Anaphylaxis: Lessons from mouse models

Department of Medicine, Cincinnati Veterans Affairs Medical Center, Ohio, USA.
Journal of Allergy and Clinical Immunology (Impact Factor: 11.48). 10/2007; 120(3):506-15; quiz 516-7. DOI: 10.1016/j.jaci.2007.07.033
Source: PubMed

ABSTRACT Studies with mouse models demonstrate 2 pathways of systemic anaphylaxis: a classic pathway mediated by IgE, FcepsilonRI, mast cells, histamine, and platelet-activating factor (PAF) and an alternative pathway mediated by IgG, FcgammaRIII, macrophages, and PAF. The former pathway requires much less antigen and antibody than the latter. This is modified, however, by IgG antibodies that prevent IgE-mediated anaphylaxis by intercepting antigen before it binds to mast cell-associated IgE. Consequently, IgG antibodies block systemic anaphylaxis induced by small quantities of antigen but mediate systemic anaphylaxis induced by larger quantities. The importance of the alternative pathway in human subjects is unknown, but human IgG, IgG receptors, macrophages, mediators, and mediator receptors have appropriate properties to support this pathway if sufficient IgG and antigen are present. The severity of systemic anaphylaxis is increased by nitric oxide produced by the enzyme endothelial nitric oxide synthase and by the cytokines IL-4 and IL-13 and decreased by endogenous beta-adrenergic stimulation and receptors that contain ITIM that bind tyrosine phosphatases. Anaphylaxis is also suppressed by other receptors and ion channels that function through distinct mechanisms. Unlike systemic anaphylaxis, intestinal anaphylaxis (allergic diarrhea) is almost totally IgE and mast cell dependent and is mediated predominantly by PAF and serotonin. Some potent food allergens, including peanuts and tree nuts, can directly enhance anaphylaxis by stimulating an anaphylactoid response through the innate immune system. Results of these studies suggest novel prophylactic agents, including nonstimulatory anti-IgE mAbs, IL-4 receptor antagonists, PAF antagonists, and agents that cross-link FcepsilonRI or FcgammaRIII to an ITIM-containing inhibitory receptor.

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    • "In mouse models, PAF antagonists effectively attenuated IgG-induced anaphylaxis (Jiao et al., 2014; Jonsson et al., 2011; Strait et al., 2002; Tsujimura et al., 2008) and peanut-induced anaphylaxis severity (Arias et al., 2009), but did not effectively attenuate IgEmediated anaphylaxis, which is more dependent on histamine release (Strait et al., 2002). In humans, it has not been clearly established whether anaphylaxis is mediated through a classical IgE-mediated pathway, an alternative IgG-mediated pathway or both (Finkelman, 2007). "
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    ABSTRACT: Sphingosine-1phosphate (S1P), platelet activating factor (PAF) and eicosanoids are bioactive lipid mediators abundantly produced by antigen-stimulated mast cells that exert their function mostly through specific cell surface receptors. Although it has long been recognized that some of these bioactive lipids are potent regulators of allergic diseases, their exact contributions to disease pathology have been obscured by the complexity of their mode of action and the regulation of their metabolism. Indeed, the effects of such lipids are usually mediated by multiple receptor subtypes that may differ in their signaling mechanisms and functions. In addition, their actions may be elicited by cell surface receptor-independent mechanisms. Furthermore, these lipids may be converted into metabolites that exhibit different functionalities, adding another layer of complexity to their overall biological responses. In some instances, a second wave of lipid mediator synthesis by both mast cell and non-mast cell sources may occur late during inflammation, bringing about additional roles in the altered environment. New evidence also suggests that bioactive lipids in the local environment can fine-tune mast cell maturation and phenotype, and thus their responsiveness. A better understanding of the subtleties of the spatiotemporal regulation of these lipid mediators, their receptors and functions may aid in the pursuit of pharmacological applications for allergy treatments. Copyright © 2015. Published by Elsevier B.V.
    European journal of pharmacology 05/2015; DOI:10.1016/j.ejphar.2015.02.058 · 2.53 Impact Factor
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    • "Thus, NTAL could play different roles in mast cells of different origin. It has been shown that human mast cells differ from mouse mast cells in cytokine production, immunoglobulin receptor expression, and the ability of different stimuli to cause degranulation and release of mediators [44]. Furthermore, when total tyrosine phosphorylated proteins were compared between RBL-2H3 cells and freshly isolated peritoneal and pleural rat mast cells, dramatic differences were observed [45]. "
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    ABSTRACT: Non-T cell activation linker (NTAL; also called LAB or LAT2) is a transmembrane adaptor protein that is expressed in a subset of hematopoietic cells, including mast cells. There are conflicting reports on the role of NTAL in the high affinity immunoglobulin E receptor (FcεRI) signaling. Studies carried out on mast cells derived from mice with NTAL knock out (KO) and wild type mice suggested that NTAL is a negative regulator of FcεRI signaling, while experiments with RNAi-mediated NTAL knockdown (KD) in human mast cells and rat basophilic leukemia cells suggested its positive regulatory role. To determine whether different methodologies of NTAL ablation (KO vs KD) have different physiological consequences, we compared under well defined conditions FcεRI-mediated signaling events in mouse bone marrow-derived mast cells (BMMCs) with NTAL KO or KD. BMMCs with both NTAL KO and KD exhibited enhanced degranulation, calcium mobilization, chemotaxis, tyrosine phosphorylation of LAT and ERK, and depolymerization of filamentous actin. These data provide clear evidence that NTAL is a negative regulator of FcεRI activation events in murine BMMCs, independently of possible compensatory developmental alterations. To gain further insight into the role of NTAL in mast cells, we examined the transcriptome profiles of resting and antigen-activated NTAL KO, NTAL KD, and corresponding control BMMCs. Through this analysis we identified several genes that were differentially regulated in nonactivated and antigen-activated NTAL-deficient cells, when compared to the corresponding control cells. Some of the genes seem to be involved in regulation of cholesterol-dependent events in antigen-mediated chemotaxis. The combined data indicate multiple regulatory roles of NTAL in gene expression and mast cell physiology.
    PLoS ONE 08/2014; 9(8):e105539. DOI:10.1371/journal.pone.0105539 · 3.23 Impact Factor
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    • "The most dramatic food hypersensitivity reaction is systemic anaphylaxis, in which vasoactive mast cell mediators induce plasma extravasation, shock, cardiopulmonary collapse, and death (Finkelman, 2007; Simons, 2010). The standard of care, namely recommendation to strictly avoid foods to which they are allergic, paradoxically deprives patients of the chance to naturally develop oral tolerance, as would probably occur if they were able to continue to ingest them without experiencing harmful effects. "
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    ABSTRACT: Immunoglobulin E (IgE) antibodies are known for triggering immediate hypersensitivity reactions such as food anaphylaxis. In this study, we tested whether they might additionally function to amplify nascent antibody and T helper 2 (Th2) cell-mediated responses to ingested proteins and whether blocking IgE would modify sensitization. By using mice harboring a disinhibited form of the IL-4 receptor, we developed an adjuvant-free model of peanut allergy. Mast cells and IgE were required for induction of antibody and Th2-cell-mediated responses to peanut ingestion and they impaired regulatory T (Treg) cell induction. Mast-cell-targeted genetic deletion of the FcεRI signaling kinase Syk or Syk blockade also prevented peanut sensitization. In mice with established allergy, Syk blockade facilitated desensitization and induction of Treg cells, which suppressed allergy when transferred to naive recipients. Our study suggests a key role for IgE in driving Th2 cell and IgE responses while suppressing Treg cells in food allergy.
    Immunity 07/2014; 41(1). DOI:10.1016/j.immuni.2014.05.017 · 21.56 Impact Factor
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