Mast cells in airway diseases and interstitial lung disease

Cruse, Glenn; Bradding, Peter

doi:10.1016/j.ejphar.2015.04.046

Cited by 58 publications

(40 citation statements)

References 250 publications

(242 reference statements)

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“…In addition to being exclusively located in mast cells and basophils, FceRIβ is critically required for trafficking of FceRI to the cell surface in mast cells (9). Although FceRIβ has been considered as a mast cell-specific target in recent years (9,10,12,38), the problem was how to effectively target FceRIβ. Delivery of siRNA or shRNA to silence FceRIβ is not totally effective in mast cells even with use of lentiviral delivery techniques and results in 50-80% reduction of protein expression (9, 39).…”

Section: Discussionmentioning

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: Discussionmentioning

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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“…It is defined by its high specifity and in contrast to the innate immunity, needs days to weeks to reach its full capacity, but it builds up a memory which in turn allows for a more rapid and effective response upon reinfection (130). inflammatory and fibrotic lung diseases, of which asthma is probably the best studied, however, there is also evidence for a mast cell involvement in idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease or in pulmonary hypertension, as established by our own group and others (23,66 Currently it is thought that any B-cell can differentiate into a Breg cell, at any developmental stage (i.e. immature B cells, mature B cells, and plasma cells).…”

Section: Current Therapiesmentioning

confidence: 99%

The mast cell–B cell axis in lung vascular remodeling and pulmonary hypertension

Breitling

Zhou

Zabini

et al. 2017

American Journal of Physiology-Lung Cellular and Molecular Phys

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Over past years, a critical role for the immune system and, in particular, for mast cells in the pathogenesis of pulmonary hypertension (PH) has emerged. However, the way in which mast cells promote PH is still poorly understood. Here, we investigated the mechanisms by which mast cells may contribute to PH, specifically focusing on the interaction between the innate and adaptive immune response and the role of B cells and autoimmunity. Experiments were performed in Sprague-Dawley rats and B cell-deficient JH-KO rats in the monocrotaline, Sugen/hypoxia, and the aortic banding model of PH. Hemodynamics, cell infiltration, IL-6 expression, and vascular remodeling were analyzed. Gene array analyses revealed constituents of immunoglobulins as most prominently regulated mast cell-dependent genes in the lung in experimental PH. IL-6 was shown to link mast cells to B cells, as 1) IL-6 was upregulated and colocalized with mast cells and was reduced by mast-cell stabilizers and 2) IL-6 or mast cell blockade reduced B cells in lungs of monocrotaline-treated rats. A functional role for B cells in PH was demonstrated in that either blocking B cells by an anti-CD20 antibody or B-cell deficiency in JH-KO rats attenuated right ventricular systolic pressure and vascular remodeling in experimental PH. We here identify a mast cell–B cell axis driven by IL-6 as a critical immune pathway in the pathophysiology of PH. Our results provide novel insights into the role of the immune system in PH, which may be therapeutically exploited by targeted immunotherapy.

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“…They are mostly described for their role in anaphylaxis and allergic response by hypersensitivity reactions via IgE binding [12]. Accumulation of MCs mediators in airway smooth muscle are correlated with asthma activity [13]. Moreover, evidence from their overabundant representation/activity in intestine is amply described in inflammatory bowel disease (Crohn's disease or ulcerative colitis) and irritable bowel [14].…”

Section: Mastocytosis and Mast Cellsmentioning

confidence: 99%

Association between rheumatoid arthritis and systemic mastocytosis: a case report and literature review

et al. 2016

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Mast cells in airway diseases and interstitial lung disease

Cited by 58 publications

References 250 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

The mast cell–B cell axis in lung vascular remodeling and pulmonary hypertension

Association between rheumatoid arthritis and systemic mastocytosis: a case report and literature review

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