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关键词： cancer immunotherapy   INHBA   Activin A   IFN-gamma signaling pathway   PD-L1  

摘要： Inhibin beta A (INHBA) and its homodimer activin A have pleiotropic effects on modulation of immune responses and tumor progression, but it remains uncertain whether tumors may release activin A to regulate anti-tumor immunity. In this study we investigated the effects and mechanisms of tumor intrinsic INHBA on carcinogenesis, tumor immunity and PD-L1 blockade. Bioinformatic analysis on the TCGA database revealed that INHBA expression levels were elevated in 33 cancer types, including breast cancer (BRCA) and colon adenocarcinoma (COAD). In addition, survival analysis also corroborated that INHBA expression was negatively correlated with the prognosis of many types of cancer patients. We demonstrated that gain or loss function of Inhba did not alter in vitro growth of colorectal cancer CT26 cells, but had striking impact on mouse tumor models including CT26, MC38, B16 and 4T1 models. By using the TIMER 2.0 tool, we figured out that in most cancer types, Inhba expression in tumors was inversely associated with the infiltration of CD4+ T and CD8+ T cells. In CT26 tumor-bearing mice, overexpression of tumor INHBA eliminated the anti-tumor effect of the PD-L1 antibody atezolizumab, whereas INHBA deficiency enhanced the efficacy of atezolizumab. We revealed that tumor INHBA significantly downregulated the interferon-gamma (IFN-gamma) signaling pathway. Tumor INHBA overexpression led to lower expression of PD-L1 induced by IFN-gamma, resulting in poor responsiveness to anti-PD-L1 treatment. On the other hand, decreased secretion of IFN-gamma-stimulated chemokines, including C-X-C motif chemokine 9 (CXCL9) and 10 (CXCL10), impaired the infiltration of effector T cells into the tumor microenvironment (TME). Furthermore, the activin A-specific antibody garetosmab improved anti-tumor immunity and its combination with the anti-PD-L1 antibody atezolizumab showed a superior therapeutic effect to monotherapy with garetosmab or atezolizumab. We demonstrate that INHBA and activin A

关键词： PF   IL   ECM   AECs  

摘要： Pulmonary fibrosis (PF) is a progressive, irreversible disease characterized by heterogeneous interstitial lung tissue damage. It originates from persistent or repeated lung epithelial injury and leads to the activation and differentiation of fibroblasts into myofibroblasts. Interleukins (ILs) are a group of lymphokines crucial for immunomodulation that are implicated in the pathogenesis of PF. However, different types of ILs exert disparate effects on PF. In the present review, based on the effect on PF, ILs are classified into three categories: i) Promotors of PF;ii) inhibitors of PF;and iii) those that exert dual effects on PF. Several types of ILs can promote PF by provoking inflammation, initiating proliferation and transdifferentiation of epithelial cells, exacerbating lung injury, while other ILs can inhibit PF through suppressing expression of inflammatory factors, modulating the Th1/Th2 balance and autophagy. The present review summarizes the association of ILs and PF, focusing on the roles and mechanisms of ILs underlying PF.

关键词： mycoplasma pneumonia   lncRNA   necroptosis  

摘要： Mycoplasma hyopneumoniae (M. hyo), a major respiratory pathogen in swine, causes chronic respiratory diseases characterized by severe lung inflammation. Alveolar macrophages, which serve as the first line of defense in the respiratory immune system, undergo necroptosis in response to M. hyo infection. This form of programmed cell death amplifies pulmonary inflammation and leads to impaired lung function, yet the precise molecular mechanisms remain poorly understood. Long non-coding RNAs (lncRNAs), known for their regulatory roles in transcriptional and epigenetic processes, have been linked to various inflammatory and infectious diseases. In this study, we identified a novel lncRNA, lncRNA-MMTP, as a critical regulator of necroptosis during M. hyo infection. Mechanistically, lncRNA-MMTP interacts with the transcription factor TFII-I to enhance c-Fos promoter activity, leading to increased transcription of TNF-alpha and activation of the RIPK1/RIPK3/MLKL necroptotic pathway. Importantly, knockdown of lncRNA-MMTP or inhibition of TFII-I significantly reduced TNF-alpha levels and necroptosis in alveolar macrophages. These findings not only elucidate a new molecular pathway underlying M. hyo-induced lung inflammation but also suggest potential therapeutic targets for managing pathogen-induced inflammatory responses in the respiratory system.

关键词： SARS-CoV-2   CTL epitope   Tetramer   COVID-19 vaccinees   PromPPD  

摘要： Purpose: SARS-CoV-2-specific CD8+ cytotoxic T lymphocytes (CTLs) are crucial in viral clearance, disease progression, and reinfection control. However, numerous SARS-CoV-2 immunodominant CTL epitopes theoretically are still unidentified due to the genetic polymorphism of human leukocyte antigen class I (HLA-I) molecules. Methods: The CTL epitopes of SARS-CoV-2 were predicted by the epitope affinity and immunogenicity prediction platforms: the NetMHCpan and the PromPPD. Individuals with HLA-A homozygous alleles were screened from 252 COVID-19 vaccinees, including the Ad5-nCoV vaccine (CanSino, n =183) and the CoronaVac inactivated vaccine (Sinovac, n = 69) using MiSeqDxTM generation sequencing, and their PBMCs were further stimulated by the predicted peptides to screen the immunodominant epitopes according to the secretion of IFN-gamma from CD8+ T cells. Peptide-MHC tetramers were constructed and used to detect the frequency of antigen specific CTLs in vivo. Results: Individuals with HLA-A homozygous alleles including HLA-A*01 (n =1), -A*02 (n = 9), - A*03 and -A*11 (n =12), and -A*24 (n = 7) supertypes were selected. Twelve immunodominant CTL epitopes for these HLA-A allotypes were finally screened based on the frequency of IFN-gamma+CD8+ T cells in homozygous individuals. The SARS-CoV-2 specific CTLs from Omicron variant infected patients were successfully evaluated by these novel peptide-HLA tetramers. Conclusion: A set of immunodominant CTL epitopes of SARS-CoV-2 was identified, and the antigen-specific CD8+ T cells in viral infected patients or COVID-19 vaccinees could be rapidly detected by a mixture of the peptideMHC tetramers.

关键词： Inactivated vaccine   Streptococcal disease   Molecular adjuvant   Immune response   Vaccine development  

摘要： Aquaculture industry frequently encounters disease outbreaks, high mortalities, as well as emergence of new pathogens due to its intensification. Streptococcus agalactiae (Lancefield's group B Streptococcus) is an important pathogen extensively causing infectious disease in tilapia resulting in huge economic loss and mortality. To date, vaccination has proved to be successful in defending against infectious diseases prevailing among farmed fish species. This study aimed to develop an S. agalactiae inactivated vaccine (SAIV) using molecular adjuvants, flagellin and tilapia interferon gamma (IFN-gamma), and to assess the generated immune response and protective efficacy of the adjuvant incorporated vaccine against S. agalactiae infection in Nile tilapia. The fish were vaccinated with SAIV together with either flagellin or IFN-gamma and both together by intraperitoneal injection. The vaccinated fish were challenged with a virulent strain of S. agalactiae on day 36 and monitored for 3 weeks to assess cumulative mortality. The results showed that the vaccine offered significant protection with relative percentage survival (RPS) of 59.37%, 71.87%, and 81.25% observed for bacterin vaccine adjuvanted with flagellin, IFN-gamma and both, respectively, with an RPS of 15.62% for the unadjuvanted bacterin control group after challenge with S. agalactiae. The vaccine induced specific IgM antibodies against S. agalactiae in the vaccinated groups, and the antibody response was significantly increased following booster vaccination in the fishes administered with vaccine adjuvanted with flagellin, IFN-gamma and both. Furthermore, after vaccination, MHC-II and IgM gene expression was found significantly upregulated in head kidney and spleen, in line with an elevated specific IgM titer. Innate immune parameters including catalase, lysozyme, superoxide dismutase, myeloperoxidase, and bactericidal activities were significantly increased in fishes immunized when compared with the unvaccin

关键词： Lead   Mice   Hippocampus   TNF-R1-RIPK1/RIPK3   Necroptosis  

摘要： Lead (Pb), a dense, soft, blue-gray metal, is widely used in metallurgy, cables, storage batteries, pigments, and other industrial applications. Pb has been shown to cause degenerative changes in the nervous system. Necroptosis, a form of non-apoptotic programmed cell death modality, is closely associated with neurodegenerative diseases. Whether the TNF-R1-RIPK1/RIPK3 pathway is involved in the neurodegeneration induced by Pb has yet to be determined. Here, we explored the role of the TNF-R1-RIPK1/RIPK3 signaling pathway in the Pb-induced necroptosis by using HT-22 cells, primary mouse hippocampal neurons, and C57BL/6 mice models, demonstrating that Pb exposure elevated lead levels in murine whole blood and hippocampal tissue in a dose-response relationship. Protein expression levels of PARP, c-PARP, RIPK1, p-RIPK1, RIPK3, MLKL, and p-MLKL in the hippocampal tissues were elevated, while the protein expression of caspase-8 was decreased. Furthermore, Pb exposure reduced the survival rates in HT-22 cells and primary mouse hippocampal neurons, while increasing the protein expressions of RIPK1 and p-MLKL. Collectively, these novel findings suggest that the TNF-R1/RIPK1/RIPK3 signaling pathway is associated with Pb-induced neurotoxicity in hippocampal neurons in mice.

关键词： ischemic stroke   IL-3/IL-3R alpha cross talk   VEGFD/VEGFR3   astrocytes   microglia   neuroinflammation  

摘要： Astrocyte-derived IL-3 activates the corresponding receptor IL-3R alpha in microglia. This cross-talk between astrocytes and microglia ameliorates the pathology of Alzheimer's disease in mice. In this study we investigated the role of IL-3/IL-3R alpha cross-talk and its regulatory mechanisms in ischemic stroke. Ischemic stroke was induced in mice by intraluminal occlusion of the right middle cerebral artery (MCA) for 60 min followed by reperfusion (I/R). Human astrocytes or microglia subjected to oxygen-glucose deprivation and reoxygenation (OGD/Re) were used as in vitro models of brain ischemia. We showed that both I/R and OGD/Re significantly induced decreases in astrocytic IL-3 and microglial IL-3R alpha protein levels, accompanied by pro-inflammatory activation of A1-type astrocytes and M1-type microglia. Importantly, astrocyte-derived VEGFD acting on VEGFR3 of astrocytes and microglia contributed to the cross-talk dysfunction and pro-inflammatory activation of the two glial cells, thereby mediating neuronal cell damage. By using metabolomics and multiple biochemical approaches, we demonstrated that IL-3 supplementation to microglia reversed OGD/Re-induced lipid metabolic reprogramming evidenced by upregulated expression of CPT1A, a rate-limiting enzyme for the mitochondrial beta-oxidation, and increased levels of glycerophospholipids, the major components of cellular membranes, causing reduced accumulation of lipid droplets, thus reduced pro-inflammatory activation and necrosis, as well as increased phagocytosis of microglia. Notably, exogenous IL-3 and the VEGFR antagonist axitinib reestablished the cross-talk of IL-3/IL-3R alpha, improving microglial lipid metabolic levels via upregulation of CPT1A, restoring microglial phagocytotic function and attenuating microglial pro-inflammatory activation, ultimately contributing to brain recovery from I/R insult. Our results demonstrate that VEGFD/VEGFR3 signaling contributes to the dysfunction of the astrocyte IL-3/m

关键词： allele   HLA   NGS   typing  

摘要： A single nucleotide mismatch within exon 4 of HLA-DQA1 differentiates the novel DQA1*05:90 allele from DQA1*05:09:01:03.

关键词： HLA   HLA-C*05:01:83   novel allele   sequencing-based typing  

摘要： HLA-C*05:01:83 differs from HLA-C*05:01:01:01 by one nucleotide substitution in codon 291 in exon 5.

摘要： HLA-B*27 confers a strong risk of developing spondyloarthritis (SpA), which includes axial SpA with or without peripheral arthritis, enthesitis, acute anterior uveitis and gastrointestinal inflammation. Although no definitive mechanism has been established to explain the role of this HLA class I protein in the pathogenesis of SpA, three main hypotheses have emerged. First is the idea that self-peptides displayed by HLA-B27 resemble microorganism-derived peptides, leading to the expansion of autoreactive CD8+ T cells that trigger disease. The second and third hypotheses focus on aberrant properties of HLA-B27, including its tendency to form cell-surface dimers that can activate innate killer immunoglobulin-like receptors on CD4+ T helper 17 cells, triggering the production of pathogenic cytokines. HLA-B27 also misfolds in the endoplasmic reticulum, which can activate the unfolded protein response, increasing IL-23 expression and thereby promoting the production of type 17 cytokines. HLA-B27 misfolding in mesenchymal stem cells has also been linked to enhanced bone formation by mesenchymal stem cell-derived osteoblasts, which could contribute to structural damage in axial SpA. In this Review we summarize prevailing ideas about the role of HLA-B27 in SpA, discuss the latest developments as well as the gaps in current knowledge, and provide recommendations for future research to address these unmet needs.