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Nature Reviews. Immunology Nov 2023IgG4 is the least abundant subclass of IgG in human serum and has unique functional features. IgG4 is largely unable to activate antibody-dependent immune effector... (Review)
Review
IgG4 is the least abundant subclass of IgG in human serum and has unique functional features. IgG4 is largely unable to activate antibody-dependent immune effector responses and, furthermore, undergoes Fab (fragment antigen binding)-arm exchange, rendering it bispecific for antigen binding and functionally monovalent. These properties of IgG4 have a blocking effect, either on the immune response or on the target protein of IgG4. In this Review, we discuss the unique structural characteristics of IgG4 and how these contribute to its roles in health and disease. We highlight how, depending on the setting, IgG4 responses can be beneficial (for example, in responses to allergens or parasites) or detrimental (for example, in autoimmune diseases, in antitumour responses and in anti-biologic responses). The development of novel models for studying IgG4 (patho)physiology and understanding how IgG4 responses are regulated could offer insights into novel treatment strategies for these IgG4-associated disease settings.
Topics: Humans; Immunoglobulin G; Autoimmune Diseases
PubMed: 37095254
DOI: 10.1038/s41577-023-00871-z -
Veterinary Journal (London, England :... 2023Steroid-responsive meningitis-arteritis (SRMA) occurs as an immune-mediated, inflammatory, and non-infectious disorder of juvenile and young-adult dogs. In principle,... (Review)
Review
Steroid-responsive meningitis-arteritis (SRMA) occurs as an immune-mediated, inflammatory, and non-infectious disorder of juvenile and young-adult dogs. In principle, SRMA is divided into two clinical courses: during the typical acute form, dogs are presented with fever, cervical hyperaesthesia, and reluctance to move. The more protracted form most probably emerges after insufficient immunosuppressive treatment or relapses, with additional neurologic deficits localized in the cervical and thoracolumbar spinal cord or multifocally. The trigger leading to SRMA still remains an unsolved riddle for immunologists and clinical neurologists. In the past, many attempts have been made to clarify the etiology of this disease without success. The purpose of writing this narrative review about SRMA is to summarize new insights on the pathogenesis of SRMA with a focus on immunologic dysregulation. Furthermore, unusual manifestations of the disease, new diagnostic approaches using possible laboratory biomarkers or diagnostic imaging tools, and potential innovative treatment strategies are discussed.
Topics: Animals; Dogs; Meningitis; Arteritis; Biomarkers; Steroids; Dog Diseases
PubMed: 37704169
DOI: 10.1016/j.tvjl.2023.106030 -
Nature Reviews. Cardiology Nov 2023Atherosclerotic diseases such as myocardial infarction, ischaemic stroke and peripheral artery disease continue to be leading causes of death worldwide despite the... (Review)
Review
Atherosclerotic diseases such as myocardial infarction, ischaemic stroke and peripheral artery disease continue to be leading causes of death worldwide despite the success of treatments with cholesterol-lowering drugs and drug-eluting stents, raising the need to identify additional therapeutic targets. Interestingly, atherosclerosis preferentially develops in curved and branching arterial regions, where endothelial cells are exposed to disturbed blood flow with characteristic low-magnitude oscillatory shear stress. By contrast, straight arterial regions exposed to stable flow, which is associated with high-magnitude, unidirectional shear stress, are relatively well protected from the disease through shear-dependent, atheroprotective endothelial cell responses. Flow potently regulates structural, functional, transcriptomic, epigenomic and metabolic changes in endothelial cells through mechanosensors and mechanosignal transduction pathways. A study using single-cell RNA sequencing and chromatin accessibility analysis in a mouse model of flow-induced atherosclerosis demonstrated that disturbed flow reprogrammes arterial endothelial cells in situ from healthy phenotypes to diseased ones characterized by endothelial inflammation, endothelial-to-mesenchymal transition, endothelial-to-immune cell-like transition and metabolic changes. In this Review, we discuss this emerging concept of disturbed-flow-induced reprogramming of endothelial cells (FIRE) as a potential pro-atherogenic mechanism. Defining the flow-induced mechanisms through which endothelial cells are reprogrammed to promote atherosclerosis is a crucial area of research that could lead to the identification of novel therapeutic targets to combat the high prevalence of atherosclerotic disease.
PubMed: 37225873
DOI: 10.1038/s41569-023-00883-1 -
Journal of Nutritional Science 2023Whilst dietary cholesterol guidelines have waivered through the years with historic restrictions lifted for the majority of the general population, recommendations to... (Review)
Review
Whilst dietary cholesterol guidelines have waivered through the years with historic restrictions lifted for the majority of the general population, recommendations to reduce saturated fat intake have been the mainstay of dietary guidelines since the 1980s and were recently reinforced by the Scientific Advisory Committee on Nutrition (SACN). Cholesterol metabolism is complex, with saturated fat known to have a more significant contribution at raising levels of low-density lipoprotein (LDL) cholesterol, a well-established risk factor for cardiovascular disease (CVD). However, it is clear from metabolic research that hyper-responsiveness to both dietary cholesterol and saturated fat exists; hence, for specific subsets of the population, reductions in both nutrients may be indicated. With this in mind, the current article aims to provide an overview of the mechanisms underlying biological variation in responsiveness and introduces research currently underway which will hopefully identify simple biomarkers that can be used to predict responsiveness and permit tailored, personalised, dietary advice. Eggs are a well-known source of dietary cholesterol whilst being low in saturated fat. A common question encountered in clinical practice is must individuals limit intake to manage blood cholesterol levels. This article summarises key recent papers which confirm that eggs can be enjoyed as part of a healthy balanced diet, whilst highlighting the need for further research in certain population groups, e.g. in individuals with diabetes.
Topics: Humans; Dietary Fats; Cholesterol, Dietary; Cardiovascular Diseases; Cholesterol; Diet
PubMed: 37706071
DOI: 10.1017/jns.2023.82 -
Cell Reports Jul 2023Plant response to pathogen infection varies within a leaf, yet this heterogeneity is not well resolved. We expose Arabidopsis to Pseudomonas syringae or mock treatment...
Plant response to pathogen infection varies within a leaf, yet this heterogeneity is not well resolved. We expose Arabidopsis to Pseudomonas syringae or mock treatment and profile >11,000 individual cells using single-cell RNA sequencing. Integrative analysis of cell populations from both treatments identifies distinct pathogen-responsive cell clusters exhibiting transcriptional responses ranging from immunity to susceptibility. Pseudotime analyses through pathogen infection reveals a continuum of disease progression from an immune to a susceptible state. Confocal imaging of promoter-reporter lines for transcripts enriched in immune cell clusters shows expression surrounding substomatal cavities colonized or in close proximity to bacterial colonies, suggesting that cells within immune clusters represent sites of early pathogen invasion. Susceptibility clusters exhibit more general localization and are highly induced at later stages of infection. Overall, our work shows cellular heterogeneity within an infected leaf and provides insight into plant differential response to infection at a single-cell level.
Topics: Arabidopsis; Pseudomonas syringae; Arabidopsis Proteins; Plant Leaves; Plant Diseases; Gene Expression Regulation, Plant
PubMed: 37342910
DOI: 10.1016/j.celrep.2023.112676 -
Journal of Hepatology May 2024Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which there is an unmet need to understand the cellular composition of the...
BACKGROUND & AIMS
Primary sclerosing cholangitis (PSC) is an immune-mediated cholestatic liver disease for which there is an unmet need to understand the cellular composition of the affected liver and how it underlies disease pathogenesis. We aimed to generate a comprehensive atlas of the PSC liver using multi-omic modalities and protein-based functional validation.
METHODS
We employed single-cell and single-nucleus RNA sequencing (47,156 cells and 23,000 nuclei) and spatial transcriptomics (one sample by 10x Visium and five samples with Nanostring GeoMx DSP) to profile the cellular ecosystem in 10 PSC livers. Transcriptomic profiles were compared to 24 neurologically deceased donor livers (107,542 cells) and spatial transcriptomics controls, as well as 18,240 cells and 20,202 nuclei from three PBC livers. Flow cytometry was performed to validate PSC-specific differences in immune cell phenotype and function.
RESULTS
PSC explants with parenchymal cirrhosis and prominent periductal fibrosis contained a population of cholangiocyte-like hepatocytes that were surrounded by diverse immune cell populations. PSC-associated biliary, mesenchymal, and endothelial populations expressed chemokine and cytokine transcripts involved in immune cell recruitment. Additionally, expanded CD4 T cells and recruited myeloid populations in the PSC liver expressed the corresponding receptors to these chemokines and cytokines, suggesting potential recruitment. Tissue-resident macrophages, by contrast, were reduced in number and exhibited a dysfunctional and downregulated inflammatory response to lipopolysaccharide and interferon-γ stimulation.
CONCLUSIONS
We present a comprehensive atlas of the PSC liver and demonstrate an exhaustion-like phenotype of myeloid cells and markers of chronic cytokine expression in late-stage PSC lesions. This atlas expands our understanding of the cellular complexity of PSC and has potential to guide the development of novel treatments.
IMPACT AND IMPLICATIONS
Primary sclerosing cholangitis (PSC) is a rare liver disease characterized by chronic inflammation and irreparable damage to the bile ducts, which eventually results in liver failure. Due to a limited understanding of the underlying pathogenesis of disease, treatment options are limited. To address this, we sequenced healthy and diseased livers to compare the activity, interactions, and localization of immune and non-immune cells. This revealed that hepatocytes lining PSC scar regions co-express cholangiocyte markers, whereas immune cells infiltrate the scar lesions. Of these cells, macrophages, which typically contribute to tissue repair, were enriched in immunoregulatory genes and demonstrated a lack of responsiveness to stimulation. These cells may be involved in maintaining hepatic inflammation and could be a target for novel therapies.
Topics: Humans; Cholangitis, Sclerosing; Cicatrix; Ecosystem; Liver; Liver Cirrhosis; Cytokines; Inflammation; Gene Expression Profiling
PubMed: 38199298
DOI: 10.1016/j.jhep.2023.12.023 -
Frontiers in Immunology 2023Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune... (Review)
Review
Sepsis is a hyper-heterogeneous syndrome in which the systemic inflammatory response persists throughout the course of the disease and the inflammatory and immune responses are dynamically altered at different pathogenic stages. Gasdermins (GSDMs) proteins are pore-forming executors in the membrane, subsequently mediating the release of pro-inflammatory mediators and inflammatory cell death. With the increasing research on GSDMs proteins and sepsis, it is believed that GSDMs protein are one of the most promising therapeutic targets in sepsis in the future. A more comprehensive and in-depth understanding of the functions of GSDMs proteins in sepsis is important to alleviate the multi-organ dysfunction and reduce sepsis-induced mortality. In this review, we focus on the function of GSDMs proteins, the molecular mechanism of GSDMs involved in sepsis, and the regulatory mechanism of GSDMs-mediated signaling pathways, aiming to provide novel ideas and therapeutic strategies for the diagnosis and treatment of sepsis.
Topics: Humans; Gasdermins; Sepsis; Cell Death; Inflammation Mediators; Syndrome
PubMed: 38022612
DOI: 10.3389/fimmu.2023.1203687