Human IgE-independent systemic anaphylaxis Finkelman, Fred D., MD; Khodoun, Marat V., PhD; Strait, Richard, MD
Journal of allergy and clinical immunology,
06/2016, Letnik:
137, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Anaphylaxis is a rapidly developing, life-threatening, generalized or systemic allergic reaction that is classically elicited by antigen crosslinking of antigen-specific IgE bound to the ...high-affinity IgE receptor FcεRI on mast cells and basophils. This initiates signals that induce cellular degranulation with release and secretion of vasoactive mediators, enzymes, and cytokines. However, IgE-independent mechanisms of anaphylaxis have been clearly demonstrated in experimental animals. These include IgG-dependent anaphylaxis, which involves the triggering of mediator release by IgG/antigen complex crosslinking of FcγRs on macrophages, basophils, and neutrophils; anaphylaxis mediated by binding of the complement-derived peptides C3a and C5a to their receptors on mast cells, basophils, and other myeloid cells; and direct activation of mast cells by drugs that interact with receptors on these cells. Here we review the mechanisms involved in these IgE-independent forms of anaphylaxis and the clinical evidence for their human relevance. We conclude that this evidence supports the existence of all 3 IgE-independent mechanisms as important causes of human disease, although practical and ethical considerations preclude their demonstration to the degree of certainty possible with animal models. Furthermore, we cite evidence that different clinical situations can suggest different mechanisms as having a primal role in anaphylaxis and that IgE-dependent and distinct IgE-independent mechanisms can act together to increase anaphylaxis severity. As specific agents become available that can interfere with mechanisms involved in the different types of anaphylaxis, recognition of specific types of anaphylaxis is likely to become important for optimal prophylaxis and therapy.
Anaphylaxis: Lessons from mouse models Finkelman, Fred D., MD
Journal of allergy and clinical immunology,
09/2007, Letnik:
120, Številka:
3
Journal Article
Recenzirano
Studies with mouse models demonstrate 2 pathways of systemic anaphylaxis: a classic pathway mediated by IgE, FcεRI, mast cells, histamine, and platelet-activating factor (PAF) and an alternative ...pathway mediated by IgG, FcγRIII, 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 β-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 FcεRI or FcγRIII to an ITIM–containing inhibitory receptor.
Background Cutaneous exposure to food allergens predisposes to food allergy, which is commonly associated with atopic dermatitis (AD). Levels of the epithelial cytokine IL-33 are increased in skin ...lesions and serum of patients with AD. Mast cells (MCs) play a critical role in food-induced anaphylaxis and express the IL-33 receptor ST2. The role of IL-33 in patients with MC-dependent food anaphylaxis is unknown. Objective We sought to determine the role and mechanism of action of IL-33 in patients with food-induced anaphylaxis in a model of IgE-dependent food anaphylaxis elicited by oral challenge of epicutaneously sensitized mice. Methods Wild-type, ST2-deficient, and MC-deficient Kit W-sh/W-sh mice were epicutaneously sensitized with ovalbumin (OVA) and then challenged orally with OVA. Body temperature was measured by means of telemetry, Il33 mRNA by means of quantitative PCR, and IL-33, OVA-specific IgE, and mouse mast cell protease 1 by means of ELISA. Bone marrow–derived mast cell (BMMC) degranulation was assessed by using flow cytometry. Results Il33 mRNA expression was upregulated in tape-stripped mouse skin and scratched human skin. Tape stripping caused local and systemic IL-33 release in mice. ST2 deficiency, as well as ST2 blockade before oral challenge, significantly reduced the severity of oral anaphylaxis without affecting the systemic TH 2 response to the allergen. Oral anaphylaxis was abrogated in Kit W-sh/W-sh mice and restored by means of reconstitution with wild-type but not ST2-deficient BMMCs. IL-33 significantly enhanced IgE-mediated degranulation of BMMCs in vitro. Conclusion IL-33 is released after mechanical skin injury, enhances IgE-mediated MC degranulation, and promotes oral anaphylaxis after epicutaneous sensitization by targeting MCs. IL-33 neutralization might be useful in treating food-induced anaphylaxis in patients with AD.
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.
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•Multi-functional MMC9s produce prodigious amounts of IL-9 and mast cell mediators•MMC9 development increases in mice susceptible to IgE-mediated food allergy•Induction of MMC9s requires T cells and IL-4, not IL-9, signals•MMC9s amplify intestinal mastocytosis that drives IgE-mediated food allergy
Current knowledge cannot explain why only some patients and murine strains that acquire high amounts of dietary allergen-specific IgE develop life-threatening anaphylaxis. Wang and colleagues identify and characterize the IL-9-producing mucosal mast cells that amplify anaphylactic response to dietary proteins by producing large amounts of IL-9 and mast cell mediators.
Mast cell (MC) mediator release after crosslinking of surface-bound IgE antibody by ingested antigen underlies food allergy. However, IgE antibodies are not uniformly associated with food allergy, ...and intestinal MC load is an important determinant. Atopic dermatitis (AD), characterized by pruritis and cutaneous sensitization to allergens, including foods, is strongly associated with food allergy. Tape stripping mouse skin, a surrogate for scratching, caused expansion and activation of small intestinal MCs, increased intestinal permeability, and promoted food anaphylaxis in sensitized mice. Tape stripping caused keratinocytes to systemically release interleukin-33 (IL-33), which synergized with intestinal tuft-cell-derived IL-25 to drive the expansion and activation of intestinal type-2 innate lymphoid cells (ILC2s). These provided IL-4, which targeted MCs to expand in the intestine. Duodenal MCs were expanded in AD. In addition to promoting cutaneous sensitization to foods, scratching may promote food anaphylaxis in AD by expanding and activating intestinal MCs.
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•Mechanical skin injury promotes intestinal mast-cell expansion•Intestinal mast-cell expansion requires skin-derived IL-33 and gut-derived IL-25•Intestinal mast-cell expansion requires ILC2 activation by IL-33 and IL-25•ILC2-derived IL-4 and IL-13 directly cause intestinal mast-cell expansion
Atopic dermatitis is a pruritic inflammatory skin disease highly associated with food allergy. Leyva-Castillo and colleagues demonstrate that a skin-to-gut crosstalk initiated by mechanical skin injury promotes food anaphylaxis by increasing mast cells in the gut.
Unraveling the exact signaling events mediating the distinct functions of the T cell-derived cytokines interleukin-4 (IL-4) and IL-13 has been challenging because they are structurally similar and ...share a functional signaling receptor chain. A study now proposes a potential molecular mechanism to explain the functional differences between IL-4 and IL-13 that involves the ability of IL-4, but not IL-13, to effectively activate the insulin receptor substrate-2 (IRS-2) signaling cascade through binding to its receptor. A better understanding of the interactions of IL-4 and IL-13 with their cognate receptors may facilitate the development of therapies without unintended side effects.
BRD4 is a BET family protein that binds acetylated histones and regulates transcription. BET/BRD4 inhibitors block blood cancer growth and inflammation and serve as a new therapeutic strategy. ...However, the biological role of BRD4 in normal hematopoiesis and inflammation is not fully understood. Analysis of Brd4 conditional knockout (KO) mice showed that BRD4 is required for hematopoietic stem cell expansion and progenitor development. Nevertheless, BRD4 played limited roles in macrophage development and inflammatory response to LPS. ChIP‐seq analysis showed that despite its limited importance, BRD4 broadly occupied the macrophage genome and participated in super‐enhancer (SE) formation. Although BRD4 is critical for SE formation in cancer, BRD4 was not required for macrophage SEs, as KO macrophages created alternate, BRD4‐less SEs that compensated BRD4 loss. This and additional mechanisms led to the retention of inflammatory responses in macrophages. Our results illustrate a context‐dependent role of BRD4 and plasticity of epigenetic regulation.
Synopsis
New conditional mouse knockout models of the BET family protein BRD4, involved in transcriptional control in hematopoietic cancers, reveal its differential requirement in normal hematopoiesis and inflammation.
BRD4 is required for development and proliferation of mouse hematopoietic stem cells.
BRD4 is dispensable for macrophage differentiation and inflammatory response.
BRD4 broadly occupies genic and intergenic regions of transcribed genes in both unstimulated and LPS‐stimulated macrophages.
Brd4 deletion is associated with increased NF‐κB occupancy and increase of other BET proteins.
New mouse models and genomic analyses reveal context‐dependent roles for BRD4 during normal hematopoiesis and inflammation.
Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis, a neurotransmitter and a regulator of gastric acid secretion. Histamine is a monoamine synthesized from the amino acid ...histidine through a reaction catalyzed by the enzyme histidine decarboxylase (HDC), which removes carboxyl group from histidine. Despite the importance of histamine, transcriptional regulation of
gene expression in mammals is still poorly understood. In this review, we focus on discussing advances in the understanding of molecular regulation of mammalian histamine synthesis.
Food-mediated allergic reactions have emerged as a major health problem. The underlying mechanisms that promote uncontrolled type 2 immune responses to dietary allergens in the gastrointestinal tract ...remain elusive.
We investigated whether altering IL-25 signaling enhances or attenuates allergic responses to food allergens.
Mice of an IL-25 transgenic mouse line (iIL-25Tg mice), which constitutively overexpress intestinal IL-25, and Il17rb−/− mice, in which Il17rb gene expression is disrupted, were sensitized and gavage fed with ovalbumin (OVA). We assessed symptomatic characteristics of experimental food allergy, including incidence of diarrhea, incidence of hypothermia, intestinal TH2 immune response, and serum OVA-specific IgE and mast cell protease 1 production.
Rapid induction of Il25 expression in the intestinal epithelium preceded onset of the anaphylactic response to ingested OVA antigen. iIL-25Tg mice were more prone and Il17rb−/− mice were more resistant to experimental food allergy. Resident intestinal type 2 innate lymphoid cells (ILC2s) were identified as the major producers of IL-5 and IL-13 in response to IL-25. Reconstituting irradiated wild-type mice with Rora−/− or Il17rb−/− bone marrow resulted in a deficiency or dysfunction of the ILC2 compartment, respectively, and resistance to experimental food allergy. Repeated intragastric antigen challenge induced a significant increase in numbers of CD4+ TH2 cells, which enhance IL-25–stimulated IL-13 production by ILC2s ex vivo and in vivo. Finally, reconstituted IL-13–deficient ILC2s had reduced capability to promote allergic inflammation, resulting in increased resistance to experimental food allergy.
IL-25 and CD4+ TH2 cells induced by ingested antigens enhance ILC2-derived IL-13 production, thereby promoting IgE-mediated experimental food allergy.
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