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关键词： Sepsis   IFN gamma   Hyperinflammation   Immunosuppression   Immunosuppressive therapy   Immunostimulatory therapy  

摘要： BackgroundThe cytokine IFN gamma is released primarily by lymphocytes to initiate and orchestrate immune responses in a broad range of target cells. Whereas immune cells release inflammatory mediators and initiate antimicrobial responses when stimulated by IFN gamma, parenchymal cells frequently display increased immunogenicity and incidental cell death. In addition to these well-characterized effects of IFN gamma, recent studies disclose a key role of the cytokine in sepsis and organ *** review summarizes current knowledge on the IFN gamma response to infection and attempts to relate the IFN gamma response to endophenotypes of sepsis in the human host. Both, excessive pro-inflammatory responses with high IFN gamma and downstream mediators, such as chemokines (CXCL9), as well as immunosuppression with low IFN gamma levels are associated with unfavorable outcomes in sepsis. Pilot studies suggested beneficial effects of recombinant IFN gamma in counteracting immunosuppression associated with low IFN gamma levels. On the other hand, IFN gamma may induce macrophages to release chemokines CXCL9, 10, and 11 to attract B and T lymphocytes to the sites of infection. Downstream induction of CXCL9 (but not of CXCL10 and 11) occurring in a subset of patients with high IFN gamma levels has been shown to correlate with the hyper-inflammatory phenotype of sepsis. Both, high- and low-expressing IFN gamma phenotypes of sepsis, might be related to nucleotide polymorphisms of the human IFN gamma *** of IFN gamma activity states with sepsis outcome renders this key regulatory protein of immunity a top candidate for theranostic interventions in a "personalized medicine approach" to infection and sepsis, especially when combined with additional biomarkers, such as CXCL9, reflecting or even mediating maladaptive downstream actions.

关键词： HLA-C*03:714   NGS-based typing   novel allele  

摘要： HLA-C*03:714 differs from HLA-C*03:04:01:01 by one nucleotide substitution at position 685G>A in exon 4.

关键词： Repetitive mild traumatic brain injury (rmTBI)   Interleukin-33 (IL-33)   Microglia   Cognition  

摘要： BackgroundRepetitive mild traumatic brain injury (rmTBI) is a significant risk factor for neurodegeneration, characterized by pathological protein deposition and persistent neuroinflammation. Research has observed increased interleukin-33 (IL-33) levels in the peripheral blood of patients with rmTBI, suggesting IL-33 may participate in regulating the pathological development of rmTBI. The study aims to elucidate the impact and mechanism of IL-33 in the progression of neuropathology following rmTBI, and to explore its potential as a therapeutic target to improve the neurological *** study employed an rmTBI mouse model using the wild-type (WT) and IL-33 knockout mice. Cognitive function was assessed via the Y-maze and Barnes tests. The main cell type expressing IL-33 and its receptor, suppression of tumorigenicity 2 (ST2), was then investigated in the mouse brain through immunofluorescence colocalization. As the primary neural cell responsible for ST2 expression, microglia were studied in vitro using the BV2 cell line. The effects of lipid droplets (LDs) accumulation and amyloid-beta (A beta) phagocytosis were measured to elucidate the impact of IL-33 on BV2 cells' phagocytosis. Additionally, HT22 neuronal apoptosis was assessed by flow cytometry. Finally, the cognitive effects of intranasal administration of IL-33 were evaluated in ***-33KO mice exhibited pronounced cognitive impairment after rmTBI. In the mouse brain, astrocytes were identified as the primary source of IL-33 secretion, while microglia predominantly expressed ST2. Transcriptome sequencing revealed that IL-33 significantly influenced phagocytosis function. IL-33 mitigated LDs accumulation in BV2 cells and enhanced A beta phagocytosis in vitro. In addition, the culture medium of BV2 cells with activated IL-33/ST2 signaling reduced HT22 neuronal apoptosis and axonal damage. Furthermore, intranasal administration of IL-33 was observed to be effective in alleviating neurodegenera

关键词： clinical trials   endoscopy   pathology   ulcerative colitis   5-ASA   5-aminosalicylates   AE   adverse event   AT   advanced therapy   CCR9   C-C chemokine receptor 9 gene   C   max   maximum observed plasma concentration   CV   coefficient of variation   IL   interleukin   JAK   Janus kinase   LDV   Leu-Asp-Val   MAdCAM-1   mucosal vascular addressin cell adhesion molecule-1   MES   Mayo Endoscopic Score   mMCS   modified Mayo Clinic Score   NI   Nancy Index   PD   pharmacodynamics   PK   pharmacokinetics   RHI   Robarts Histopathology Index   RO   receptor occupancy   SAE   serious adverse event   SD   standard deviation   t   1/2   half-life   TEAE   treatment-emergent adverse event   TESAE   treatment-emergent serious adverse event   t   max   time to reach the maximum observed plasma concentration   TNF   tumor necrosis factor   UC   ulcerative colitis  

摘要： Background and Aims MORF-057 is an orally administered small-molecule drug that inhibits α4β7 integrin-mediated recruitment of α4β7-expressing lymphocytes to the gut, a process implicated in the pathology of ulcerative colitis (UC). This study evaluated the efficacy, pharmacokinetics, pharmacodynamics, safety, and tolerability of MORF-057 in participants with moderately to severely active UC. Methods This open-label, phase 2a, single-arm, multicenter trial comprised a 6-week screening period, a 52-week active treatment period (including a 12-week induction period and 40-week maintenance period) and a 4-week safety follow-up period. Of the 35 participants enrolled in the main cohort, 18 participants received 100 mg of oral MORF-057 twice daily for the entire treatment period. The primary efficacy endpoint was a change in the Robarts Histopathology Index (RHI) score from baseline to week 12 and was assessed in all participants with evaluable data. Additional clinical, endoscopic, and histological variables were assessed at screening and at weeks 12 and 52. Results MORF-057 was well tolerated, and no treatment-emergent serious adverse events were observed. At week 12, participants (n = 35) exhibited a mean (standard deviation) change from baseline in RHI score of −6.4 (11.2). Additionally, 22.9% (8/35) of participants achieved RHI remission (RHI score ≤3). In participants with evaluable data (n = 18), the effects of MORF-057 on pharmacokinetics, pharmacodynamics, and clinical efficacy were achieved at week 12 and remained consistent to week 52. Conclusion Overall, this study demonstrated that oral MORF-057 is well tolerated, with promising efficacy for individuals with moderately to severely active UC. Clinical Trial Identifier NCT05291689 Clinical Trial Registry Website https://***/study/NCT05291689

关键词： Bifidobacterium adolescentis   cell surface polysaccharide   tumor necrosis factor-alpha   LPS   TLR4  

摘要： Bifidobacterium adolescentis, a commensal probiotic, modulates immune responses and inversely correlates with TNF-alpha production. This study investigates the immunomodulatory effects of the probiotic B. adolescentis FXJWS49M31 and its cell surface polysaccharide (CSP) on lipopolysaccharide (LPS)-induced inflammation. In vitro coculture and in vivo LPS-induced mouse models demonstrated that FXJWS49M31 and its CSP significantly suppressed the secretion of TNF-alpha and other pro-inflammatory cytokines, alleviating inflammation in the colon and liver. Mechanistic analysis revealed that CSP competitively binds to CD14, blocking the LPS-CD14 interaction and inhibiting activation of the TLR4-NF-kappa B signaling pathway. Structural modeling identified specific binding sites between CSP1 and CD14, elucidating the molecular basis of its immunoregulatory function. These findings provide a theoretical foundation for the anti-inflammatory properties of probiotic polysaccharides and their potential therapeutic applications.

关键词： Acetic acid   caspase-1   febuxostat   IL-1 beta   NLRP3   ulcerative colitis  

摘要： BackgroundUlcerative colitis (UC) is a persistent inflammation of the mucous membrane of the large intestine, mostly impacting the colon and rectum. Lack of secure and efficient medical treatments motivates the search for new therapeutic agents to efficiently manage UC and its associated outcomes. The objective of this study was to investigate the preventive effect of febuxostat in rats with UC caused by acetic acid (AA).MethodsAA (2 ml, 3% v/v) was administered intrarectally to induce UC. Preceding the administration of AA, febuxostat (10 mg/kg/day) was orally administered for two *** suppressed AA-induced UC by ameliorating colonic histological alterations, including inflammation, glandular hyperplasia, goblet cell loss, and mucosal ulcerations, while simultaneously reducing colon weight, malondialdhyde, and interleukin-18 contents. Febuxostat successfully rectified the metabolic imbalance between oxidants and antioxidants induced by AA. Furthermore, febuxostat decreased the levels of caspase-1 and NOD-LRR and pyrin domain containing protein 3 and increased colon length, catalase activity, and zonula occludens-1 *** mitigated AA-induced UC in rats by influencing the NLRP3/caspase-1/IL-1 beta signaling pathway, controlling the equilibrium between oxidants and antioxidants, and improving the integrity of the barrier of the colon.

关键词： HTLV-I infection   inflammatory diseases   toll-like receptor 3   polymorphism genetic   cytokines  

摘要： Introduction Alterations in the immune response may influence the development of HTLV-1-associated diseases. TLR3 detects viral nucleic acids, including HTLV-1, and triggers the production of IFN-I and other cytokines. Genetic variations in TLR3 may alter the antiviral and inflammatory responses and contribute to the progression of HTLV-1 infection. The present study investigated the association of polymorphisms in the TLR3 gene (rs5743305 T/A and rs3775291 C/T) with HTLV-1 infection status and their relationship with infection-associated diseases, receptor expression levels, proviral load, and inflammatory and antiviral *** Blood samples were collected from 179 individuals with HTLV-1 infection (82 with inflammatory diseases and 97 asymptomatic individuals) and 179 controls. Genotyping of polymorphisms, analysis of TLR3 gene expression, and quantification of proviral load were performed by real-time PCR, and cytokine levels were measured by enzyme-linked immunosorbent assay (ELISA).Results The polymorphisms showed no correlation with susceptibility to HTLV-1 infection, or the occurrence of disease symptoms linked to the infection. The presence of disease symptoms was associated with higher TNF-alpha levels and proviral load. TLR3 rs5743305 T/A polymorphism was not associated with variations in TLR3 and IFN-alpha levels. For the TLR3 rs3775291 C/T polymorphism, asymptomatic individuals carrying the TT polymorphic genotype presented significantly higher IFN-alpha levels and lower proviral load. The profile of asymptomatic individuals carrying the polymorphic genotypes for TLR3 rs3775291 C/T was characterized by higher levels of TLR3 and IFN-alpha and lower levels of proviral load, TNF-alpha and IL-6 compared to those with the wild-type *** Although polymorphisms in the TLR3 gene have not been associated with the presence of symptoms of HTLV-1-related inflammatory diseases, the TLR3 rs3775291 C/T polymorphism appears to contribute to a be

关键词： 基因修饰猪   恒河猴   异种心脏移植   免疫抑制药   补体   细胞因子   免疫细胞   共刺激通路  

摘要： 目的 探讨联合免疫抑制方案调控基因修饰猪-猴异种心脏移植排斥反应的效果。方法 构建2例基因修饰猪-猴异种心脏移植模型，动态监测受体外周血免疫指标并观察移植物病理变化。结果 第1例方案主要通过B细胞清除+T细胞抑制+补体C3抑制降低了淋巴细胞水平，但未能完全控制急性体液性排斥反应及巨噬细胞浸润；第2例方案在第1例方案基础上增加了补体C5抑制及白细胞介素（IL）-6抑制,与第1例方案相比，在降低淋巴细胞的同时，显著抑制了急性体液性排斥反应及补体激活，减少了抗体沉积，但移植晚期仍出现细胞因子风暴及T细胞残留。结论 第2例方案通过多靶点干预降低超急性和急性排斥反应的风险，但需平衡药物复杂性与安全性，提示需优化细胞免疫调控，并通过动态多维度监测调整方案。

关键词： 白细胞介素6   肺炎,支原体   肺炎支原体   综述  

摘要： 肺炎支原体肺炎(MPP)是由肺炎支原体(MP)感染引发的呼吸系统疾病,是儿科最常见的非典型肺炎之一。白细胞介素6(IL-6)作为一种炎性细胞因子,在MPP发生发展的过程中发挥重要作用。本文主要综述了IL-6参与MPP发生发展的机制、IL-6水平与MPP病程的关系,以及IL-6与其他炎症因子联合检测的价值,以期为后续进一步研究IL-6与MPP的相关性提供参考。