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Nature Apr 2022Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies...
Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (T2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent T17 inflammation. We also observed divergent responses to biologic therapies targeting T2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in T2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo T response towards a T2-predominant state and prevent aberrant non-T2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of T17 pathology and unlocked therapeutic responsiveness to targeted anti-T2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.
Topics: Animals; Cytokines; Dermatitis, Atopic; Disease Models, Animal; Inflammation; Mice; Obesity; PPAR gamma; Precision Medicine; Sequence Analysis, RNA; Th2 Cells
PubMed: 35355021
DOI: 10.1038/s41586-022-04536-0 -
Nature Aug 2019Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis. However, both the exact origin and the role of macrophages in...
Macrophages are considered to contribute to chronic inflammatory diseases such as rheumatoid arthritis. However, both the exact origin and the role of macrophages in inflammatory joint disease remain unclear. Here we use fate-mapping approaches in conjunction with three-dimensional light-sheet fluorescence microscopy and single-cell RNA sequencing to perform a comprehensive spatiotemporal analysis of the composition, origin and differentiation of subsets of macrophages within healthy and inflamed joints, and study the roles of these macrophages during arthritis. We find that dynamic membrane-like structures, consisting of a distinct population of CXCR1 tissue-resident macrophages, form an internal immunological barrier at the synovial lining and physically seclude the joint. These barrier-forming macrophages display features that are otherwise typical of epithelial cells, and maintain their numbers through a pool of locally proliferating CXCR1 mononuclear cells that are embedded into the synovial tissue. Unlike recruited monocyte-derived macrophages, which actively contribute to joint inflammation, these epithelial-like CXCR1 lining macrophages restrict the inflammatory reaction by providing a tight-junction-mediated shield for intra-articular structures. Our data reveal an unexpected functional diversification among synovial macrophages and have important implications for the general role of macrophages in health and disease.
Topics: Animals; Arthritis; CX3C Chemokine Receptor 1; Cell Tracking; Female; Gene Expression Profiling; Humans; Inflammation; Joints; Macrophages; Male; Mice; Mice, Inbred C57BL; Principal Component Analysis; RNA-Seq; Single-Cell Analysis; Synovial Membrane; Synoviocytes; Tight Junctions; Transcriptome
PubMed: 31391580
DOI: 10.1038/s41586-019-1471-1 -
Translational Lung Cancer Research Feb 2020Malignant peritoneal mesothelioma (MPM) is a rare and lethal disease of the peritoneal lining, with high variability in biologic aggressiveness. Morbidity and mortality... (Review)
Review
Malignant peritoneal mesothelioma (MPM) is a rare and lethal disease of the peritoneal lining, with high variability in biologic aggressiveness. Morbidity and mortality of the disease are related to progressive locoregional effects within the abdominal cavity, such as distention, pain, early satiety, and decreased oral intake that can ultimately lead to bowel obstruction and cachexia. The standard of care for patients with resectable disease remains cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC), with potential survival outcomes greater than 5 years in appropriately selected patients. Patients with inoperable MPM can be offered systemic treatment, although the disease is usually refractory to standard chemotherapic regimens. Patients with MPM should be treated at high volume centers with strong consideration for inclusion in tumor registries and clinical trials. In 2020, research will continue to explore promising genetic and immunologic targets and focus on refinement of surgical methods to optimize CRS-HIPEC approaches.
PubMed: 32206577
DOI: 10.21037/tlcr.2019.12.15 -
Clinical Reviews in Allergy & Immunology Oct 2022Autoantibodies represent a hallmark of rheumatoid arthritis (RA), with the rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA) being the most... (Review)
Review
Autoantibodies represent a hallmark of rheumatoid arthritis (RA), with the rheumatoid factor (RF) and antibodies against citrullinated proteins (ACPA) being the most acknowledged ones. RA patients who are positive for RF and/or ACPA ("seropositive") in general display a different etiology and disease course compared to so-called "seronegative" patients. Still, the seronegative patient population is very heterogeneous and not well characterized. Due to the identification of new autoantibodies and advancements in the diagnosis of rheumatic diseases in the last years, the group of seronegative patients is constantly shrinking. Aside from antibodies towards various post-translational modifications, recent studies describe autoantibodies targeting some native proteins, further broadening the spectrum of recognized antigens. Next to the detection of new autoantibody groups, much research has been done to answer the question if and how autoantibodies contribute to the pathogenesis of RA. Since autoantibodies can be detected years prior to RA onset, it is a matter of debate whether their presence alone is sufficient to trigger the disease. Nevertheless, there is gathering evidence of direct autoantibody effector functions, such as stimulation of osteoclastogenesis and synovial fibroblast migration in in vitro experiments. In addition, autoantibody positive patients display a worse clinical course and stronger radiographic progression. In this review, we discuss current findings regarding different autoantibody types, the underlying disease-driving mechanisms, the role of Fab and Fc glycosylation and clinical implications.
Topics: Arthritis, Rheumatoid; Autoantibodies; Humans; Rheumatoid Factor
PubMed: 34495490
DOI: 10.1007/s12016-021-08890-1 -
Gut Sep 2022We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct... (Review)
Review
We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct therapies. We predict that the most valuable data will be produced by systems that are highly dynamic in both time and space. Three-dimensional (3D) organoids are poised to be such a highly valuable system for a variety of gastrointestinal (GI) diseases. In the lab, organoids have emerged as powerful systems to model molecular and cellular processes orchestrating natural and pathophysiological human tissue formation in remarkable detail. Preclinical studies have impressively demonstrated that these organs-in-a-dish can be used to model immunological, neoplastic, metabolic or infectious GI disorders by taking advantage of patient-derived material. Technological breakthroughs now allow to study cellular communication and molecular mechanisms of interorgan cross-talk in health and disease including communication along for example, the gut-brain axis or gut-liver axis. Despite considerable success in culturing classical 3D organoids from various parts of the GI tract, some challenges remain to develop these systems to best help patients. Novel platforms such as organ-on-a-chip, engineered biomimetic systems including engineered organoids, micromanufacturing, bioprinting and enhanced rigour and reproducibility will open improved avenues for tissue engineering, as well as regenerative and personalised medicine. This review will highlight some of the established methods and also some exciting novel perspectives on organoids in the fields of gastroenterology. At present, this field is poised to move forward and impact many currently intractable GI diseases in the form of novel diagnostics and therapeutics.
Topics: Bioprinting; Gastrointestinal Diseases; Humans; Models, Theoretical; Organoids; Reproducibility of Results
PubMed: 35636923
DOI: 10.1136/gutjnl-2021-326560 -
Journal of the Belgian Society of... 2021The main differential diagnosis of leukodystrophy associated with macrocephaly consists of Alexander disease, Canavan disease, and megalencephalic leukodystrophy with...
The main differential diagnosis of leukodystrophy associated with macrocephaly consists of Alexander disease, Canavan disease, and megalencephalic leukodystrophy with subcortical cysts. Distinguishing imaging characteristics of Alexander disease are an apicoposterior gradient of white matter involvement and a periventricular T2-hypointense rim.
PubMed: 34723085
DOI: 10.5334/jbsr.2588 -
International Journal of Molecular... Sep 2023This Special Issue-dedicated to high-quality review papers in molecular microbiology-is highlighting two important developments in the field: (i) the analysis of...
This Special Issue-dedicated to high-quality review papers in molecular microbiology-is highlighting two important developments in the field: (i) the analysis of microbiome data in health and disease and (ii) the search for strategies against bacteria showing antimicrobial resistance [...].
Topics: Microbiota; Review Literature as Topic; Drug Resistance, Bacterial
PubMed: 37762293
DOI: 10.3390/ijms241813990 -
Frontiers in Cellular Neuroscience 2020Defective astrocyte function due to a genetic mutation can have major consequences for microglia and oligodendrocyte physiology, which in turn affects the white matter... (Review)
Review
Defective astrocyte function due to a genetic mutation can have major consequences for microglia and oligodendrocyte physiology, which in turn affects the white matter integrity of the brain. This review addresses the current knowledge on shared and unique pathophysiological mechanisms of astrocytopathies, including vanishing white matter, Alexander disease, megalencephalic leukoencephalopathy with subcortical cysts, Aicardi-Goutières syndrome, and oculodentodigital dysplasia. The mechanisms of disease include protein accumulation, unbalanced secretion of extracellular matrix proteins, pro- and anti-inflammatory molecules, cytokines and chemokines by astrocytes, as well as an altered gap junctional network and a changed ionic and nutrient homeostasis. Interestingly, the extent to which astrogliosis and microgliosis are present in these astrocytopathies is highly variable. An improved understanding of astrocyte-microglia-oligodendrocyte crosstalk might ultimately lead to the identification of druggable targets for these, currently untreatable, severe conditions.
PubMed: 33328899
DOI: 10.3389/fncel.2020.608073