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关键词： PI3K   TRPV1   inflammatory bowel disease   interleukin 17   interleukin 23   nociception   visceral pain  

摘要： Managing visceral pain associated with gastrointestinal (GI) disease remains a significant challenge due to the gut-related side effects and contraindicated use of many commonly used painkillers in people with inflammatory bowel disease (IBD). Consequently, it is crucial to deepen our understanding of the mediators and mechanisms underlying inflammatory pain in people with IBD. To do this, we compared bulk RNA sequencing data from colonic biopsy samples from people with IBD with single-cell RNA sequencing data from colon-projecting dorsal root ganglion (DRG) neurons in mice to generate an interactome of putative pro-nociceptive cytokine signalling pathways. This in silico analysis revealed a 10-fold increase in IL17A expression in samples from people with ulcerative colitis (UC) alongside marked co-expression of Il17ra with Trpv1 in colon-projecting DRG neurons in mice, highlighting a likely role for interleukin-17 (IL-17) in colonic nociceptor signalling in people with UC. In support of this, Ca imaging studies demonstrated that IL-17 stimulates DRG sensory neurons co-sensitive to capsaicin in male and female mice, with a similar proportion responding in neuron-enriched cultures generated by magnetic-activated cell sorting, thus confirming that IL-17 directly activates DRG neurons. IL-17-evoked Ca signals were attenuated by TRPV1 inhibition, consistent with nociceptor activation, and blocked by inhibition of phosphoinositide 3-kinase (PI3K) activity, consistent with the known role for PI3K as a downstream effector of IL-17 receptor signalling. In keeping with these observations, IL-17 enhanced colonic afferent responses to colorectal distension at noxious distension pressures in male mice, an effect also blocked by PI3K inhibition. Overall, these findings demonstrate a pro-nociceptive effect of IL-17 in the GI tract, thus highlighting the potential utility of IL-17-targeting therapies to reduce pain in people with UC.

关键词： HSCT   Chimerism   HLA   CMV   GvHD  

摘要： Several studies have investigated the association between HLA alleles and cytomegalovirus (CMV) infection following hematopoietic stem cell transplantation (HSCT). It was found that many HLA alleles were associated with increased rate of CMV infection, while others had a protective effect against infection. However, to our knowledge no studies have investigated the effect of this relation on chimerism status post transplantation. Previous results concluded that CMV reactivation or infection increases conversion from mixed chimerism toward complete chimerism (CC) as a consequence of concomitant activation of immune system. Our aim is to study the association of CMV and certain HLA alleles and their effect on chimerism status post transplantation and identify other factors affecting chimerism status. 165 patients who underwent allogeneic HSCT for different hematological indications were studied. Both recipients (R) and donors (D) underwent serological testing for CMV-specific IgG and IgM, HLA typing, and chimerism analysis. CMV infection or reactivation was assessed in recipients through weekly monitoring of CMV DNA. Patients were followed up for 100 days where chimerism analysis was performed at 28, 60, 90, and 100 days post-transplantation. Eighty-five patients were positive for CMV by PCR post transplantation while eighty patients were CMV negative. Acute graft versus host disease (aGvHD) was significantly increased in CMV positive patients. Multivariate analysis (MVA) has indicated that HLA-A*2, HLA-B*14, HLA-B*41, HLA-DRB1*04 and HLA-DRB1*13, as well as a diagnosis of myelodysplastic syndrome and bone marrow aplasia, significantly increased the risk for CMV positivity post transplantation. HLA-DRB1*11 positivity was associated with a higher rate of aGvHD. CMV infection/reactivation as indicated by positive CMV PCR post-transplant was associated with a faster rate of conversion toward CC, and this effect was independent of the implemented conditioning regimen or t

关键词： Doxorubicin   Interleukin-17A   Secukinumab   Nuclear factor kappa beta   Pyrin domain containing 3   Interleukin-1 beta  

摘要： Doxorubicin (DOX) is used as a chemotherapeutic drug for treating cancer. Nevertheless, it causes damage to the heart by activating inflammatory pathways, resulting in cardiotoxicity. Imbalance in cytokine production is a crucial component that might trigger the initiation of inflammatory processes. Inflammatory cytokines could be targeted therapies against cardiovascular diseases (CVDs). Interleukin-17A (IL-17A) is a cytokine that promotes inflammation and stimulates harmful immunological reactions. The objective of the study was to determine the efficacy of secukinumab (SEC), a completely human monoclonal IgG1/kappa antibody that targets IL-17A, in ameliorating DOX-induced cardiotoxicity (DIC). We administered 2.5 mg/kg of DOX intraperitoneally to male Wistar rats three times a week for 2 weeks and simultaneously administered 0.9 mg/kg of SEC along with 2.5 mg/kg of DOX injection three times a week for a duration of two weeks. The findings indicated that DOX induced damage to the heart tissue, resulting in a significant rise in indicators of cardiotoxicity (P < 0.001), as well as oxidative stress and inflammation. DIC may have arisen from DOX's activation of the Pyrin domain containing 3 (NLRP3) inflammasome and the nuclear factor kappa beta (NF-kappa B) pathway. The co-administration of SEC successfully reversed all DOX-induced abnormalities by restoring cardiac functions to their baseline levels, decreasing levels of inflammatory mediators such as IL-17A and interleukin-1 beta (IL-1 beta), and improving oxidative stress by reducing levels of malondialdehyde (MDA) and increasing levels of reduced glutathione (GSH). Furthermore, it mitigated the heightened activation of the NF-kappa B/NLRP3 pathway caused by DOX. This study shows that IL-17A neutralization can prevent DIC by regulating the NF-kappa B/NLRP3/Caspase-1/IL-1 beta pathway to be used as potential therapeutic target for CVDs.

关键词： HLA‐DQB1   HLA‐DRB1   NGS   novel allele  

摘要： Seven HLA class II alleles were detected and confirmed.

关键词： HLA‐A*25:95   NGS   coding change   exon 2  

摘要： The novel HLA-A*25:95 allele differs from HLA-A*25:01:01:01 by one nucleotide substitution in exon 2.

关键词： Trained immunity   Neutrophils   Bactericidal activity   Turbot  

摘要： Trained immunity refers to the immune memory of innate immune cells, which is driven by metabolic rewiring and epigenetic reprogramming after initial stimulation. Several endogenous inducers of trained immunity have been reported, such as oxidized low-density lipoprotein (oxLDL), interleukin, and interferon. However, the negative regulatory molecules of trained immunity remain largely elusive. In this study, we identify a member of IL-1 family receptors, interleukin-1 receptor 2 (IL-1R2), as a potential inhibitory regulator of trained immunity in turbot. Pre-incubating recombinant IL-1R2 protein (rIL-1R2) with turbot neutrophils could inhibit (3-glucaninduced training phenotypes. Specifically, rIL-1R2 incubation significantly decreases the expression of genes involved in the TLR/IL-1R and downstream MAPK/NF-kappa B signaling pathway in trained neutrophils, and further reversing the elevated expression of pro-inflammatory cytokines such as IL-6 and TNF-alpha in response to bacterial reinfection. Moreover, rIL-1R2 inhibits the increasing production of intracellular reactive oxygen (ROS), myeloperoxidase (MPO) activity and neutrophil extracellular traps (NETs) in trained neutrophils, ultimately impairing the bacterial killing ability. Taken together, our work demonstrates that the decoy receptor IL-1R2 could negatively regulate trained immunity activation in turbot neutrophils. These findings enrich the theory of trained immunity in teleost fish and provide a potential target for disease prevention and treatment in aquaculture.

摘要： Background and Aims: Pro-inflammatory cytokines, such as IL-1β, play a crucial role in propagating atherogenesis. Pharmacological blockade of IL-1β is effective in reducing atherosclerosis-associated cardiac events, however, additional anti-IL-1β ...

关键词： Chronic rhinosinusitis   Nasal polyps   Regulatory T cell   Interleukin-17A  

摘要： During nasal polyp (NP) development, activated T cells differentiate into T helper (Th) 1, Th2, and Th17 cells. Additionally, regulatory T cells (Tregs) that have an immune suppressive function are involved in the pathophysiology of chronic rhinosinusitis (CRS) with NP (CRSwNP). Tregs can act as effector cells that produce inflammatory cytokines, such as interleukin (IL)-17A. We sought to identify the cellular expression of IL-17A and Treg markers in sinonasal tissue from CRSwNP patients and to investigate whether Tregs are involved in IL-17A secretion. The uncinate process (UP) and NP tissues were harvested from patients with CRSwNP, CRS without NP (CRSsNP), and normal controls. Expression of IL-17A and Foxp3 in each group was observed with immunohistochemistry and immunofluorescence. Expression of IL-17A in Treg was evaluated by flow cytometry of single cells isolated from sinonasal tissues. UP tissue from controls (n = 17), UP from CRSsNP (n = 24), and UP (n = 19) and NP (n = 29) from CRSwNP were obtained. The percentage of Foxp3+ cells was higher in CRS tissues compared with normal controls. IL-17A+ cells were most increased in NP tissues from CRSwNP patients. Expression of IL-17A in some Foxp3+ cells was observed in double immunofluorescence. Foxp3+ cells, IL-17A+ cells, and Foxp3+IL-17A+ cells were increased in the UP and NP tissues from CRSwNP patients. CD45RA-Foxp3+ cells were increased in CRSwNP, and IL-17A+ cells were observed most frequently in CD4+CD45RA-Foxp3+ cells from NP tissues. These findings show that CD4+CD45RA-Foxp3+ Tregs are involved in NP pathogenesis by producing IL-17A.

关键词： Cyprinid herpesvirus 2 (CyHV-2)   ORF67   IFN   Phosphorylation   Immune escape  

摘要： Cyprinid herpesvirus 2 (CyHV-2) caused hematopoietic necrosis in crucian carp (Carassius auratus) has resulted in huge economic losses to the carp aquaculture. Interferon (IFN) response serves as a crucial line of defense for fish against CyHV-2 infection;however, CyHV-2 frequently overcomes this defense, resulting in damage and even substantial mortality. The mechanism by which CyHV-2 evades the fish IFN antiviral response remains unclear. In this study, we chose the open reading frame 67 (ORF67) of CyHV-2 as the target of our research. Firstly, the results of Co-immunoprecipitation (Co-IP) assay and in vitro phosphorylation showed that the ORF67 inhibited the expression of IFN by binding to TBK1-A/B and competitively blocking STING-A/B phosphorylation. Then, we elaborated on the effect of ORF67 on the cell's antiviral function by cytopathic effect (CPE) and immunoblot analysis. In summary, this study has clarified the molecular mechanism of immune evasion by ORF67 through the inhibition of host IFN expression. This research enhances our understanding of the pathogenesis of CyHV-2 and provides theoretical references for the prevention and treatment of hematopoietic necrosis.