IgE alone promotes human lung mast cell survival through the autocrine production of IL-6

Cruse, Glenn; Cockerill, Sarah; Bradding, Peter

doi:10.1186/1471-2172-9-2

Cited by 44 publications

(38 citation statements)

References 39 publications

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“…In addition to the classical view that IgE binding to FceRI on mast cells primes mast cells for activation by bivalent/multivalent antigens, it is now recognized that IgE binding to FceRI leads to activation of mast cells to release prosurvival cytokines that maintain viability of the cells (29)(30)(31). In the absence of external supporting cytokines, mast cells rapidly undergo apoptosis, which is suppressed by the addition of IgE.…”

Section: Resultsmentioning

confidence: 99%

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

Cruse

Yin

Fukuyama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Allergic diseases are driven by activation of mast cells and release of mediators in response to IgE-directed antigens. However, there are no drugs currently available that can specifically down-regulate mast cell function in vivo when chronically administered. Here, we describe an innovative approach for targeting mast cells in vitro and in vivo using antisense oligonucleotide-mediated exon skipping of the β-subunit of the high-affinity IgE receptor (FceRIβ) to eliminate surface high-affinity IgE receptor (FceRI) expression and function, rendering mast cells unresponsive to IgE-mediated activation. As FceRIβ expression is restricted to mast cells and basophils, this approach would selectively target these cell types. Given the success of exon skipping in clinical trials to treat genetic diseases such as Duchenne muscular dystrophy, we propose that exon skipping of FceRIβ is a potential approach for mast cell-specific treatment of allergic diseases.A sthma and related allergic diseases affect up to 1 in 10 people in developed countries, and about 10% of patients with asthma cannot be controlled with current therapeutic approaches. The most widely used therapies for asthma rely upon dampening the inflammatory response with either oral or inhaled glucocorticosteroids and relaxing the constricted airway smooth muscle cells with β-adrenoreceptor agonists. However, high doses of steroids when needed for severe asthma are associated with undesirable side effects and inhaled β-adrenoreceptor agonists can increase the risk of death from asthma if not used in combination with glucocorticosteroids. It is suggested that β-adrenoreceptor agonists may promote underlying inflammation that could contribute to the airway wall remodeling seen in asthma (1). Other clinical approaches that aim for more long-term alleviation of symptoms, including desensitization with incremental increases in dose of allergen or hyposensitization to induce immune tolerance, have proven beneficial for some, but not all, patients, and serious adverse effects can occur (2).In addition to asthma, other allergic diseases have similar treatment strategies and also have an unmet clinical need. An example is atopic dermatitis (AD), which like asthma, is also a multifactorial disease with complex pathophysiology, remains incurable, and affects 10-20% of children in the United States (3). The two major symptoms of AD are inflammatory lesions and severe pruritus. Both the prevalence and the economic burden of AD are increasing worldwide. Symptomatic treatment with topical and/or systemic glucocorticosteroids or calcineurin inhibitors are still considered the gold standard. However, due to the known adverse effects of these drugs, prescription rates are low and patient compliance is often poor (3). Thus, there is still a need for new therapeutic approaches with a better safety profile.An approach for intervention in allergic inflammation that we have pursued is based on the finding that the gene loci 11q12-q13 are strongly linked to allergy and asthma suscepti...

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Section: Resultsmentioning

confidence: 99%

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

Cruse

Yin

Fukuyama

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…Previous studies showed that IL-8 inhibited IL-4-induced IgE production and endogenous TNF-α and IL-6 are essential for IgE production in atopic patients [25,26]. In addition, IgE promotes the autocrine production of IL-6 in human lung mast cells [27]. Recently, a study showed that IgE-secreting cells differentiation and IgE production could be directly promoted by IL-17 [28].…”

Section: Discussionmentioning

confidence: 99%

High Serum IgE Concentration in Patients with Psoriasis

Zheng¹

2017

CRDOA

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“…Mast cell survival and histamine content is increased in cultured mouse mast cells after monoclonal IgEs incubation [4,5,7]. Monomeric IgE binding to FcRI directly activates human lung mast cells leading to the release of inflammatory mediators and chemokines and the enhancement of mast cell survival [6,9]. We previously demonstrated that mast cells from sensitized animals increase the expression of syntaxin 4 and SNAP-23, two exocytotic proteins involved in the degranulation process [12].…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that the signaling from IgE alone in the absence of allergen is a result of FcRI aggregation, in the same way as FcRI cross-linking with allergen [6,8]. Synergistic signals are mediated by activation of FcRI and toll-like receptors to augment production of inflammatory cytokines [27].…”

Section: Discussionmentioning

confidence: 99%

“…Several recent studies indicate that at high concentrations some monoclonal IgEs bound to FcRI have effects on mast cells [2], like up-regulation of FcRI expression [3], prolonged survival [4][5][6], increase in histamine synthesis [7], histamine release [8,9], cytokine secretion [9,4] and migration [10] and enhanced response to compound 48/80 and substance P [11]. Moreover, OVAsensitization assays demonstrate that mast cells from sensitized rats enhance the expression of the exocytotic proteins syntaxin 4 and synaptosomal-associated protein of 23 kDa (SNAP-23) [12].…”

Section: Introductionmentioning

confidence: 99%

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Allergen-sensitization in vivo enhances mast cell-induced inflammatory responses and supports innate immunity

et al. 2009

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IgE alone promotes human lung mast cell survival through the autocrine production of IL-6

Abstract: Background: Mast cells play a key role in asthma and recent evidence indicates that their ongoing activation in this disease is mediated, in part, via IgE in the absence of antigen. In this study we have examined whether IgE alone enhances human lung mast cell (HLMC) survival.

Cited by 44 publications

References 39 publications

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

Exon skipping of FcεRIβ eliminates expression of the high-affinity IgE receptor in mast cells with therapeutic potential for allergy

High Serum IgE Concentration in Patients with Psoriasis

Allergen-sensitization in vivo enhances mast cell-induced inflammatory responses and supports innate immunity

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