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关键词： Allograft   Sensitization   Transfusion   Human leukocyte antibody   Burns  

摘要： Objective: This meta-analysis aimed to quantify sensitization rates following allograft usage and determine whether allografts have an increased risk of long-term sensitization compared to alternative therapies in burn patients. Methods: Systematic review, meta-analysis and meta-regression of post-operative sensitization in burn patients were performed following Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidance (Prospero registration: CRD42024497137). Database searches were conducted on MEDLINE, Embase, CENTRAL using ProQuest Dialog. We included all studies reporting post-operative sensitization in burn patients that were not case series or singular case reports. Meta-analysis was used to compare the risk of sensitization for allograft versus alternative therapies. Results: Six studies (Allograft Patients: 71;Non-Allograft Patients: 95) were included (n =166). Overall, 73 % (CI: 39 %-92 %) of burn patients were sensitized following allograft. Patients receiving allograft were at a significantly increased risk of sensitization (OR 13.14 [95 % CI: 1.32-131.00]). However, on sub-group analysis, when directly comparing patients who received allograft and transfusion versus those who received transfusion alone, there was not a significantly increased risk of sensitization (OR 7.68 [95 % CI:.61-95.86]). Conclusion: Allograft is associated with a significantly increased risk of sensitization in burn patients. However, it is not clear whether burn patients already receiving transfusion will have an increased risk of sensitization from adding allograft. Further studies are required to demonstrate the multifactorial causes of sensitization within the burned population to explain the significance of the contribution from allograft and/or transfusion reported within the literature. Clinicians must carefully weigh the immediate benefits of allografts against the potential long-term challenges of sensitization, especially where alternative wound

关键词： Antibody   Coinfection   Epitope   Eplet   Immunogenic   Polyreactive   Superinfection  

摘要： Chronic rejection remains an obstacle to long-term allograft survival. Donor-specific anti-HLA antibodies (DSA) play a significant role in causing chronic antibody-mediated allograft rejection. Exposure to mismatched HLA antigens via transfusion, pregnancy, or transplanted tissue has been described in the literature as an immunogenic stimulus of anti-HLA antibodies. Yet anti-HLA antibodies also develop in the absence of traditional sensitization events and molecular mimicry has been postulated as a stimulus for these naturally occurring alloantibodies. While heterologous reactivity has been documented between virus components and allogeneic T cells, there is insufficient evidence to support the development of anti-HLA antibodies from viral components. We hypothesized that anti-HLA antibodies may develop following viral coinfection or superinfection. The objectives of this investigation included: 1) developing an in-silico algorithm to identify viral peptide components that exhibit HLA-specific homology, and 2) identifying cellular changes that take place during ischemia/reperfusion injury which could facilitate the generation of novel anti-HLA antibodies from viral sources. We developed the neoepitope transplant rejection and autoimmune disease (NETRAD) algorithm to identify amino acid sequence homology between viral envelope proteins and HLA. The algorithm integrates post-translational protein modifications that are consistent with ischemia/reperfusion injury. Seventy-two HLA-specific epitopes were demarcated as examples using this approach. In conclusion, we present in-silico evidence which supports the identification of anti-HLA antibodies as a subset of polyreactive antibodies generated from stress-modified viral envelope proteins. Remarkably, each targeted HLA epitope associated with a distinct anti-HLA antibody could be consistently attributed to a major envelope glycoprotein component of Epstein Barr virus. Transplant Immunology manuscript # TRIM-D-24-00351.

关键词： IL37   IL18 signaling   Anti-inflammation   Homology modeling   Molecular dynamics simulations  

摘要： Interleukin (IL) 37 is an anti-inflammatory cytokine belonging to the IL1 protein family. Owing to its pivotal role in modulating immune responses, elucidating the IL37 complex structures holds substantial therapeutic promise for various autoimmune disorders and cancers. However, none of the structures of IL37 complexes have been experimentally characterized. This computational study aims to address this gap through molecular modeling and classical molecular dynamics simulations. We modeled all protein-protein complexes of IL37 using a range of methods from homology modeling to AlphaFold2 multimer predictions. Models that successfully recapitulated experimental features underwent further analysis through molecular dynamics simulations. As positive controls, binary and ternary complexes of IL18 from PDB were included for comparison. Several key findings emerged from the comparative analysis of IL37 and IL18 complexes. IL37 complexes exhibited higher mobility than the IL18 complexes. Simulations of the IL37-IL18Ra complex revealed altered receptor conformations capable of accommodating a dimeric IL37, with the N-terminal loop of IL37 contributing significantly to complex mobility. Additionally, the glycosyl chain on N297 of IL18Ra, which contours one edge of the cytokine binding surface, acted as a steric block against the N-terminal loop of IL37. Further, investigations into interactions between IL37 and IL18BP suggested that a binding mode homologous to IL18 was unstable for IL37, indicating an alternative binding mechanism. Altogether, this study accesses to the structure and dynamics of IL37 complexes, revealing the structural underpinnings of the IL37's modulatory effect on the IL18 signaling pathway.

关键词： Knee osteoarthritis   Sodium hyaluronate   Platelet-rich plasma   Physical therapy   Inflammation  

摘要： The occurrence of osteoarthritis in the knee joint is regulated by a complex network, and there is currently no specific therapeutic drug available. Functional exercises and treatments targeting inflammatory factors have shown the potential to alleviate knee osteoarthritis to some extent. Therefore, the aim of this study was to assess the intra-articular injection (IAI) of autologous platelet-rich plasma (PRP) combined with physical therapy (PT) in treating knee osteoarthritis. A total of 128 patients with knee osteoarthritis were included in the study, including 64 males and 64 females. A total of 128 patients were divided into sodium hyaluronate group (HA group), PRP group, PRP + PT group, and PT group, with 32 cases in each group. Visual analog scale (VAS), Western Ontario and McMaster University Osteoarthritis Index (WOMAC), and Japanese Orthopaedic Association (JOA) were employed to evaluate the recovery of patients from pain and osteoarthritis. Color Doppler ultrasound imaging technology was utilized to assess joint effusion, synovial membrane thickness, and articular cartilage thickness in patients with knee osteoarthritis. Enzyme-linked immunosorbent assay (ELISA) was employed to detect the levels of interleukin-1 beta (IL-1 beta), transforming growth factor-beta 1 (TGF-beta 1), and matrix metallopeptidase 3 (MMP-3) in the synovial fluid. Compared to the HA group, the PT group, PRP group, and PRP combined with PT (PRP + PT) group all showed reduced VAS and WOMAC scores, increased JOA scores, decreased joint effusion, synovial membrane thickness, and articular cartilage thickness in the knee joint. Additionally, levels of IL-1 beta and MMP-3 in the synovial fluid decreased, while TGF-beta 1 levels increased (P < 0.05). Compared with the PT group, the VAS and WOMAC scores of the knee joint in the PRP group decreased, JOA scores increased, joint effusion, synovial thickness, and articular cartilage thickness decreased, but there was no statistically significant

关键词： Coxsackievirus A16   hSCARB2 mice   Nerve injury   TLR2/MYD88/TNF-alpha/Cxcl1 signaling pathway  

摘要： Coxsackievirus A16 (CVA16), a major pathogen responsible for hand-foot-and-mouth disease (HFMD) in children, has frequently replaced Enterovirus A71 as the predominant causative agent in China and other Asia-Pacific regions. The lack effective drugs and vaccines against this virus exacerbates the concerns on its outbreaks. Clinical reports and laboratory studies indicate that CVA16 infection may lead to neurological injury, but the precise mechanisms remain elusive. In this study, we meticulously established a CVA16 murine disease model using 3-week-old hSCARB2 knock-in mice through intracranial inoculation. Within 4-7 days post-infection, the infected mice exhibited severe neurological symptoms featured as limb paralysis, hind limb weakness and ataxia. Furthermore, high viral loads were detected in the brain, spleen, skeletal muscle tissues, indicating a systemic infection. A robust cytokine response was observed, characterized with the elevation of TNF-alpha, IL-12 (p40), IL-10 and MIP-1 beta. Histological and immunofluorescence staining revealed extensive inflammation, marked by the concentrated infiltration of astrocytes cells, as well as severe neurological injury, which included hypertrophic and extended pseudopodia microglia, increased astrocytes with long and stretched protuberances, markedly decreased neuronal cell bodies and nerve fibers in brain. No visible pathological changes were observed in spinal cord tissues. RNA sequencing and immunofluorescence staining of brain tissue verification assays indicated that the neurological injury may engage in TLR2/MYD88/TNF-alpha/CXCL1 signal pathway. Over all, this work addressed the gap in the availability of CVA16 disease rodent model for vaccine development and provided novel insights into the mechanisms underlying neurological injury caused by enteroviruses and other neurotropic viruses.

关键词： MAVS   Interferon   Intronic enhancer   IRFs   Large yellow croaker (Larimichthys crocea)  

摘要： The mitochondrial antiviral signaling protein (MAVS) relays signals from RIG-I-like receptors (RLRs) to induce type I interferon (IFN) production. In teleost fish, MAVS expression is significantly upregulated in response to viral infections or synthetic double-stranded RNA (dsRNA), whereas mammalian MAVS does not exhibit a similar response. However, the mechanisms regulating MAVS expression in teleosts remain unclear. In this study, we demonstrate that the viral mimic poly(I:C)-induced upregulation of Larimichthys crocea (Lc) MAVS occurs via the type I IFN signaling pathway. Inhibition of the JAK-STAT pathway significantly suppressed both poly(I:C)- and LcIFNi-induced LcMAVS expression. Further analysis revealed that an enhancer in the 5 '- untranslated region (UTR) intron of LcMAVS contains two functional interferon-stimulated response elements (ISREs), which are crucial for its activation. The enhancer activity of LcMAVS is regulated by interferon regulatory factors (IRFs), including IRF1, IRF3, IRF7, IRF9, and IRF11. These IRFs form several heterodimeric complexes, such as IRF1/3, IRF1/7, IRF3/7, and IRF3/11, to mediate LcMAVS enhancer activation. Structural analysis indicates that the ISRE motifs in the intronic enhancer can accommodate two or three DNA-binding domains (DBDs) from IRFs. These findings provide a potential explanation for the differential regulation of MAVS in response to stimuli in teleosts and mammals. Furthermore, our study demonstrates that MAVS is an interferon-stimulated gene (ISG) in a marine fish, providing insights into the evolutionary divergence of the vertebrate RLR signaling pathway.

关键词： Serum amyloid P component   Porcine epidemic diarrhea virus   Toll-like receptor 4   Interferon regulatory factors 3   Type I IFN  

摘要： Porcine epidemic diarrhea virus (PEDV) is a porcine enteropathogenic coronavirus that causes significant economic losses in many Asian and European countries. It is characterized by lethal watery diarrhea and high mortality rate in piglets. Serum amyloid P component (SAP), a member of acute response phase protein (APP) family, has been reported to play a crucial role in innate immune response against various microbial pathogens. However, its antiviral activities are little known. In this study, the antiviral activity of SAP during PEDV infection was investigated. In virus-infected IPEC cells, it was found that SAP expression was significantly upregulated. To study the role of SAP in PEDV replication, the expression of SAP was regulated in cells using eukaryotic expression plasmids expressing the SAP protein and sgRNA. PEDV replication was then assessed through realtime PCR, Western blotting, and TCID50 assays. The result showed that PEDV replication was inhibited in cells overexpressing SAP and promoted in cells with SAP knocking out. To further investigate the mechanism by which SAP inhibits PEDV replication, Interferon Beta (IFN-(3) and its related signaling pathway proteins were detected. The results demonstrated that SAP activates the promoter of (IFN-(3) and IFN regulatory factor 3 (IRF3) mediated by Toll-Like Receptor 4 (TLR4) signaling. During PEDV infection, SAP enhances TLR4-mediated IFN-(3 signaling, leading to increased IFN-(3 expression, which subsequently suppresses PEDV replication. By using TBK1/IKBKE inhibitor MRT67307 in PEDV-infected cells, the antiviral activity of SAP was inhibited. This suggests that the antiviral effect of SAP may rely on the activation of the TBK1/IKBKE signaling pathway, which is critical for the induction of type I interferons and other antiviral responses. Moreover, the interaction between SAP and PEDV N protein and the functional domain of SAP were investigated. From the results of this study, it can be concluded that the

关键词： IL-6   Inflammation   Pig   Rejection   Xenotransplantation  

摘要： The inflammatory cytokine interleukin 6 (IL-6) plays a role in both acute and chronic organ allotransplant rejection. Data suggest that IL-6 inhibition may help prevent or reverse rejection, with large multi-center trials now underway. However, the evidence for the benefit of IL-6 inhibitors in xenotransplantation is limited. IL-6 inhibition has been explored in nonhuman-primate models of xenotransplantation, but no clear consensus exists on its efficacy or the best mode of IL-6 inhibition (anti-IL-6 antibodies, or through IL-6 receptor [IL-6R] blockade). Extra considerations for IL-6 blockade exist in xenotransplantation, as both recipient (human) and xenograftderived (porcine) IL-6 may play roles. The systemic inflammation seen in xenograft recipients (SIXR) contributes to significant morbidity and mortality for the recipient through coagulation dysfunction and augmentation of the immune response. Anti-IL-6 antibodies (e.g., siltuximab) bind to human IL-6 and prevent IL-6R activation, but do not bind to porcine IL-6, and so have no effect in preventing graft-driven inflammatory processes. In contrast, IL6R inhibitors (e.g., tocilizumab) inhibit IL-6 activity by blocking binding of human and porcine IL-6 to human IL6R. Although IL-6R blockade cannot prevent the effect of IL-6 on porcine cells, it probably prevents graft-derived IL-6 from contributing to an inflammatory response in the host. This review outlines the role of IL-6 in xenotransplantation and discusses mechanisms for inhibiting IL-6 to improve recipient survival.

关键词： acute-on-chronic liver failure (ACLF)   acute kidney injury (AKI)   serum   cystatin C   metallothionein  

摘要： Background/Aims: Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis associated with systemic inflammation and organ dysfunction. In ACLF, the development of acute kidney injury (AKI) is associated with poor outcomes. FABP1, NGAL, Cys C and IL-18 have been shown to correlate with ACLF severity and mortality. Hence, our study aimed to evaluate the association of these biomarkers with organ dysfunctions, particularly AKI, in an Indian ACLF patient cohort. Methods: 151 study participants including ACLF (n = 91;with AKI n = 63, no-AKI n = 28), non-liver AKI (n = 30) and healthy controls (n = 30) were recruited. Serum ELISA was performed for biomarker estimation. Data interpolation and graphical representation were performed using GraphPad Prism and statistical analyses performed using STATA 14.0. Results: FABP1 and Cys C levels were higher in ACLF-AKI patients compared to ACLF no-AKI (P-value <= 0.0005). Serum Cys C levels were significantly increased in non-liver AKI compared to ACLF-AKI (P-value <= 0.001). AUROC analysis showed better performance of Cys C (AUC 0.79;95% CI (0.68-0.89)) compared to serum creatinine (AUC 0.71;95% CI (0.61-0.82)) in discriminating AKI and noAKI. Correlation analysis revealed positive correlations of FABP1 with creatinine and urea, Cys C with creatinine, urea and OF-Kidney, NGAL, and IL-18 with general markers of organ dysfunction. Plasma MTs) measured in a subset of ACLF patients were elevated in progression-to-AKI. Conclusion: Our study showed that in an Indian population of ACLF patients with a high short-term mortality, serum Cys C and FABP1 were elevated in ACLF-AKI, however did not have predictive potential for ACLF-AKI. Cys C levels were significantly higher in non-liver AKI patients vs. ACLF-AKI and correlated with markers of kidney dysfunction whereas NGAL and IL-18 represented higher inflammation and total organ dysfunction. Hence, we conclude that these biomarkers were elevated in ACLF-AKI but did not have predi

关键词： kidney transplantation   human leukocyte antigen   complement-dependent cytotoxicity crossmatch   delayed graft function   prognosis  

摘要： Kidney transplantation remains the preferred treatment for patients with end-stage kidney failure. Complement-dependent cytotoxicity (CDC) crossmatch (CDC-XM) and human leukocyte antigen (HLA) typing are two important methods of donor-recipient matching prior to kidney transplantation. The purpose of the present study was to explore the effects of CDC-XM levels and HLA matching on early post-operative clinical outcomes in kidney transplant recipients. A total of 112 consecutive recipients who underwent allogeneic kidney transplantation were selected and their data collected, including pre-operative general information, indicators associated with renal function, red blood cell and white blood cell counts, the blood glucose level at each follow-up time point and both the incidence of adverse events following transplantation and their risk factors. During the follow-up period, statistical methods were used to compare and systematically analyze the differences in clinical indicators and adverse events between each groups. In each different groups that were assigned for the CDC-XM levels and HLA matching, the differences in the clinical indicators between the groups during the follow-up period were mainly centered on the first week post-transplantation, with the greatest differences being identified for the renal function-associated indicators, whereas the observed recovery was essentially comparable between 1-6 months. According to the multivariate analysis, recipients of age >= 40 years and with a BMI >= 25 tended to have an increased risk of delayed graft function (DGF), whereas the risk was reduced when the organ had been donated by a living donor and also when the number of HLA mismatches was 0-2. In conclusion, the present study showed that CDC-negativity and improved HLA matching help to promote the recovery of renal function in kidney transplant recipients during the early post-operative period. Patients who met the conditions of CDC-negativity and fewer HLA mism