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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 -
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 -
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 -
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 -
Trends in Neurosciences Jun 2015Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) III protein uniquely found in astrocytes in the central nervous system (CNS), non-myelinating... (Review)
Review
Glial fibrillary acidic protein (GFAP) is an intermediate filament (IF) III protein uniquely found in astrocytes in the central nervous system (CNS), non-myelinating Schwann cells in the peripheral nervous system (PNS), and enteric glial cells. GFAP mRNA expression is regulated by several nuclear-receptor hormones, growth factors, and lipopolysaccharides (LPSs). GFAP is also subject to numerous post-translational modifications (PTMs), while GFAP mutations result in protein deposits known as Rosenthal fibers in Alexander disease. GFAP gene activation and protein induction appear to play a critical role in astroglial cell activation (astrogliosis) following CNS injuries and neurodegeneration. Emerging evidence also suggests that, following traumatic brain and spinal cord injuries and stroke, GFAP and its breakdown products are rapidly released into biofluids, making them strong candidate biomarkers for such neurological disorders.
Topics: Animals; Biomarkers; Glial Fibrillary Acidic Protein; Gliosis; Humans; Intermediate Filaments
PubMed: 25975510
DOI: 10.1016/j.tins.2015.04.003 -
Current Opinion in Neurobiology Feb 2022Alexander disease is a primary disorder of astrocytes caused by gain-of-function mutations in the gene for glial fibrillary acidic protein (GFAP), which lead to protein... (Review)
Review
Alexander disease is a primary disorder of astrocytes caused by gain-of-function mutations in the gene for glial fibrillary acidic protein (GFAP), which lead to protein aggregation and a reactive astrocyte response, with devastating effects on the central nervous system. Over the past two decades since the discovery of GFAP as the culprit, several cellular and animal models have been generated, and much has been learned about underlying mechanisms contributing to the disease. Despite these efforts, many aspects of Alexander disease have remained enigmatic, particularly the initiating events in GFAP accumulation and astrocyte pathology, the relation between astrocyte dysfunction and myelin deficits, and the variability in age of onset and disease severity. More recent work in both old and new models has begun to address these complex questions and identify new therapeutics that finally offer the promise of effective treatment.
Topics: Alexander Disease; Animals; Astrocytes; Central Nervous System; Glial Fibrillary Acidic Protein; Humans; Mutation; Protein Aggregates
PubMed: 34826654
DOI: 10.1016/j.conb.2021.10.002 -
RNA Biology 2022RNA therapeutics comprise a diverse group of oligonucleotide-based drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and short hairpin...
RNA therapeutics comprise a diverse group of oligonucleotide-based drugs such as antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs) that can be designed to selectively interact with drug targets currently undruggable with small molecule-based drugs or monoclonal antibodies. Furthermore, RNA-based therapeutics have the potential to modulate entire disease pathways, and thereby represent a new modality with unprecedented potential for generating disease-modifying drugs for a wide variety of human diseases, including central nervous system (CNS) disorders. Here, we describe different strategies for delivering RNA drugs to the CNS and review recent advances in clinical development of ASO drugs and siRNA-based therapeutics for the treatment of neurological diseases and neuromuscular disorders. 2'-MOE: 2'--(2-methoxyethyl); 2'--Me: 2'--methyl; 2'-F: 2'-fluoro; AD: Alzheimer's disease; ALS: Amyotrophic lateral sclerosis; ALSFRS-R: Revised Amyotrophic Lateral Sclerosis Functional Rating Scale; ARC: Antibody siRNA Conjugate; AS: Angelman Syndrome; ASGRP: Asialoglycoprotein receptor; ASO: Antisense oligonucleotide; AxD: Alexander Disease; BBB: Blood brain barrier; Bp: Basepair; CNM: Centronuclear myopathies; CNS: Central Nervous System; CPP: Cell-penetrating Peptide; CSF: Cerebrospinal fluid; DMD: Duchenne muscular dystrophy; DNA: Deoxyribonucleic acid; FAP: Familial amyloid polyneuropathy; FALS: Familial amyotrophic lateral sclerosis; FDA: The United States Food and Drug Administration; GalNAc: N-acetylgalactosamine; GoF: Gain of function; hATTR: Hereditary transthyretin amyloidosis; HD: Huntington's disease; HRQOL: health-related quality of life; ICV: Intracerebroventricular; IT: Intrathecal; LNA: Locked nucleic acid; LoF: Loss of function; mRNA: Messenger RNA; MS: Multiple Sclerosis; MSA: Multiple System Atrophy; NBE: New Biological Entity; NCE: New Chemical Entity; NHP: Nonhuman primate; nt: Nucleotide; PD: Parkinson's disease; PNP: Polyneuropathy; PNS: Peripheral nervous system; PS: Phosphorothioate; RISC: RNA-Induced Silencing Complex; RNA: Ribonucleic acid; RNAi: RNA interference; s.c.: Subcutaneous; siRNA: Small interfering RNA; SMA: Spinal muscular atrophy; SMN: Survival motor neuron; TTR: Transthyretin.
Topics: Animals; Amyloid Neuropathies, Familial; Amyotrophic Lateral Sclerosis; Neuromuscular Diseases; Oligonucleotides, Antisense; Quality of Life; RNA, Messenger; RNA, Small Interfering; United States; Genetic Therapy; Humans; Disease Models, Animal
PubMed: 35482908
DOI: 10.1080/15476286.2022.2066334 -
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