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关键词： HLA   HLA-B*51:409N   next-generation sequencing   novel allele  

摘要： HLA-B*51:409N differs from the HLA-B*51:01:01:01 by one nucleotide at position 923 in exon 3.

关键词： Heparan sulfate   Interferon   Inflammation   Macrophage  

摘要： Heparan sulfate (HS) proteoglycans are important regulators of cellular responses to soluble mediators such as chemokines, cytokines and growth factors. We profiled changes in expression of genes encoding HS core proteins, biosynthesis enzymes and modifiers during macrophage polarisation, and found that the most highly regulated gene was Sulf2, an extracellular HS 6-O-sulfatase that was markedly downregulated in response to pro-inflammatory stimuli. We then generated Sulf2+/- bone marrow chimeric mice and examined inflammatory responses in antigen-induced arthritis, as a model of rheumatoid arthritis. Resolution of inflammation was impaired in myeloid Sulf2+/- chimeras, with elevated joint swelling and increased abundance of pro-arthritic Th17 cells in synovial tissue. Transcriptomic and in vitro analyses indicated that Sulf2 deficiency increased type I interferon signaling in bone marrow-derived macrophages, leading to elevated expression of the Th17-inducing cytokine IL6. This establishes that dynamic remodeling of HS by Sulf2 limits type I interferon signaling in macrophages, and so protects against Th17-driven pathology.

关键词： EBV-associated T/NK-cell lymphoproliferative diseases (EBV-T/NK-LPDs)   EBV plus lymphoblastoid cell lines (LCLs)   Exosomes   Cutaneous T-cell lymphoma (CTCL)   Immune evasion  

摘要： EBV-associated T/NK-cell lymphoproliferative diseases (EBV-T/NK-LPDs) are characterized by the clonal proliferation of EBV-positive ( +) T/NK cells. EBV is typically latent in B cells and the mechanism by which the EBV genome invades T/NK cells remains unknown. Recent studies have demonstrated that exosomes derived from EBV + B cells play a pivotal role in immunosuppressive microenvironment remodeling. Moreover, the existence of an immunosuppressive microenvironment is known to be critical in the development of EBV-T/NK-LPDs. Hence, we hypothesized that exosomes derived from EBV + B cells might promote the development of EBV-T/NK-LPDs by stimulating immune evasion. In this study, we utilized paraffin sections to clarify the STAT3/IL-10/PD-L1-associated immunosuppressive microenvironment in EBV-T/NK-LPDs. Further, we extracted exosomes from BL2009 (EBV + B cell lymphoma) and CA46 (EBV- B cell lymphoma) cell lines to co-culture with cutaneous T-cell lymphoma (CTCL) cell lines, to verify the changes in the above immune evasion pathway. The paraffin sections of EBV-T/NK-LPDs showed high-expression levels of IL-10/PD-L1, which might be related to the phosphorylation of STAT3. Exosomes derived from EBV + B cells could significantly activate the STAT3/IL-10/PD-L1 pathway. After being treated with C188-9, EBV + B cell-derived exosomes were no longer able to stimulate the expression of IL-10/PD-L1 in CTCL cells. EBV-T/NK-LPDs have a STAT3/IL-10/PD-L1 overactivation-associated immunosuppressive microenvironment. Our study elucidated part of this mechanism. Exosomes derived from EBV + B could induce phosphorylation of STAT3 in CTCL cells, leading to the overexpression of IL-10/PD-L1. Our findings might shed light on new directions for understanding immune evasion in EBV-T/NK-LPDs.

关键词： Rheumatoid arthritis   Peripheral helper T cells   Interleukin-7  

摘要： Objective: Dysregulated T cell homeostasis has long been implicated in the pathogenesis of rheumatoid arthritis (RA), in the joint of which peripheral helper T (Tph) cells accumulate and form ectopic lymphoid organs. We examined whether homeostatic signals are involved in the development of Tph cells. Methods: Human peripheral blood mononuclear cells were cultured with IL-7, the critical cytokine for T cell homeostasis. Development of Tph-like cells was assessed by flow cytometry, gene expression, and functional analysis. Chemotaxis of the Tph-like cells to RA synovial fluid (RASF) and the effect of RASF on the development of Tph-like cells was examined. Results: PD-1highCXCR5- Tph-like cells developed from human peripheral blood CD4 T cells after proliferation in response to IL-7. Signals from self-MHC recognition and CD28 co-stimulation were also involved. The IL-7induced Tph-like (IL-7-Tph) cells produced CXCL13 and IL-21 and helped B cells produce IgG. Comprehensive gene expression analysis further supported the similarity with Tph cells in RA joint. IL-7-Tph cells exhibited chemotaxis toward synovial fluid from RA patients (RASF), and RASF promoted the development of IL-7-Tph cells, which were also induced from CD4 T cells residing in non-inflamed joints. Conclusions: Our results demonstrate an antigen-nonspecific developmental pathway of Tph cells triggered by homeostatic signals and promoted by the local environment of RA, which accounts for the accumulation of Tph cells in inflamed joints.

关键词： Tanshinone IIA   Microglia   Inflammation   Neuronal apoptosis   Signaling pathway   Stroke  

摘要： Tanshinone IIA (Tan IIA), a neuroprotective natural compound extracted from Salvia miltiorrhiza, is used in stroke treatment. However, elucidating Tan IIA's neuroprotective mechanisms remains challenging due to limitations in assessing drug efficacy and biochemical parameters in clinical studies. This study investigated Tan IIA's impact on neuroinflammatory responses and its neuroprotective mechanisms using HMGB1- or TNF-alpha-stimulated BV2 microglia in a co-culture system with primary neuron cells. The results indicated that Tan IIA significantly reduced microglial activation induced by TNF-alpha or HMGB1. Concurrently, Tan IIA disrupted the interactions between HMGB1 and toll-like receptor 4 (TLR4), and between TNF-alpha and TNF receptor 1 (TNFR1), modulating the HMGB1/TLR4/nuclear factor-kappa B (NF-kappa B) and TNF-alpha/TNFR1/NF-kappa B signaling pathways and related protein expressions. Moreover, co-culture experiments showed that neuronal apoptosis induced by microglial activation was reversed by Tan IIA. In conclusion, Tan IIA provides neuroprotection by modulating signaling pathways in microglia, thus preventing neuronal apoptosis. This study offers new insights into therapeutic targets for ischemic stroke.

关键词： CIWD   equity   HLA eplet frequency   HLA eplets   molecular compatibility  

摘要： The degree of immunological compatibility between donors and recipients greatly impacts allograft survival. In the United States kidney allocation system, HLA antigen-level matching has been shown to cause ethnic disparities and thus, has been de-emphasised. However, priority points are still awarded for antigen-level zero-ABDR matching, zero-DR matching and one-DR matching. Recently, the degree of HLA molecular (eplet) mismatch has emerged as a more accurate measure of immunological risk, and eplet mismatch load has gained attention as a possible biomarker to improve HLA compatibility. However, little is known about the frequency of eplets in population groups, which is a necessary step to ensure that candidates from any ethnical background can have similar chances at a well-matched organ. Eplet frequencies were estimated using HLA alleles in the Common, Intermediate and Well-Documented (CIWD) 3.0.0 catalogue for six population groups: African-American (AFA), Asian-Pacific Islander (API), European/European descent (EURO), Middle East/North Coast of Africa (MENA), Hispanic/Latino (HIS) and Native-American (NAM). We determined that 98.6% (484 out of 491) of HLA eplets are expressed by the common HLA alleles in all population groups. Of the seven eplets that were expressed by less common HLA alleles, six were Class I eplets and one was expressed by HLA-DQB1 alleles and most were expressed by HLA alleles that were more commonly observed in European/European descent populations. Our observations indicate that HLA eplets will not cause any significant disparity if applied to HLA molecular compatibility, regardless of the ethnic origin of both recipients and donors.

关键词： Animal nutrition   Bacteria   Cancer   Gene expression   Human nutrition   Probiotics  

摘要： Lactic acid bacteria (LAB) probiotics are health-promoting but their characteristics, safety profile and functional mechanisms are not fully understood. Hence, this study aimed to characterize some hypothetical proteins of the chicken-isolated Limosilactobacillus reuteri genome and unravel their IL-2 and IL-10-inducing potential to understand mechanisms of their immunological functionality for sustainable applications. The selected proteins were subjected to in silico analyses for transmembrane topology, sub-cellular localization, IL-2 and IL-10-inducing ability and IL-2 and IL-10 gene expression across various conditions. IL-2 and IL-10-inducing mutants were statistically analyzed using a one-way analysis of variance of a general linear model of SAS and statistical significance was set at p < 0.05. The analyzed proteins are stable under a wide temperature range. All the hypothetical proteins are IL-2 and IL-10-inducing but QHPv.2.12, QHPv.2.13 and QHPv.2.15 are non-immunogenic. The evaluated mutants are IL-2 and IL-10-inducers but QHPv.2.13 and QHPv.2.15 are not immunogenic. This study sheds light on understanding the functional mechanisms of chicken-isolated L. reuteri and suggests it or its proteins as potent candidates for feed additive and therapeutic purposes.

关键词： HLA-C   NGS   novel allele   Russian  

摘要： The novel HLA-C*03:694, HLA-C*05:301 and HLA-C*07:1160Q alleles were detected during the HLA typing process.

关键词： Chlamydia psittaci   mtROS   mtDNA   CGAS-STING   Type I interferon  

摘要： Chlamydia psittaci (C. psittaci) is a multi-host pathogen that elicits robust innate immune responses in macrophages. Chlamydiae target host mitochondria to manipulate the cellular fate and metabolic functions. However, the effect of C. psittaci on the host mitochondria remains obscure. This study investigated how C. psittaci, postinfection in human macrophages, induces mitochondrial oxidative stress and damage to activate the cGASSTING-IRF3/NLRP3 pathway for IFN-I and IL-1(3 production. Results demonstrate that C. psittaci increased mitochondrial ROS (mtROS) production. This induced the release of oxidized mitochondrial DNA (mtDNA) into the cytoplasm of macrophages. It also augmented IFN-I and IL-1(3 production dependent on the cGAS-STING pathway. Macrophages pre-treated with mtROS inhibitor mito-TEMPO displayed reduced oxidized mtDNA. This consequently lowered IFN-I and IL-1(3 production via the cGAS-STING pathway induced by C. psittaci. Additionally, we found that mtROS production may inhibit C. psittaci proliferation through the synergistic action of IFN-I and IL-1(3. In conclusion, our study reveals that C. psittaci induces mtROS production leading to mtDNA release. This activates the cGAS-STING-IRF3/NLRP3 pathway to increase IFN-I and IL-1(3 production. This study elucidates a novel mechanism of bacterial pathogen activation in the cGAS-STING pathway. This reveals the molecular mechanisms underlying the immune response to C. psittaci infection and proposes potential targets for the treatment of C. psittaci related diseases.

关键词： Monkeypox virus   Innate immunity   Type I IFN   IFN-gamma   ISG   IDO  

摘要： The recent outbreak of monkeypox virus (MPXV) has caused global concern. How the virus evades the interferon (IFN) response is still poorly understood. We analyzed type I/II IFN (IFN-I/II) expression in clinical samples from MPXV-infected patients and measured IFN-I kinetics in MPXV-infected cells. We also evaluated the anti-MPXV activity of IFN-I/II in A549, HeLa and Vero-E6 cell lines. IFN-I/II mRNA expression was detected in skin lesions, anal swabs, nasopharyngeal samples and peripheral blood mononuclear cells (PBMC), with the highest levels in skin lesions (p < 0.05). High MPXV DNA levels in clinical samples were associated with increased IFN-I levels. In vitro, MPXV infection induced a peak of IFN-I between 48 and 72 h post-infection (p < 0.01). Pre-treatment of the A549, HeLa and Vero-E6 cells with high concentrations (>= 100,000 International Unit, IU/ml) of IFN-alpha and IFN-omega did not inhibit or had little effect on MPXV replication, while IFN-beta moderately reduced MPXV replication by 2.7-1.5 log(10) at 100,000 IU/ml. In clinical samples there was a trend for elevated levels of IFN-gamma in association with lower MPXV load and in vitro IFN-gamma (3,600 IU/ml) strongly reduced viral titers by 3.4-1.6 log(10). There were no significant differences in expression of select IFN-stimulated genes (ISGs) in MPXV infection in vitro. This study shows that MPXV delays IFN-I induction and inhibits expression of selected ISGs in vitro and is associated with an IFN-I resistance phenotype in vivo. However, MPXV is less resistant to IFN-gamma in vivo and is sensitive to IFN-gamma treatment in vitro, suggesting a potential therapeutic role for IFN-gamma.