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- Carlsson, Michael, et al.
(författare)
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Galectin-8 in IgA Nephritis: Decreased Binding of IgA by Galectin-8 Affinity Chromatography and Associated Increased Binding in Non-IgA Serum Glycoproteins
- 2012
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Ingår i: Journal of Clinical Immunology. - : Springer Verlag (Germany). - 0271-9142 .- 1573-2592. ; 32:2, s. 246-255
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Tidskriftsartikel (refereegranskat)abstract
- Background Immunoglobulin A nephritis (IgAN) is the most common primary glomerulonephritis worldwide. It is caused by accumulation of IgA1-containing immune complexes in the kidney resulting in renal failure, which is thought to be due to altered glycosylation of IgA with a decrease of 2-3-sialylated galactosides (NeuAc alpha 2-3Gal). less thanbrgreater than less thanbrgreater thanPurpose The purpose of this study was to analyze whether altered glycosylation of IgA would lead to an altered binding to galectin-8, an endogenous lectin with strong affinity for 2-3-sialylated galactosides. Galectins are a family of beta-galactoside-binding proteins; by binding various glycoproteins, they play important roles in the regulation of cellular functions in inflammation and immunity. Hence, an altered binding of IgA to galectin-8 could lead to pathologic immune functions, such as glomerulonephritis. less thanbrgreater than less thanbrgreater thanMethods Affinity chromatography of serum glycoproteins on the human sialogalactoside-binding lectin galectin-8N permitted quantitation of bound and unbound fractions, including IgA. less thanbrgreater than less thanbrgreater thanResults Analysis of similar to 100 IgA nephritis sera showed that the galectin-8N unbound fraction of IgA increased compared to similar to 100 controls, consistent with the known loss of galactosylation. A subgroup of similar to 15% of the IgAN patients had a ratio of galectin-8 bound/unbound IgA andlt;0.09, not found for any of the controls. Unexpectedly, the galectin-8N-binding fraction of serum glycoproteins other than IgA increased in the sera of IgAN patients but not in controls, suggesting a previously unrecognized change in this disease. less thanbrgreater than less thanbrgreater thanConclusion This is the first study that relates a galectin, an endogenous lectin family, to IgA nephritis and thus should stimulate new avenues of research into the pathophysiology of the disease.
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| 2. |
- Larsson, Olivia, et al.
(författare)
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Substance P represents a novel first-line defense mechanism in the nose
- 2018
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 0091-6749 .- 1097-6825. ; 141:1, s. 3-136
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuropeptides, such as substance P (SP), have long been seen as mediators of widespread continuous airway inflammation, a process known as neurogenic inflammation. However, this has been difficult to demonstrate clinically, suggesting an alternative role for these signaling molecules. Objectives: We sought to examine the role of SP in nasal infection by assessing the release of SP in response to viral stimulation and characterizing the effects of SP on innate immunity, with the latter reflected in changes in local Toll-like receptor (TLR) expression. Methods: The distribution of SP and TLRs in the nasal mucosa and local airway neurons was assessed with immunohistochemistry. The TLR7 agonists R-837 and R-848 were used to mimic a viral insult in the upper airways represented by primary human nasal epithelial cells (HNECs) and murine nasal epithelial cells (MNECs) and isolated murine trigeminal ganglial neurons. SP release from HNECs, MNECs, and trigeminal ganglial neurons was quantified with EIA. The effects of SP on TLR expression on HNECs were determined by using flow cytometry and confocal microscopy. Results: SP was released from the sensory neurons, MNECs, and HNECs within 15 minutes of local TLR7 stimulation. Subsequently, stimulation with SP induced upregulation of TLR expression in HNECs within 30 minutes through induction of TLR movement within HNECs. Upregulation of TLR expression was not evident when cells were treated with the neurokinin 1 receptor antagonist aprepitant before SP stimulation. Conclusions: This highlights a novel role for sensory neuropeptides as acute and local mediators of pathogen-driven inflammation, rapidly priming innate immune defenses in the airway.
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| 3. |
- Tengroth, Lotta, et al.
(författare)
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Functional Effects of Toll-Like Receptor (TLR)3, 7, 9, RIG-I and MDA-5 Stimulation in Nasal Epithelial Cells.
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- The human nasal epithelium is an important physical barrier, and a part of the innate immune defense that protect against pathogens. The epithelial cells recognize microbial components by pattern-recognition receptors (PRRs), and thereby trigger an immune response. Even though TLR3, TLR7, TLR9, RIG-I and MDA-5 are all known to respond to viral stimulation, their potential role in chronic airway inflammation triggered by local cytokine release remains to be established.
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| 4. |
- Tengroth, Lotta
(författare)
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Nasal epithelial cells : innate immunity and inflammation
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The surface epithelium that lines the nasal passages is often the first tissue in the airway to encounter inhaled pathogens. It collaborates closely with the innate immune system, a subsystem of the immune system that defends the host from infection by organisms, mainly by initiating a local inflammatory reaction. Pattern-recognition receptors (PRRs) are important in pathogen recognition, cell activation and regulation of immune responses and include Toll-like receptors (TLRs), nucleotide-binding oligomerization domain-like receptors (NLRs) and retinoic acid-inducible gene 1 (RIG-I)-like receptors (RLRs). The transforming growth-factor beta (TGF-β) superfamily and their type I receptors, the activin receptor-like kinases (ALKs), are important mediators that promote remodelling and have recently also been shown to regulate airway inflammation. Even though PRRs and ALKs are essential in preventing disease, disruption of these systems is generally believed to be involved in the pathogenesis of airway inflammatory diseases such as asthma and chronic rhinosinusitis with nasal polyp (CRSwNP). Hence, the overall aim with this thesis was to investigate the role of PRRs and ALKs in airway inflammation. Human airway smooth muscle cells (HASMCs) are essential for the regulation of airflow; importantly, they are also involved in the shortness of breath that characterises microbialinduced exacerbations of asthma. The present thesis showed that stimulation of TLR2, TLR3, TLR4, TLR7 and NOD1 on HASMCs resulted in cytokine release, upregulation of inflammatory cell surface markers and downregulation of receptors involved in smooth muscle cell contraction. The nasal epithelium was found to express TLR3, TLR7, TLR9, RIG-I and MDA-5 and stimulation resulted in an increased inflammatory response characterised by the release of chemokines and cytokines. In addition, a specific role for TLR9 was found in patients with CRSwNP that might be linked to polyp growth via downregulation of VEGFR expression and lowered release of inflammatory cytokines. Virus-related ligand stimulation of TLR7 induced a rapid release of the neuropeptide, substance P (SP), from human nasal epithelial cells (HNECs) and sensory neurons. The released SP promptly upregulated the epithelial TLR expression. This suggests a role for SP in rapid priming of the innate immune system during viral infections. Polyp epithelial cells from patients with CRSwNP expressed high levels of ALK1-6. Polyp epithelial cells stimulated with ALK-ligands demonstrated a potential anti-inflammatory role for ALKs in polyps. Previous reports have demonstrated low levels of ALK-ligands in patients with CRSwNP, suggesting that ALKs could contribute to uncontrolled inflammation promoting the progression of CRSwNP. BMP4, an ALK-ligand, suppressed inflammation and hyperplasia in the turbinate tissue of patients with CRSwNP. This effect was absent in the corresponding polyp, suggesting that BMP4-ALK3 interaction might be involved in polyp growth in patients. In summary, this thesis demonstrates a role for specific epithelial PRRs and ALKs in CRSwNP and for smooth muscle PRRs in asthma. In addition, it proposes a novel role for substance P in kick starting the innate immune system by upregulating PRRs in response to microbial stimulation. These findings could generate new potential targets for the treatment of inflammatory airway diseases.
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