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摘要： The type 2 cytokines, interleukin (IL)-4, IL-13 and IL-5 reside within a multigene cluster. Both innate (ILC2) and adaptive T helper 2 (TH2) lymphocytes secrete type 2 cytokines with diverse production spectra. Using transcription factor footprint and chromatin accessibility, we systemically cataloged regulatory elements (REs) denoted as SHS-I/II, KHS-I/II, +6.5kbIl13, 5HS-I(a, b, c, d, e), 5HS-II and 5HS-III(a, b, c) across the extended Il4-Il13-Il5 locus in mice. Physical proximities among REs were coordinately remodeled in three-dimensional space after cell activation, leading to divergent compartmentalization of Il4, Il13 and Il5 with varied combinations of REs. Deletions of REs revealed no single RE solely accounted for selective regulation of a given cytokine in vivo. Instead, individual RE differentially contribute to proper genomic positioning of REs and target genes. RE deletions resulted in context-dependent dysregulation of cytokine expression and immune response in tissue. Thus, signal-dependent remodeling of three-dimensional configuration underlies divergent cytokine outputs from the type 2 loci. O'Shea and colleagues examine the three-dimensional chromatin architecture of the type 2 cytokine locus and how it differs between innate ILC2 cells and adaptive TH2 lymphocytes.

关键词： Molecular dynamics   Cancer   Protein design  

摘要： Interleukin-2 (IL-2) is an immune system regulator that has received approval for cancer treatment. However, high-dose IL-2 therapy has seen restricted use due to its low efficacy and on-target toxicity. To enhance the effectiveness of IL-2 therapy, it is essential to engineer IL-2 molecules to enhance their specificity toward target cell populations. In this study, molecular dynamics (MD) simulations and Rosetta software were utilized to design novel high-affinity IL-2R alpha-binding IL-2 muteins. MD simulations were used to identify the target residues of IL-2 for design, and Rosetta software were then employed to predict potential IL-2 muteins with higher binding affinity toward IL-2R alpha. Rosetta generated two potential designed IL-2 muteins. The results of the MD validation and MM/GBSA analysis indicated that both designed IL-2 muteins exhibited greater predicted binding affinities toward IL-2R alpha than that of the native proteins. RMSF analysis demonstrated that the structural fluctuations of free IL-2 and designed muteins were similar, indicating that the mutations did not alter the intramolecular force responsible for IL-2's stability and folding. These designed IL-2 muteins may have potential benefits for cancer immunotherapy.

关键词： HLA‐B   NGS   bone marrow donor   novel allele  

摘要： Four novel HLA-B alleles are described from bone marrow volunteers of Russian Registry.

关键词： Coxsackievirus B3   Acute pancreatitis   Neutrophil   IL-10   Macrophage  

摘要： Acute pancreatitis (AP) is a lethal inflammatory disease of the pancreas. Its pathogenesis remains obscure and specific treatments are lacking. An increase in Interleukin-10 (IL-10) in the early stage of AP patients is closely related to AP severity. In Coxsackievirus B3 (CVB3) induced murine AP model, we found early IL-10 increased viral replication and pancreatic inflammation, yet the cellular source of IL-10 and the immunomodulatory role of neutrophils during viral infection remains unknown. Here we show that CVB3 infection enhanced neutrophil infiltration and IL-10 expression in the pancreas at day3 post infection (p.i.). Neutrophils served as an important early source of pancreatic IL-10 at the initiation of infection. Day3 pancreas extracts (D3P) also induced bone- marrow derived neutrophils (BMneu) to secrete IL-10. Adoptive transfer of D3P-pretreated BMneu into IL-10 KO mice increased viral replication and pancreas histopathology, which effect was blunted by the absence of IL-10 in BMneu. Mechanically, IL-10+ neutrophil increased IL-10R1 expression on M Phi s and activated STAT3-IL6/IL-10 signaling cascade while decreased IL-12 and MHC II expression in M Phi s, thus impairing IFN-gamma+Granzyme B+CD8+T cell activation and viral clearance. Adoptive transferring infected mice with activated CD8+T cells 4 days p.i. attenuated viral load and AP pathology indicating an AP-protective effect. Our findings document a novel immunoregulatory function of neutrophils in acute CVB3 infection, in which neutrophil-derived IL-10 impairs anti-viral CD8+T activation, and amplifies intrapancreatic inflammation via activating M Phi STAT3-IL-6 signaling cascade. An IL-10-targeting option is suggested for the future treatment of viral AP.

关键词： Stroke   Interleukin-17A   gamma delta T cells   Microbiota   Meninges  

摘要： The activation of the immune system is crucial for the fate of the ischemic brain tissue and neurological outcome in experimental stroke. Rapidly after stroke gamma delta (gamma delta 17), T cells release IL-17A in the ischemic brain and thereby amplify the early detrimental immune response. Notably, IL-17A levels in gamma delta 17 T cells are modulated by the intestinal microbiota which is, in turn, shaped by the diet. Importantly, besides their proinflammatory effects, meningeal gamma delta 17 T cells have been recently implicated in regulating neuronal signaling, behavior, and cognition under homeostatic and pathological conditions at the brain-meningeal interface. Against this background, we propose that a dietary intervention represents a promising treatment option to improve poststroke outcomes by the modulation of the microbiota composition and IL-17A levels in gamma delta T cells. In stroke, gamma delta T cells orchestrate the postischemic immune response in the CNS through their IL-17A production. Notably, the intestinal microbiota and the diet influence IL-17A levels in gamma delta T cells, offering the potential to modulate gamma delta 17 T cells in the postischemic CNS and to improve stroke outcome. image

关键词： Cytokines   Early life   Neuroinflammation   CNS   Development   Dura mater   Macrophage  

摘要： Multiple studies have shown that clinical events resulting into neonatal IL-4 over-exposure, such as asthma in early life and food allergy, were associated with brain damage and that the neuroinflammation induced by them might lead to cognitive impairments, anxiety-/depressive-like behaviors. IL-4 is the most major elevated cytokine in periphery when these clinical events occur and peripheral IL-4 level positively correlates with the severity of those events. Our previous studies have verified that neonatal IL-4 over-exposure induced a delayed neuroinflammatory damage in rodents, which might have adverse implications for brain development and cognition. Neuroinflammation in brain parenchyma is often accompanied by changes in CSF cytokines levels. However, whether the cytokines levels in CSF change after neonatal IL-4 over-exposure is unknown. Here, we found a delayed pro-inflammatory cytokines response (higher IL-6, IL-1 beta and, TNF levels) in both hippocampus and CSF after an instant anti-inflammatory cytokine response in IL-4 over-exposed rats. Moreover, the pro-inflammatory cytokines response appeared earlier in CSF than in hippocampus. The level of each of the pro-inflammatory cytokines in CSF positively correlated with that in hippocampus at the age of postnatal day 42. More microglia numbers/activation and higher M-CSF level in the hippocampus in IL-4 over-exposed rats were also observed. Furthermore, there were more macrophages with inflammatory activation in dural mater of IL-4 over-exposed rats. In sum, neonatal IL-4 over-exposure in rats induces delayed inflammation in CSF, suggesting CSF examination may serve as a potential method in predicting delayed neuroinflammation in brain following neonatal IL-4 over-exposure.

关键词： Sleep apnoea   Obstructive   CPAP therapy   Interleukins   Inflammatory markers   Meta-analysis  

摘要： Introduction > Obstructive sleep apnoea (OSA) is a long-term disorder characterized by frequent blockages in the upper respiratory tract during sleep, often leading to abrupt awakenings, with or without a decrease in oxygen levels. The systematic review and meta-analysis aimed to assess the effect of continuous positive airway pressure therapy (CPAP) on blood interleukin (IL) levels of IL-6, IL-10, IL-18, IL-1 beta, IL-4, and IL-17 in OSA adults. Materials and methods > The published databases from PubMed, Scopus, Web of Science, and Cochrane Library were searched from 2003 to 2024, without any restrictions. The Review Manager software 5.3 was employed to compute effect sizes, which were presented as the standardized mean difference (SMD) along with a 95% confidence interval (CI). Results > In total, 320 records were identified through database searching;ultimately, 42 articles were included in the qualitative synthesis and then the meta-analysis. The CPAP therapy significantly reduces IL-6 levels, as indicated SMD = 0.64 [95% CI: 0.35, 0.93] and P < 0.0001. CPAP therapy significantly reduced IL-18 and IL-1 beta levels in adults with OSA, but there is no significant difference in IL-10, IL-4, or IL-17 levels. Age, blood sample, body mass index, ethnicity, and treatment duration for IL-6 and apnoea-hypopnea index with IL-10 levels were effective factors in the pooled results. Experimentally, there was an interaction between IL-18 and IL-1 beta. Conclusions > CPAP therapy has a positive impact on inflammatory markers in OSA adults;remarkably, it reduces IL-6 and IL-1 beta levels. Nevertheless, more evidence (such as the role of ethnicity) and understanding of interactions are needed.

关键词： gene delivery   gene therapy   tumor biology   tumor immunology   tumor targeting  

摘要： Immunotherapy describes a class of therapies in which the immune system is manipulated for therapeutic benefit. These treatments include immune checkpoint inhibitors, adoptive cell therapy, and vaccines. For many hematological malignancies, immunotherapy has emerged as an essential treatment component. However, this success has yet to be replicated for solid tumors, which develop advanced physical and molecular mechanisms for suppressing and evading immune destruction. Nevertheless, cytokine immunotherapy presents a potential remedy to these barriers by delivering a proinflammatory immune signal to the tumor and thereby transforming it from immunologically "cold" to "hot." Interleukin-12 (IL-12), one of the most potent proinflammatory cytokines, was initially investigated for this purpose. However, initial murine and human studies in which IL-12 was administered systemically resulted in dangerous immunotoxicity associated with off-target immune activation. As a result, recent studies have employed advanced cell and molecular engineering approaches to reduce IL-12 toxicity while increasing or maintaining its efficacy such that its effective doses can be tolerated in humans. This review highlights such developments and identifies promising future directions.

关键词： Eosinophil   mast cell   systemic mastocytosis  

摘要： Background: Bidirectional interactions between eosinophils and mast cells (MCs) have been reported in various allergic diseases. Bone marrow (BM) eosinophilia, and to a lesser extent blood eosinophilia, is common in systemic mastocytosis (SM), but its significance remains unknown. Objective: We described blood and BM eosinophil characteristics in SM. Methods: A large collection of BM biopsy samples was analyzed using immunohistochemical staining and whole-slide imaging. Eosinophil and extracellular granules were detected by eosinophil peroxidase (EPX) staining and MCs by KIT staining. Complementary analyses were conducted using flow cytometry and immunofluorescence. Results: Eosinophil infiltrates and large areas of eosinophil degranulation were observed within or around BM MC infiltrates in SM. EPX staining surface, highlighting intact eosinophils and eosinophil degranulation, was higher in nonadvanced SM (n = 37 BM biopsy samples) compared with both controls (n = 8, P = .0003) and advanced SM (n = 24, P = .014). In nonadvanced SM, positive correlations were observed between serum tryptase levels and percentages of eosinophil counts in BM aspirations (Spearman r coefficient r = 0.38, P = .038), eosinophils count in BM biopsy samples (r = 0.45, P = .007), EPX staining (r = 0.37, P = .035), and eosinophil degranulation (r = 0.39, P = .023). Eosinophil counts in BM biopsy samples also correlated with MC counts (r = 0.47, P = .006) and KIT staining surface (r = 0.49, P = .003). BM MCs expressed IL-5 receptor and other usual eosinophil cytokine/chemokine receptors, and blood eosinophils displayed several increased surface markers compared with controls, suggesting an activated state. Conclusion: Our data suggest possible cross talk between MCs and eosinophils, supporting MC tryptase release and MC activation-related symptoms. This suggests a rationale for targeting eosinophils in nonadvanced SM not fully controlled by other therapies. (J Allergy Clin Immunol 2024;154:15