辨荧光微球   免疫层析法   定量检测  

摘要： 本研究旨在建立一种快速、敏感、可定量检测猪流行性腹泻病毒（porcine epidemic diarrhea virus，PEDV）N蛋白抗原的荧光微球免疫层析抗原检测方法，为猪流行性腹泻（porcine epidemic diarrhea，PED）的临床快速检测提供技术支持。本研究采用双抗体夹心法，结合荧光微球免疫层析技术，以时间分辨荧光微球（time-resolved fluorescence nanoparticles，TRFNPs）标记PEDV鼠源多克隆抗体制备荧光探针，以PEDV N蛋白单克隆抗体和羊抗鼠IgG抗体分别作检测线（T线）和质控线（C线），组装成荧光微球免疫层析抗原检测试纸条。通过梯度稀释的PEDV培养病毒液验证该方法的灵敏度。通过检测常见猪病病毒验证该方法的特异性。通过检测模拟粪便样品和临床采集病料验证该方法的临床适用性。结果显示：本方法灵敏度高，最低检测限达103.1TCID50·mL-1，试纸条T/C值呈现良好线性关系，可用于PEDV的定量检测。操作简单、耗时短，检测时间为15 min，较商品化胶体金试纸条检测灵敏性提高至少10倍。方法学验证显示，试纸条与TGEV、PoRV、PDCoV、PRRSV、CSFV、ASFV不存在交叉反应，特异性良好；试纸条的批内、批间变异系数均小于10%，重复性良好。50份临床样品的检测结果与国标RT-PCR方法总体符合率为96%，方法一致性高。本研究成功建立了基于TRFNPs的PEDV荧光微球免疫层析抗原检测方法，为临床中PEDV的快速检测提供了工具。