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


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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    • "Alternatively, at 28-days of age, the second group of pups received 2 g/kg of bLF intraperitoneally. We observed these pups for 2 h for signs or symptoms of anaphylaxis, including sneezing, coughing, respiratory distress, movement disorders, shaking/tremors, and/or fur changes [15] "
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    ABSTRACT: Health policy precludes neonatal vaccination against influenza. Hence, morbidity and mortality are high under 6 months of age. Lactoferrin may activate diminished numbers of dysfunctional dendritic cells and reverse neonatal vaccine failures. Aluminum hydroxide/ALUM recruits neutrophils that secrete lacto-ferrin at deposition sites of antigen. We theorized lactoferrin þ influenza antigen initiates an equivalent antibody response compared to ALUM. Three-day-old mice received subcutaneously 30 mg of H1N1 hemagglutinin þ 200 mg of bovine lactoferrin versus hemagglutinin þ ALUM. Controls received hem-agglutinin, lactoferrin, or ALUM. After 21 days, sera measured anti-H1N1 (ELISA) and neutralizing antibody (plaque assays). ELISA detected equal antibody production with lactoferrin þ hemagglutinin compared to hemagglutinin þ ALUM; both sera also neutralized H1N1 virus at a 1:20 dilution (p < 0.01). Controls had no anti-H1N1 antibody. Neonates given lactoferrin had no anaphylaxis when challenged four weeks later. Lactoferrin is a safe and effective adjuvant for inducing antibody against influenza in neonates.
    Biochemical and Biophysical Research Communications 10/2015; DOI:10.1016/j.bbrc.2015.10.067 · 2.30 Impact Factor
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    • "Two major protocols are available for inducing systemic anaphylaxis in animals, active and passive ones in terms of sensitization [7]. In both models, soluble proteins such as bovine serum albumin (BSA) and ovalbumin (OVA) are commonly used as allergens, and the sign of anaphylaxis, including hypothermia, becomes evident within minutes after the challenge of allergens to sensitized animals [7]. "
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    ABSTRACT: Anaphylaxis is a rapid-onset, life-threatening allergic reaction in that IgE, mast cells and histamine are commonly involved. It can be experimentally induced in IgE-sensitized animals by intravenous injection of corresponding allergens, and the sign of anaphylactic reaction can be detected within minutes after allergen challenge. However, it remains puzzling why the anaphylactic reaction can be initiated in vivo so quickly, considering that allergens are delivered into the blood circulation while mast cells reside within peripheral tissues but not in the blood circulation. To address this issue, we compared two different forms of the same allergen, small soluble and large particulate ones, in their ability to induce anaphylaxis in IgE-sensitized mice. In contrast to our expectation, particulate allergens could induce anaphylaxis as quickly and efficiently as did soluble allergens, even though they remained inside of blood vessels. In vivo imaging analysis suggested the direct interaction of intravascular particulate allergens and perivascular mast cells across the capillary wall. Taken together with previous report that perivascular mast cells can capture IgE in the blood circulation by extending cell processes across the vessel wall, our findings imply that blood-circulating allergens, regardless of their size, can stimulate mast cells without exit from blood vessels, by means of cross-linking IgE on mast cell processes inserted into the vessel lumen, and hence initiate anaphylactic reaction so quickly.
    Biochemical and Biophysical Research Communications 09/2015; 467(1). DOI:10.1016/j.bbrc.2015.09.120 · 2.30 Impact Factor
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    • "Clinical symptoms of food allergy patients range from a mild skin reaction to lethal shock (Boyce et al., 2010; Sicherer and Sampson, 2010). The anaphylactic response to ingested food antigens usually results from the activation of intestinal mast cells (MCs) through food-specific IgE antibodies (Finkelman, 2007; Galli and Tsai, 2012). However, it is perplexing as to why only some patients and murine strains that acquire high amounts of dietary allergen-specific IgE develop a severe immediate intestinal hypersensitivity response that can result in life-threatening anaphylaxis. "
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    ABSTRACT: Experimental IgE-mediated food allergy depends on intestinal anaphylaxis driven by interleukin-9 (IL-9). However, the primary cellular source of IL-9 and the mechanisms underlying the susceptibility to food-induced intestinal anaphylaxis remain unclear. Herein, we have reported the identification of multifunctional IL-9-producing mucosal mast cells (MMC9s) that can secrete prodigious amounts of IL-9 and IL-13 in response to IL-33, and mast cell protease-1 (MCPt-1) in response to antigen and IgE complex crosslinking, respectively. Repeated intragastric antigen challenge induced MMC9 development that required T cells, IL-4, and STAT6 transcription factor, but not IL-9 signals. Mice ablated of MMC9 induction failed to develop intestinal mastocytosis, which resulted in decreased food allergy symptoms that could be restored by adoptively transferred MMC9s. Finally, atopic patients that developed food allergy displayed increased intestinal expression of Il9- and MC-specific transcripts. Thus, the induction of MMC9s is a pivotal step to acquire the susceptibility to IgE-mediated food allergy.
    Immunity 09/2015; 43(4). DOI:10.1016/j.immuni.2015.08.020 · 21.56 Impact Factor
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