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关键词： Cartilage   Synovial membrane   Osteoarthritis (OA)   Inflammation   Interleukin-1 beta (IL-1 beta)   Inorganic pyrophosphate (PPi)  

摘要： Objective: Osteoarthritis (OA) is the most common form of chronic joint disease, affecting mainly the elderly population. This disorder is caused by cartilage degeneration with complex changes in the chondrocyte phenotype. Inorganic pyrophosphate (PPi) was shown to counteract the detrimental effect of interleukin (IL)-1 beta challenging in an in vitro OA model based on rat articular chondrocytes. It also maintained the differentiated articular phenotype, mostly by down regulating wingless-related integration site (Wnt)-5a secretion. These observations suggest a PPi protective role for chondrocyte in vitro. Methods: To address this hypothesis in vivo, we investigated the impact on knee joint of three intra-articular injection (IAI) of PPi in a rat model of cartilage damage induced by IAI of IL-1 beta, where cartilage degradation and synovial inflammation are similar to that observed in OA. Cartilage and synovial membrane were collected after 7 days of challenge by IL-1 beta. Results: PPi was able to reduce the deleterious effect of IL-1 beta. This effect was observable on the expression of cartilage extracellular matrix metabolism markers and confirmed by histology with safranin O and hematoxylineosin-saffron (HES) staining. Inorganic pyrophosphate also repressed the Wnt5a expression induced by IL-1 beta. No effect was observed on the inflammatory response of the synovial membrane. Conclusion: These results demonstrate that PPi improves IL-1 beta-induced cartilage damage in rat but not the associated inflammation of synovial membrane. Thus, PPi could become a molecule of interest to restrict the progression of this disorder.

关键词： HLA   HLA-C novel allele   sequencing-based typing  

摘要： The novel allele HLA-C*07:1102 differs from HLA-C*07:02:01:01 by one non-synonymous nucleotide substitution in exon 2.

关键词： atopic dermatitis   interleukin 33   semaphorin  

摘要： Neuroimmune interaction is crucial to inducing pruritic sensations in atopic dermatitis (AD). In this study, we examine the neuroimmune pathways involved in children with AD. HumanMethylation450 BeadChip and GeneChip Human Transcriptome Array 2.0 from 24 children with ad and 24 healthy controls were cross-referenced with gene expression data from GSE116486. SEMA7A, which encodes for semaphorin 7a and is associated with neuron development and immune response and was identified on pathway analysis as a crucial gene in children with ad. In addition, we found that SEMA7A cytosine-phosphate-guanine sites (CpG sites) cg13557411 and cg17917837 were hypomethylated, and mRNA expression of SEMA7A was higher in children with ad. Vectors containing SEMA7A were then transfected into Jurkat T cells, which increased the protein excretion of interleukin 4 (IL-4) and the mRNA expression of interleukin 1 receptor-like 1 (IL1RL1, receptor for the cytokine IL-33). Furthermore, stimulation of HaCaT keratinocytes with SEMA7A protein resulted in increased mRNA expression of the genes interleukin 33 (IL33) and IL1RL1, but suppressed mRNA expression of the tight junction protein ZO-1(TJP1). In conclusion, in this study, we found that SEMA7A is overexpressed in patients with AD and is a central gene on pathway analysis. Results of our study suggest that overexpression of SEMA7A is associated with increased expression of IL4, IL33 and its receptor IL1RL1, which are associated with pruritic sensation in AD. SEMA7A also appears to suppress the expression of TJP1 in keratinocytes, thereby possibly increasing the permeability of the skin barrier. SEMA7A may be an alternative therapeutic target in AD, especially for neuroimmune-related pruritis.

摘要： Given the growing number of HLA alleles, typing methodologies utilizing specific primers or probes are facing increasing difficulty in keeping up with such an increase. Indeed, sequencing of HLA alleles seems to be the methodology of the future for solid organ patients and donors. Due to the time constraints of traditional Sanger-based sequencing and sequencing by synthesis of next generation sequencing, sequencing for HLA typing has not been used for initial deceased donor (DD) typing. Since next generation sequencing methodologies have become more rapid, it is now possible to perform high resolution HLA typing on deceased donors in a timeframe commensurate with real-time PCR. In this case-study, a null allele was not adequately resolved by the originating HLA laboratory typing of a deceased donor utilizing real-time PCR. The laboratory of the center receiving a kidney from the same deceased donor performed confirmatory typing of the deceased donor by next generation sequencing and discovered the discrepancy at HLA-A. The case presented in this manuscript demonstrates the need for laboratories to adopt next generation sequencing for DD HLA typing as soon as possible.

关键词： Lung function impairment   Platelet   Cytokine   Biomarkers   Hexavalent chromium  

摘要： Recent research has highlighted the crucial role of immune regulation in lung function impairment due to exposure to hazardous materials. This study aimed to identify dynamic network biomarkers for lung function damage caused by hexavalent chromium inhalation exposure, using immune-related indicators in blood. An 11- year follow-up longitudinal study was conducted on a population occupationally exposed to hexavalent chromate (Cr [VI]) from 2010 to 2020, consisting of sixty-one subjects with 328 repeat measurements. Quantitative analysis of immune-related indicators, including white blood cells, cytokines, and platelet count, was performed. The concentration of urinary Cr served as an indicator of internal exposure, confirming its association with lung function impairment. Dynamic network analysis revealed that platelet count was connected to neutrophils, IL-8, IL-6, and IL-33 when the exposure time was equal to or longer than 9.2 years (the median exposure time). Notably, the association between platelet count and IL-33 was specific to long-term (>= 9.2 years) exposure. The areas under the receiver operating characteristic (ROC) curves (AUCs) for platelet count combined with IL-33 to predict lung function impairment in the long-term and short-term Cr [VI]-exposed populations were 80.5 % and 55.4 %, respectively. These findings provide evidence that the combination of platelets and IL-33 holds significant promise as biomarkers for predicting lung function impairment. Moreover, they shed light on the potential mechanism involving immune and hematopoiesis functions in the context of environmental hazardous exposure.

关键词： hypertension, pulmonary   inflammation   interleukin   macrophage   mice  

摘要： BACKGROUND:The infiltration of macrophages into the lungs is a common characteristic of perivascular inflammation, contributing to vascular remodeling in pulmonary hypertension (PH). Peli1 (pellino E3 ubiquitin-protein ligase 1) plays a critical role in regulating the production of proinflammatory cytokines and the polarization of macrophages in various diseases. However, the role of Peli1 in PH remains to be ***:The expression and biological function of Peli1 were investigated in both human and experimental models of PH. Peli1-deficient mice and bone marrow transplant mice were utilized to explore the roles of Peli1 in macrophages in vivo. Proteomic analysis and molecular biology techniques were used to uncover the underlying ***:The upregulation of Peli1 in the lungs and alveolar macrophages was observed in hypoxia-treated mice. Peli1 knockout mice and myeloid Peli1-deficient mice significantly ameliorated hypoxia-induced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling. Mechanistically, Peli1 facilitated the ubiquitination and subsequent proteasomal degradation of Foxp1 (forkhead box p1), thereby alleviating its suppression of IL (interleukin)-6 transcription and contributing to macrophage activation. Furthermore, myeloid Foxp1 deficiency partially eliminates the protective effect of myeloid Peli1 deficiency in hypoxia-induced PH ***:Our findings demonstrate that the Peli1-Foxp1-IL-6 pathway plays a crucial role in macrophage activation and recruitment during the development of PH, underscoring the potential of Peli1 as a therapeutic target for PH.

关键词： TNF   XPro1595   Neurodegeneration   Microgliosis   rAAV   alpha-synuclein  

摘要： The underlying cause of neuronal loss in Parkinson's disease (PD) remains unknown, but evidence implicates neuroinflammation in PD pathobiology. The pro-inflammatory cytokine soluble tumor necrosis factor (TNF) seems to play an important role and thus has been proposed as a therapeutic target for modulation of the neuroinflammatory processes in PD. In this regard, dominant-negative TNF (DN-TNF) agents are promising antagonists that selectively inhibit soluble TNF signaling, while preserving the beneficial effects of transmembrane TNF. Previous studies have tested the protective potential of DN-TNF-based therapy in toxin-based PD models. Here we test for the first time the protective potential of a DN-TNF therapeutic against alpha-synucleindriven neurodegeneration in the viral vector-based PD female rat model. To do so, we administered the DN-TNF agent XPro1595 subcutaneously for a period of 12 weeks. In contrast to previous studies using different PD models, neuroprotection was not achieved by systemic XPro1595 treatment. alpha-Synuclein-induced loss of nigrostriatal neurons, accumulation of pathological inclusions and microgliosis was detected in both XPro1595and saline-treated animals. XPro1595 treatment increased the percentage of the hypertrophic/ameboid Iba1+ cells in SN and reduced the striatal MHCII+ expression in the alpha-synuclein-overexpressing animals. However, the treatment did not prevent the MHCII upregulation seen in the SN of the model, nor the increase of CD68+ phagocytic cells. Therefore, despite an apparently immunomodulatory effect, this did not suffice to protect against viral vector-derived alpha-synuclein-induced neurotoxicity. Further studies are warranted to better elucidate the therapeutic potential of soluble TNF inhibitors in PD.

关键词： human leukocyte antigen (HLA)   HLA typing   HLA inferences from sequencing data   long-read sequencing for HLA prediction   next-generation sequencing-based HLA analysis  

摘要： Long-read sequencing platforms such as the Oxford Nanopore Technologies (ONT) and Pacific Biosciences (PacBio) platforms now offer sufficient read lengths, throughput, and accuracy at competitive costs to analyze polymorphic regions of the human genome, including the highly complex human leukocyte antigen (HLA) gene cluster-a cornerstone of human immunity. Here, we present a streamlined protocol for predicting HLA signatures from whole-genome shotgun (WGS) long-read sequencing data by directly streaming sequence alignments into HLAminer. This method is as simple as running minimap2, scales efficiently with the number of sequences, and works with any read aligner compatible with the SAM file format-eliminating the need to store bulky alignment files on disk. We provide a step-by-step guide for predicting HLA class I and class II alleles from third-generation long-read sequencing data and demonstrate the robustness of predictions even with older, less accurate WGS nanopore datasets and relatively low (10x) sequencing coverage. Code availability: HLAminer is available under the BC Cancer software license agreement (academic use) at . (c) 2025 The Author(s). Current Protocols published by Wiley Periodicals *** Protocol: HLA prediction from streamed ONT or PacBio long-read alignments

关键词： Familial Mediterranean fever   biomarkers   interleukin 18  

关键词： Hepatitis B virus   Kupffer cells   CD163   T cells   Antiviral immunity  

摘要： Background & aims: Chronic hepatitis B (CHB) arises from a persistent hepatitis B virus (HBV) infection, complicating efforts for a functional cure. Kupffer cells (KCs), liver-resident macrophages, are pivotal in mediating immune tolerance to HBV. Although CD163 marks M2-polarized KCs, its precise role in HBV infection remains unclear and warrants further investigation. Methods: CD163 expression in liver tissues of patients with CHB was analyzed using the Gene Expression Omnibus (GEO) database. Cd163 knockout mice were utilized to establish HBV-persistent mouse model, and CD163 deficiency effect on HBV viral markers and T cell immune responses were examined in vivo and in vitro. Results: CD163 expression was elevated and correlated with ALT levels in the liver of patients with CHB. In HBVpersistent mouse model, CD163 deficiency facilitated the clearance of HBsAg, HBeAg, HBV DNA, and HBcAg. Additionally, CD163 deficiency promoted the differentiation of na & iuml;ve T cells into HBV-specific effector T cells. Further, we found that CD163 deficiency reduces KCs-derived IL-10 secretion, and blocking IL-10 further strengthens the enhanced HBV-specific T cell response due to CD163 deficiency. Conclusions: Our findings indicate that CD163 deficiency enhances the HBV-specific T cell response, thereby facilitating HBV clearance through reducing KCs-derived IL-10 secretion. This suggests that CD163 may serve as a potential target for the restoration of exhausted T cell function.