Identification of a Neuronal Receptor Controlling Anaphylaxis

Rogóż, Katarzyna; Aresh, Bejan; Freitag, Fabio Batista; Pettersson, Hanna; Magnúsdóttir, Elín Ingibjörg; Ingwall, Linn Larsson; Andersen, Helena Haddadi; Franck, Marina C. M.; Nagaraja, Chetan; Kullander, Klas; Lagerström, Malin C.

doi:10.1016/j.celrep.2015.12.033

Cited by 9 publications

(8 citation statements)

References 35 publications

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“…Allergen-induced activation of mast cells could lead to alterations in the function of afferent neurons like intrapulmonary airway C-fiber ( 45 ), neurons within the CNS ( 46 , 47 ), and somatosensory itch fiber in the skin ( 48 ), sensory nerve excitability ( 49 ) and neuroplasticity ( 50 ), increases in synaptic efficacy in autonomic ganglia ( 51 , 52 ) and stimulation of enteric neurons ( 53 , 54 ) – an effect which might be more prominent in atopic individuals compared to non-atopic controls ( 44 ). Of note, a recent neuronal receptor-based controlling mechanism of anaphylaxis involving the glutamatergic receptor mGluR7was described ( 55 ). These data would therefore be consistent with our hypothesis that upregulation of neuroinflammatory signalling pathways might impact neuromodulation in anaphylaxis.…”

Section: Discussionmentioning

confidence: 99%

Integrative transcriptomic analysis in human and mouse model of anaphylaxis identifies gene signatures associated with cell movement, migration and neuroinflammatory signalling

Rijavec

Maver²,

Turner³

et al. 2022

Front. Immunol.

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BackgroundAnaphylaxis is an acute life-threatening allergic reaction and a concern at a global level; therefore, further progress in understanding the underlying mechanisms and more effective strategies for diagnosis, prevention and management are needed.ObjectiveWe sought to identify the global architecture of blood transcriptomic features of anaphylaxis by integrating expression data from human patients and mouse model of anaphylaxis.MethodsBulk RNA-sequencings of peripheral whole blood were performed in: i) 14 emergency department (ED) patients with acute anaphylaxis, predominantly to Hymenoptera venom, ii) 11 patients with peanut allergy undergoing double-blind, placebo-controlled food challenge (DBPCFC) to peanut, iii) murine model of IgE-mediated anaphylaxis. Integrative characterisation of differential gene expression, immune cell-type-specific gene expression profiles, and functional and pathway analysis was undertaken.Results1023 genes were commonly and significantly dysregulated during anaphylaxis in ED and DBPCFC patients; of those genes, 29 were also dysregulated in the mouse model. Cell-type-specific gene expression profiles showed a rapid downregulation of blood basophil and upregulation of neutrophil signature in ED and DBPCFC patients and the mouse model, but no consistent and/or significant differences were found for other blood cells. Functional and pathway analysis demonstrated that human and mouse blood transcriptomic signatures of anaphylaxis follow trajectories of upregulation of cell movement, migration and neuroinflammatory signalling, and downregulation of lipid activating nuclear receptors signalling.ConclusionOur study highlights the matched and extensive blood transcriptomic changes and suggests the involvement of discrete cellular components and upregulation of migration and neuroinflammatory pathways during anaphylaxis.

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Section: Discussionmentioning

confidence: 99%

Integrative transcriptomic analysis in human and mouse model of anaphylaxis identifies gene signatures associated with cell movement, migration and neuroinflammatory signalling

Rijavec

Maver²,

Turner³

et al. 2022

Front. Immunol.

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“…For instance, a study by Wu et al showed that calpain 1 contributes to mast cell degranulation (96). Furthermore, inhibition of mGluRs, known to regulate histamine (34), abolished the anti-PrP antibody toxic effects (28). Taken together and in addition to the allergenic-related proteins associated with ICSM35 treatment reported by Tayebi and colleagues (21), this provides sufficient evidence to investigate the allergenic pathways potentially induced by treatment with anti-PrP antibodies which we refer to as "IgG-Mediated Neuronal Hypersensitivity".…”

Section: Discussionmentioning

confidence: 99%

“…PGs are synthesized by the cyclooxygenase (COX) enzymes in the arachidonic acid metabolic pathway and have been shown to play an important role in hypersensitivity (33). The neuronexpressed mGluR7 was shown to regulate histamine and ablation of mGluR7 in mice led to anaphylaxis (34). Of importance, mGluR7-interactors; mGluR1 and mGluR5 were shown to form complexes with PrP C and their pharmacological inhibition cancelled the 'neurotoxic' effects caused by anti-PrP antibodies (28).…”

Section: Introductionmentioning

confidence: 99%

Cross-Linking Cellular Prion Protein Induces Neuronal Type 2-Like Hypersensitivity

et al. 2021

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BackgroundPrevious reports identified proteins associated with ‘apoptosis’ following cross-linking PrPC with motif-specific anti-PrP antibodies in vivo and in vitro. The molecular mechanisms underlying this IgG-mediated neurotoxicity and the role of the activated proteins in the apoptotic pathways leading to neuronal death has not been properly defined. Previous reports implicated a number of proteins, including apolipoprotein E, cytoplasmic phospholipase A2, prostaglandin and calpain with anti-PrP antibody-mediated ‘apoptosis’, however, these proteins are also known to play an important role in allergy. In this study, we investigated whether cross-linking PrPC with anti-PrP antibodies stimulates a neuronal allergenic response.MethodsInitially, we predicted the allergenicity of the epitope sequences associated with ‘neurotoxic’ anti-PrP antibodies using allergenicity prediction servers. We then investigated whether anti-PrP antibody treatment of mouse primary neurons (MPN), neuroblastoma cells (N2a) and microglia (N11) cell lines lead to a neuronal allergenic response.ResultsIn-Silico studies showed that both tail- and globular-epitopes were allergenic. Specifically, binding regions that contain epitopes for previously reported ‘neurotoxic’ antibodies such as ICSM18 (146-159), ICSM35 (91-110), POM 1 (138-147) and POM 3 (95-100) lead to activation of allergenic related proteins. Following direct application of anti-PrPC antibodies on N2a cells, we identified 4 neuronal allergenic-related proteins when compared with untreated cells. Furthermore, we identified 8 neuronal allergenic-related proteins following treatment of N11 cells with anti-PrPC antibodies prior to co-culture with N2a cells when compared with untreated cells. Antibody treatment of MPN or MPN co-cultured with antibody-treated N11 led to identifying 10 and 7 allergenic-related proteins when compared with untreated cells. However, comparison with 3F4 antibody treatment revealed 5 and 4 allergenic-related proteins respectively. Of importance, we showed that the allergenic effects triggered by the anti-PrP antibodies were more potent when antibody-treated microglia were co-cultured with the neuroblastoma cell line. Finally, co-culture of N2a or MPN with N11-treated with anti-PrP antibodies resulted in significant accumulation of NO and IL6 but not TNF-α in the cell culture media supernatant.ConclusionsThis study showed for the first time that anti-PrP antibody binding to PrPC triggers a neuronal hypersensitivity response and highlights the important role of microglia in triggering an IgG-mediated neuronal hypersensitivity response. Moreover, this study provides an important impetus for including allergenic assessment of therapeutic antibodies for neurodegenerative disorders to derive safe and targeted biotherapeutics.

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“…For instance, a study by Wu et al showed that calpain 1 contributes to mast cell degranulation [98]. Furthermore, inhibition of mGluRs, known to regulate histamine [34], abolished the anti-PrP antibody toxic effects [28]. Taken together and in addition to the allergenic-related proteins associated with ICSM35 treatment reported by Tayebi and colleagues [21], this provides su cient evidence to investigate the allergenic pathways potentially induced by treatment with anti-PrP antibodies which we refer to as "IgG-Mediated Neuronal Allergenic Toxicity".…”

Section: Discussionmentioning

confidence: 99%

Treatment of Microglia with Anti-PrP Antibodies Induces Neuronal Allergenicity

Adhikari

Sakiz

Habiba

et al. 2020

Preprint

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Background: Previous reports identified proteins associated with ‘apoptosis’ following cross-linking PrPC with motif-specific anti-PrP antibodies in vivo and in vitro. The molecular mechanisms underlying this IgG-mediated neurotoxicity and the role of the activated proteins in the apoptotic pathways leading to neuronal death has not been properly defined. Previous reports implicated a number of proteins, including apolipoprotein E, cytoplasmic phospholipase A2, prostaglandin and calpain with anti-PrP antibody-mediated ‘apoptosis’, however, these proteins are also known to play an important role in allergy. In this study, we investigated whether cross-linking PrPC with anti-PrP antibodies stimulates a neuronal allergenic response.Methods: Initially, we predicted the allergenicity of the epitope sequences associated with ‘neurotoxic’ anti-PrP antibodies using allergenicity prediction servers. We then investigated whether anti-PrP antibody treatment of neuronal (N2a) and microglia (N11) cell lines leads to a neuronal allergenic response.Results: We found that both tail- and globular-epitopes were allergenic. Specifically, binding regions that contain epitopes for ‘neurotoxic’ antibodies such as ICSM18 (146-159), ICSM35 (91-110), POM 1 (138-147), POM 2 (57-88) and POM 3 (95-100) lead to activation of allergenic related proteins. Following direct application of anti-PrPC antibodies on N2a cells, mass spectrometry analysis identified 4 neuronal allergenic-related proteins when compared with untreated cells. Furthermore, mass spectrometry analysis identified 8 neuronal allergenic-related proteins following cross-linking N11 cells with anti-PrPC antibodies prior to co-culture with N2a cells, when compared with untreated cells. Of importance, we showed that the allergenic effects triggered by the anti-PrP antibodies were more potent when antibody-treated microglia were co-cultured with the neuroblastoma cell line. Furthermore, in both direct and co-culture with antibody-treated microglia, we demonstrate that the allergenic proteome was part of the PrPC-interactome. Conclusions: This study showed for the first time that anti-PrP antibody binding to PrPC triggers a neuronal allergenic response (we termed ‘IgG-Mediated Neuronal Allergenic Toxicity’) and highlights the important role of microglia in triggering IgG-mediated neuronal allergenic toxicity. Moreover, this study provides an important impetus for including allergenic assessment of therapeutic antibodies for neurodegenerative to derive safe and targeted biotherapeutics.

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Identification of a Neuronal Receptor Controlling Anaphylaxis

Cited by 9 publications

References 35 publications

Integrative transcriptomic analysis in human and mouse model of anaphylaxis identifies gene signatures associated with cell movement, migration and neuroinflammatory signalling

Integrative transcriptomic analysis in human and mouse model of anaphylaxis identifies gene signatures associated with cell movement, migration and neuroinflammatory signalling

Cross-Linking Cellular Prion Protein Induces Neuronal Type 2-Like Hypersensitivity

Treatment of Microglia with Anti-PrP Antibodies Induces Neuronal Allergenicity

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