Expression of the anaphylatoxin receptors C3aR and C5aR is increased in fatal asthma

Fregonese, Laura; Swan, Fiona J.; Schadewijk, Annemarie van; Dolhnikoff, Marisa; Santos, Mario Adriano Dos; Daha, Mohamed R.; Stolk, Jan; Tschernig, Thomas; Sterk, Peter J.; Hiemstra, Pieter S.; Rabe, Klaus F.; Mauad, Thaís

doi:10.1016/j.jaci.2005.01.068

Cited by 58 publications

(53 citation statements)

References 52 publications

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“…C5a levels also are reportedly elevated in induced asthmatic sputum (74). Furthermore, receptors for these anaphylatoxins are elevated on the airway epithelium and bronchial smooth muscle of living asthmatics (72) on submucosal vessels, airway epithelium and smooth muscle cells in fatal asthma (75).…”

Section: Discussionmentioning

confidence: 99%

Generation of Anaphylatoxins by Human β-Tryptase from C3, C4, and C5

Fukuoka

Xia

Sánchez‐Muñoz

et al. 2008

The Journal of Immunology

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Both mast cells and complement participate in innate and acquired immunity. The current study examines whether β-tryptase, the major protease of human mast cells, can directly generate bioactive complement anaphylatoxins. Important variables included pH, monomeric vs tetrameric forms of β-tryptase, and the β-tryptase-activating polyanion. The B12 mAb was used to stabilize β-tryptase in its monomeric form. C3a and C4a were best generated from C3 and C4, respectively, by monomeric β-tryptase in the presence of low molecular weight dextran sulfate or heparin at acidic pH. High molecular weight polyanions increased degradation of these anaphylatoxins. C5a was optimally generated from C5 at acidic pH by β-tryptase monomers in the presence of high molecular weight dextran sulfate and heparin polyanions, but also was produced by β-tryptase tetramers under these conditions. Mass spectrometry verified that the molecular mass of each anaphylatoxin was correct. Both β-tryptase-generated C5a and C3a (but not C4a) were potent activators of human skin mast cells. These complement anaphylatoxins also could be generated by β-tryptase in releasates of activated skin mast cells. Of further biologic interest, β-tryptase also generated C3a from C3 in human plasma at acidic pH. These results suggest β-tryptase might generate complement anaphylatoxins in vivo at sites of inflammation, such as the airway of active asthma patients where the pH is acidic and where elevated levels of β-tryptase and complement anaphylatoxins are detected.

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Section: Discussionmentioning

confidence: 99%

Generation of Anaphylatoxins by Human β-Tryptase from C3, C4, and C5

Fukuoka

Xia

Sánchez‐Muñoz

et al. 2008

The Journal of Immunology

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“…This is expected to significantly limit the inflammatory effects of complement activation, since C3a and C5a are important in local inflammation and immune responses [45]. Compared to C3a and C5a, C4a, is a much weaker anaphylatoxin, and has comparatively little chemotactic activity [46].…”

Section: Discussionmentioning

confidence: 99%

Regulated complement deposition on the surface of human endothelial cells: Effect of tobacco smoke and shear stress

Yin

Ghebrehiwet

Weksler

et al. 2008

Thrombosis Research

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Cigarette smoke and hemodynamic stress both contribute to vascular inflammation and associated atherosclerosis. We recently demonstrated direct activation of complement components C4 and C3 on human endothelial cells (EC). The present study was designed to explore complement activation on bone marrow microvascular endothelial cells (BMEC) and human umbilical vein endothelial cells (HUVEC) in response to endothelial cell injury by tobacco smoke extract, shear stress, or other known inflammatory and atherogenic mediators, lipopolysaccharide (LPS) and INF-γ. Following treatment, confluent EC monolayers were exposed to plasma (60 min, 37 °C), and cell surface deposition of stable complement derivatives C4d, iC3b and SC5b-9 was measured in situ using an ELISA approach. Consistent with previous results, moderate levels of C4d, iC3b and SC5b-9 deposition were observed on native EC monolayers exposed to human plasma. Tobacco smoke and shear stress enhanced EC C4d deposition. In contrast, LPS and INF-γ failed to affect EC mediated complement activation, despite evidence of EC activation illustrated by ICAM-1 expression. The combination of tobacco smoke and shear stress nearly doubled EC C4d expression. No increases in iC3b or SC5b-9 were noted, suggesting inhibition of classical and alternative pathway C3 convertase assembly or activity. Indeed, concomitantly increased surface expression of complement regulatory proteins CD35 (CR1) and CD55 was observed following EC exposure to tobacco smoke and shear stress. These results suggest that a balance between complement activation and regulation exists at the EC surface, and may impact vascular injury leading to thrombosis, arteriosclerosis, and atherogenesis.

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“…Bronchial bioptates from asthma patients, independent of atopic status, and from atopic controls found a greater number of cells presenting FceRI on their surface (mainly mast cells and macrophages) compared to healthy subjects without signs of atopy [10]. Particularly high expression was found in bronchial tissue taken from patients who had died during the course of a severe acute asthma attack [11]. It is known that FceRI expression on effector cells correlates with IgE concentration in serum and is dependent on the stimulation of these receptors through the IgE molecules bound to them.…”

Section: Pharmacodynamic Properties Of Omalizumabmentioning

confidence: 94%

The Effect of Omalizumab on Eosinophilic Inflammation of the Respiratory Tract in Patients with Allergic Asthma

Kupryś‐Lipińska¹,

Molińska²,

Kuna³

2016

Advances in Respiratory Medicine

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Bronchial asthma is characterised by high levels of immunoglobulin E (IgE) and overproduction of pro-inflammatory cytokines, including interleukins IL-4, IL-13 and IL-5 needed for, amongst other things, the production of IgE and the differentiation, maturation, migration and survival of eosinophils. Eosinophils are one of the most important cells in allergic inflammation. Their presence in tissue is linked to the persistence of inflammatory infiltrate, tissue damage and remodelling. Although these cells are very sensitive to corticosteroids, some asthmatic patients do not respond to high doses of these drugs, even when administered systemically. Transbronchial biopsies and bronchoalveolar lavage performed in patients with steroid-resistant asthma have demonstrated higher levels of eosinophils and Th2-type cytokines (IL-4 and IL-5) compared to steroid-sensitive patients. Clinical studies have confirmed that the very effective treatment in these cases is therapy with omalizumab -an anti-IgE monoclonal antibody. The paper discusses the efficacy of omalizumab in reducing eosinophil number in peripheral blood and in the airways of asthmatic patients based on basic, clinical, observational studies and case reports. The significance of omalizumab therapy in asthma control and mechanisms that regulate the effects of omalizumab on eosinophils are evaluated.

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Expression of the anaphylatoxin receptors C3aR and C5aR is increased in fatal asthma

Cited by 58 publications

References 52 publications

Generation of Anaphylatoxins by Human β-Tryptase from C3, C4, and C5

Generation of Anaphylatoxins by Human β-Tryptase from C3, C4, and C5

Regulated complement deposition on the surface of human endothelial cells: Effect of tobacco smoke and shear stress

The Effect of Omalizumab on Eosinophilic Inflammation of the Respiratory Tract in Patients with Allergic Asthma

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