| 1. |
- Pröbstel, Anne-Katrin, et al.
(författare)
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Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis
- 2020
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Ingår i: Science immunology. - : American Association for the Advancement of Science. - 2470-9468. ; 5:53
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Tidskriftsartikel (refereegranskat)abstract
- Changes in gut microbiota composition and a diverse role of B cells have recently been implicated in multiple sclerosis (MS), a central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is a key regulator at the mucosal interface. However, whether gut microbiota shape IgA responses and what role IgA+ cells have in neuroinflammation are unknown. Here, we identify IgA-bound taxa in MS and show that IgA-producing cells specific for MS-associated taxa traffic to the inflamed CNS, resulting in a strong, compartmentalized IgA enrichment in active MS and other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal IgA responses, CNS IgA cross-reacts with surface structures on specific bacterial strains but not with brain tissue. These findings establish gut microbiota-specific IgA+ cells as a systemic mediator in MS and suggest a critical role of mucosal B cells during active neuroinflammation with broad implications for IgA as an informative biomarker and IgA-producing cells as an immune subset to harness for therapeutic interventions.
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| 2. |
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| 3. |
- Gray, Christopher J., et al.
(författare)
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Advancing Solutions to the Carbohydrate Sequencing Challenge
- 2019
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 141:37, s. 14463-14479
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Forskningsöversikt (refereegranskat)abstract
- Carbohydrates possess a variety of distinct features with stereochemistry playing a particularly important role in distinguishing their structure and function. Monosaccharide building blocks are defined by a high density of chiral centers. Additionally, the anomericity and regiochemistry of the glycosidic linkages carry important biological information. Any carbohydrate-sequencing method needs to be precise in determining all aspects of this stereodiversity. Recently, several advances have been made in developing fast and precise analytical techniques that have the potential to address the stereochemical complexity of carbohydrates. This perspective seeks to provide an overview of some of these emerging techniques, focusing on those that are based on NMR and MS-hybridized technologies including ion mobility spectrometry and IR spectroscopy.
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| 4. |
- Gustafsen, Camilla, et al.
(författare)
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Heparan sulfate proteoglycans present PCSK9 to the LDL receptor
- 2017
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Coronary artery disease is the main cause of death worldwide and accelerated by increased plasma levels of cholesterol-rich low-density lipoprotein particles (LDL). Circulating PCSK9 contributes to coronary artery disease by inducing lysosomal degradation of the LDL receptor (LDLR) in the liver and thereby reducing LDL clearance. Here, we show that liver heparan sulfate proteoglycans are PCSK9 receptors and essential for PCSK9-induced LDLR degradation. The heparan sulfate-binding site is located in the PCSK9 prodomain and formed by surface-exposed basic residues interacting with trisulfated heparan sulfate disaccharide repeats. Accordingly, heparan sulfate mimetics and monoclonal antibodies directed against the heparan sulfate-binding site are potent PCSK9 inhibitors. We propose that heparan sulfate proteoglycans lining the hepatocyte surface capture PCSK9 and facilitates subsequent PCSK9: LDLR complex formation. Our findings provide new insights into LDL biology and show that targeting PCSK9 using heparan sulfate mimetics is a potential therapeutic strategy in coronary artery disease.
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| 5. |
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| 6. |
- Ito, Yuki, et al.
(författare)
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Helicobacter pylori Cholesteryl α-Glucosides Contribute to Its Pathogenicity and Immune Response by Natural Killer T Cells
- 2013
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Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:12
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 10-15% of individuals infected with Helicobacter pylori will develop ulcer disease (gastric or duodenal ulcer), while most people infected with H. pylori will be asymptomatic. The majority of infected individuals remain asymptomatic partly due to the inhibition of synthesis of cholesteryl α-glucosides in H. pylori cell wall by α1,4-GlcNAc-capped mucin O-glycans, which are expressed in the deeper portion of gastric mucosa. However, it has not been determined how cholesteryl α-glucosyltransferase (αCgT), which forms cholesteryl α-glucosides, functions in the pathogenesis of H. pylori infection. Here, we show that the activity of αCgT from H. pylori clinical isolates is highly correlated with the degree of gastric atrophy. We investigated the role of cholesteryl α-glucosides in various aspects of the immune response. Phagocytosis and activation of dendritic cells were observed at similar degrees in the presence of wild-type H. pylori or variants harboring mutant forms of αCgT showing a range of enzymatic activity. However, cholesteryl α-glucosides were recognized by invariant natural killer T (iNKT) cells, eliciting an immune response in vitro and in vivo. Following inoculation of H. pylori harboring highly active αCgT into iNKT cell-deficient (Jα18(-/-)) or wild-type mice, bacterial recovery significantly increased in Jα18(-/-) compared to wild-type mice. Moreover, cytokine production characteristic of Th1 and Th2 cells dramatically decreased in Jα18(-/-) compared to wild-type mice. These findings demonstrate that cholesteryl α-glucosides play critical roles in H. pylori-mediated gastric inflammation and precancerous atrophic gastritis.
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| 7. |
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| 8. |
- Li, Chunxia, et al.
(författare)
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Noncovalent microarrays from synthetic amino-terminating glycans : Implications in expanding glycan microarray diversity and platform comparison
- 2021
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Ingår i: Glycobiology. - : Oxford University Press. - 0959-6658 .- 1460-2423. ; 31:8, s. 931-946
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Tidskriftsartikel (refereegranskat)abstract
- Glycan microarrays have played important roles in detection and specificity assignment of glycan recognition by proteins. However, the size and diversity of glycan libraries in current microarray systems are small compared to estimated glycomes, and these may lead to missed detection or incomplete assignment. For microarray construction, covalent and noncovalent immobilization are the two types of methods used, but a direct comparison of results from the two platforms is required. Here we develop a chemical strategy to prepare lipid-linked probes from both naturally derived aldehyde-terminating and synthetic amino-terminating glycans that addresses the two aspects: expansion of sequence-defined glycan libraries and comparison of the two platforms. We demonstrate the specific recognition by plant and mammalian lectins, carbohydrate-binding modules and antibodies and the overall similarities from the two platforms. Our results provide new knowledge on unique glycan-binding specificities for the immune receptor Dectin-1 toward beta-glucans and the interaction of rotavirus P[19] adhesive protein with mucin O-glycan cores.
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| 9. |
- Mackinnon, Alison, et al.
(författare)
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Design, synthesis, And applications of galectin modulators in human health
- 2014
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Ingår i: Carbohydrates as Drugs. - Cham : Springer International Publishing. - 1862-247X .- 1862-2461. - 9783319086743 - 9783319345376 - 9783319086750 ; , s. 95-122
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Bokkapitel (refereegranskat)abstract
- Over the last decade, the family of galectin proteins has been identified as key regulators of important biological processes. They bind β-D-galactopyranoside residues in glycoconjugates, and by presenting multiple binding sites, within one galectin or by forming dimers or multimers, they can cross-link glycoproteins and form galectin-glycoprotein lattices. Such lattices formed on the cell surface or in vesicles have been shown to control, for example, surface residence time and signaling by receptors. Hence, compounds modulating galectin binding to their glycoprotein ligands are of potential clinical interest. This chapter describes the design and development of disubstituted thiodigalactoside derivatives that form optimal interactions with the galectin-3 binding site resulting in double-digit nanomolar affinities. Studies are discussed in which such galectin-3-modulating compounds have been important in elucidating galectin-3 mechanisms, including galectin-3 trafficking, cancer, inflammation, fibrosis, and angiogenesis. Medically relevant models using the galectin-3 modulators in characterizing macrophage alternative activation and chronic inflammation, myofibroblast activation and fibrosis, and ocular angiogenesis are discussed in more detail. In summary, the high galectin-3 affinity and definitive effects in relevant models of the disubstituted thiodigalactosides identify them as promising as lead compounds for drug development, albeit leaving a challenge in terms of optimizing PK/ADME properties.
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