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Frontiers in Immunology 2023Hemophagocytic Lymphohistiocytosis (HLH) is a rare clinical condition characterized by sustained but ineffective immune system activation, leading to severe and systemic... (Review)
Review
Hemophagocytic Lymphohistiocytosis (HLH) is a rare clinical condition characterized by sustained but ineffective immune system activation, leading to severe and systemic hyperinflammation. It may occur as a genetic or sporadic condition, often triggered by an infection. The multifaceted pathogenesis results in a wide range of non-specific signs and symptoms, hampering early recognition. Despite a great improvement in terms of survival in the last decades, a considerable proportion of patients with HLH still die from progressive disease. Thus, prompt diagnosis and treatment are crucial for survival. Faced with the complexity and the heterogeneity of syndrome, expert consultation is recommended to correctly interpret clinical, functional and genetic findings and address therapeutic decisions. Cytofluorimetric and genetic analysis should be performed in reference laboratories. Genetic analysis is mandatory to confirm familial hemophagocytic lymphohistiocytosis (FHL) and Next Generation Sequencing is increasingly adopted to extend the spectrum of genetic predisposition to HLH, though its results should be critically discussed with specialists. In this review, we critically revise the reported laboratory tools for the diagnosis of HLH, in order to outline a comprehensive and widely available workup that allows to reduce the time between the clinical suspicion of HLH and its final diagnosis.
Topics: Humans; Lymphohistiocytosis, Hemophagocytic; Genetic Predisposition to Disease
PubMed: 37426667
DOI: 10.3389/fimmu.2023.1210041 -
Allergology International : Official... Jul 2023The signs and symptoms of chronic urticaria (CU) are caused by the activation and degranulation of skin mast cells (MCs). Recent studies have added to our understanding... (Review)
Review
The signs and symptoms of chronic urticaria (CU) are caused by the activation and degranulation of skin mast cells (MCs). Recent studies have added to our understanding of how and why skin MCs are involved and different in CU. Also, novel and relevant mechanisms of MC activation in CU have been identified and characterized. Finally, the use of MC-targeted and MC mediator-specific treatments has helped to better define the role of the skin environment, the contribution of specific MC mediators, and the relevance of MC crosstalk with other cells in the pathogenesis of CU. Here, we review these recent findings and their impact on our understanding of CU, with a focus on chronic spontaneous urticaria (CSU). Also, we highlight open questions, issues of controversy, and unmet needs, and we suggest what studies should be performed moving forward.
Topics: Humans; Urticaria; Mast Cells; Chronic Urticaria; Skin
PubMed: 37210251
DOI: 10.1016/j.alit.2023.05.003 -
Seminars in Immunology Nov 2023Neutrophils are among the most abundant immune cells, representing about 50%- 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed... (Review)
Review
Neutrophils are among the most abundant immune cells, representing about 50%- 70% of all circulating leukocytes in humans. Neutrophils rapidly infiltrate inflamed tissues and play an essential role in host defense against infections. They exert microbicidal activity through a variety of specialized effector mechanisms, including phagocytosis, production of reactive oxygen species, degranulation and release of secretory vesicles containing broad-spectrum antimicrobial factors. In addition to their homeostatic turnover by apoptosis, recent studies have revealed the mechanisms by which neutrophils undergo various forms of regulated cell death. In this review, we will discuss the different modes of regulated cell death that have been described in neutrophils, with a particular emphasis on the current understanding of neutrophil pyroptosis and its role in infections and autoinflammation.
Topics: Humans; Neutrophils; Pyroptosis; Phagocytosis; Apoptosis
PubMed: 37939552
DOI: 10.1016/j.smim.2023.101849 -
Nature Communications Sep 2023Neutrophils have a pathogenic function in inflammation via releasing pro-inflammatory mediators or neutrophil extracellular traps (NETs). However, their heterogeneity...
Neutrophils have a pathogenic function in inflammation via releasing pro-inflammatory mediators or neutrophil extracellular traps (NETs). However, their heterogeneity and pro-inflammatory mechanisms remain unclear. Here, we demonstrate that CXCR4 neutrophils accumulate in the blood and inflamed skin in human psoriasis, and correlate with disease severity. Compared to CXCR4 neutrophils, CXCR4 neutrophils have enhanced NETs formation, phagocytic function, neutrophil degranulation, and overexpression of pro-inflammatory cytokines and chemokines in vitro. This is accompanied by a metabolic shift in CXCR4 neutrophils toward glycolysis and lactate release, thereby promoting vascular permeability and remodeling. CXCR4 expression in neutrophils is dependent on CREB1, a transcription factor activated by TNF and CXCL12, and regulated by de novo synthesis. In vivo, CXCR4 neutrophil infiltration amplifies skin inflammation, whereas blockade of CXCR4 neutrophils through CXCR4 or CXCL12 inhibition leads to suppression of immune responses. In this work, our study identifies CREB1 as a critical regulator of CXCR4 neutrophil development and characterizes the contribution of CXCR4 neutrophils to vascular remodeling and inflammatory responses in skin.
Topics: Animals; Humans; Mice; Cyclic AMP Response Element-Binding Protein; Dermatitis; Disease Models, Animal; Inflammation; Neutrophils; Psoriasis; Receptors, CXCR4; Skin
PubMed: 37736772
DOI: 10.1038/s41467-023-41484-3 -
Allergology International : Official... Jul 2023Chronic spontaneous urticaria (CSU) is a common skin disease without an etiology in the vast majority of cases. The similarity of symptoms and pathology to... (Review)
Review
Chronic spontaneous urticaria (CSU) is a common skin disease without an etiology in the vast majority of cases. The similarity of symptoms and pathology to allergen-induced skin reactions supports that skin mast cell IgE receptor activation is also involved in CSU. Accumulating evidence also supports a role for blood basophils in disease expression. Blood basopenia is noted in active CSU disease with the recruitment of blood basophils to skin lesion sites. Blood basophils further display altered IgE receptor mediated degranulation patterns in two phenotypes that improve in remission. In active CSU subjects, changes in IgE receptor signaling molecule expression levels accompany the altered degranulation function in blood basophils. The success of therapies targeting IgE in CSU patients have also shown that altered blood basophil phenotypes and enumeration have potential use as a disease biomarker.
Topics: Humans; Basophils; Receptors, IgE; Chronic Disease; Urticaria; Chronic Urticaria
PubMed: 37221123
DOI: 10.1016/j.alit.2023.05.001 -
Cell Reports. Medicine Nov 2023The post-acute sequelae of COVID-19 (PASC), also known as long COVID, is often associated with debilitating symptoms and adverse multisystem consequences. We obtain...
The post-acute sequelae of COVID-19 (PASC), also known as long COVID, is often associated with debilitating symptoms and adverse multisystem consequences. We obtain plasma samples from 117 individuals during and 6 months following their acute phase of infection to comprehensively profile and assess changes in cytokines, proteome, and metabolome. Network analysis reveals sustained inflammatory response, platelet degranulation, and cellular activation during convalescence accompanied by dysregulation in arginine biosynthesis, methionine metabolism, taurine metabolism, and tricarboxylic acid (TCA) cycle processes. Furthermore, we develop a prognostic model composed of 20 molecules involved in regulating T cell exhaustion and energy metabolism that can reliably predict adverse clinical outcomes following discharge from acute infection with 83% accuracy and an area under the curve (AUC) of 0.96. Our study reveals pertinent biological processes during convalescence that differ from acute infection, and it supports the development of specific therapies and biomarkers for patients suffering from long COVID.
Topics: Humans; Post-Acute COVID-19 Syndrome; Convalescence; Multiomics; COVID-19; Biomarkers; Phenotype
PubMed: 37890487
DOI: 10.1016/j.xcrm.2023.101254 -
Frontiers in Endocrinology 2023Diabetic nephropathy (DN), which is the main cause of renal failure in end-stage renal disease, is becoming a common chronic renal disease worldwide. Mendelian...
BACKGROUND
Diabetic nephropathy (DN), which is the main cause of renal failure in end-stage renal disease, is becoming a common chronic renal disease worldwide. Mendelian randomization (MR) is a genetic tool that is widely used to minimize confounding and reverse causation when identifying the causal effects of complex traits. In this study, we conducted an integrated multiple microarray analysis and large-scale plasma proteome MR analysis to identify candidate biomarkers and evaluate the causal effects of prospective therapeutic targets in DN.
METHODS
Five DN gene expression datasets were selected from the Gene Expression Omnibus. The robust rank aggregation (RRA) method was used to integrate differentially expressed genes (DEGs) of glomerular samples between patients with DN and controls, followed by functional enrichment analysis. Protein quantitative trait loci were incorporated from seven different proteomic genome-wide association studies, and genetic association data on DN were obtained from FinnGen (3676 cases and 283,456 controls) for two-sample MR analysis. External validation and clinical correlation were also conducted.
RESULTS
A total of 82 DEGs (53 upregulated and 29 downregulated) were identified through RRA integrated analysis. The enriched Gene Ontology annotations and Kyoto Encyclopedia of Genes and Genomes pathways of the DEGs were significantly enriched in neutrophil degranulation, neutrophil activation, proteoglycan binding, collagen binding, secretory granule lumen, gluconeogenesis, tricarboxylic acid cycle, and pentose phosphate pathways. MR analysis revealed that the genetically predicted levels of MHC class I polypeptide-related sequence B (MICB), granzyme A (GZMA), cathepsin S (CTSS), chloride intracellular channel protein 5, and ficolin-1 (FCN1) were causally associated with DN risk. Expression validation and clinical correlation analysis showed that MICB, GZMA, FCN1, and insulin-like growth factor 1 may participate in the development of DN, and carbonic anhydrase 2 and lipoprotein lipase may play protective roles in patients with DN.
CONCLUSION
Our integrated analysis identified novel biomarkers, including MICB and GZMA, which may help further understand the complicated mechanisms of DN and identify new target pathways for intervention.
Topics: Humans; Diabetic Nephropathies; Gene Expression Profiling; Genome-Wide Association Study; Proteomics; Mendelian Randomization Analysis; Microarray Analysis; Biomarkers; Quantitative Trait Loci; Diabetes Mellitus
PubMed: 37492198
DOI: 10.3389/fendo.2023.1191768 -
Journal of Inflammation Research 2023Osteoarthritis (OA) is a common joint disease with long-term pain and dysfunction that negatively affects the quality of life of patients. Neutrophil extracellular traps...
BACKGROUND
Osteoarthritis (OA) is a common joint disease with long-term pain and dysfunction that negatively affects the quality of life of patients. Neutrophil extracellular traps (NETs), consisting of DNA, proteins and cytoplasm, are released by neutrophils and play an important role in a variety of diseases. However, the relationship between OA and NETs is unclear.
METHODS
In our study, we used bioinformatics to explore the relationship between OA and NETs and the potential biological markers. GSE55235, GSE55457, GSE117999 and GSE98918 were downloaded from the Gene Expression Omnibus (GEO) database for subsequent analysis.After differential analysis of OA expression matrices, intersection with NET-related genes (NRGs) was taken to identify Differentially expressed NRGs (DE-NRGs) in OA processes. Evaluation of immune cell infiltration by ssGSEA and CIBERSORT algorithm. The GSVA method was used to analyze the activity changes of Neutrophils pathway, Neutrophil degranulation and Neutrophil granule constituents pathway.
RESULTS
Based on RandomForest (RF), Least Absolute Shrinkage and Selection Operator (LASSO), and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) learning algorithms, five core genes (CRISPLD2, IL1B, SLC25A37, MMP9, and TLR7) were identified to construct an OA-related nomogram model for predicting OA progression. ROC curve results for these genes validated the nomogram's reliability. Correlation analysis, functional enrichment, and drug predictions were performed for the core genes. TLR7 emerged as a key focus due to its high importance ranking in RF and SVM-RFE analyses. Gene Set Enrichment Analysis (GSEA) revealed a strong association between TLR7 and the Neutrophil extracellular trap pathway. Expression of core genes was demonstrated in mice OA models and human OA samples. TLR7 expression in ATDC5 cell line was significantly higher than control after TNFα induction, along with increased IL6 and MMP13.
CONCLUSION
TLR7 may be related to NETs and affects OA.
PubMed: 37671131
DOI: 10.2147/JIR.S414452