Although there is much circumstantial evidence implicating eosinophils as major orchestrators in the pathophysiology of asthma, recent studies have cast doubt on their importance.
Not only does anti-interleukin-5 treatment not alter the course of the disease, but some patients with asthma do not have eosinophils in their airways, whereas patients with eosinophilic bronchitis exhibit a florid tissue eosinophilia but do not have asthma.
In contrast, mast cells are found in all airways and localize specifically to key tissue structures such as the submucosal glands and airway smooth muscle within asthmatic bronchi, irrespective of disease severity or phenotype. Here they are activated and interact exclusively with these structural cells via adhesive pathways and through the release of soluble mediators acting across the distance of only a few microns.
The location of mast cells within the airway smooth muscle bundles seems particularly important for the development and propagation of asthma, perhaps occurring in response to, and then serving to aggravate, an underlying abnormality in asthmatic airway smooth muscle function.
Targeting this mast cell-airway smooth muscle interaction in asthma offers exciting prospects for the treatment of this common disease.
Sebastian Reuter, Michael Stassen, and Christian Taube
Yonsei Med J. 2010 Nov 1; 51(6): 797â807.
doi: 10.3349/ymj.2010.51.6.797
PMCID: PMC2995967
PMID: 20879044
Mast cells have been regarded for a long time as effector cells in IgE mediated type I reactions and in host defence against parasites.
However, they are resident in all environmental exposed tissues and express a wide variety of receptors, suggesting that these cells can also function as sentinels in innate immune responses.
Indeed, studies have demonstrated an important role of mast cells during the induction of life-saving antibacterial responses.
Furthermore, recent findings have shown that mast cells promote and modulate the development of adaptive immune responses, making them an important hinge of innate and acquired immunity.
In addition, mast cells and several mast cell-produced mediators have been shown to be important during the development of allergic airway diseases.
In the present review, we will summarize findings on the role of mast cells during the development of adaptive immune responses and highlight their function, especially during the development of allergic asthma.
The emerging role of mast cell proteases in asthma
Gunnar Pejler
European Respiratory Journal 2019
Vol54: 1900685;
DOI: 10.1183/13993003.00685-2019
(Paywall)
It is now well established that mast cells (MCs) play a crucial role in asthma. This is supported by multiple lines of evidence, including both clinical studies and studies on MC-deficient mice. However, there is still only limited knowledge of the exact effector mechanism(s) by which MCs influence asthma pathology.
MCs contain large amounts of secretory granules, which are filled with a variety of bioactive compounds including histamine, cytokines, lysosomal hydrolases, serglycin proteoglycans and a number of MC-restricted proteases.
When MCs are activated, e.g. in response to IgE receptor cross-linking, the contents of their granules are released to the exterior and can cause a massive inflammatory reaction.
The MC-restricted proteases include tryptases, chymases and carboxypeptidase A3, and these are expressed and stored at remarkably high levels.
There is now emerging evidence supporting a prominent role of these enzymes in the pathology of asthma. Interestingly, however, the role of the MC-restricted proteases is multifaceted, encompassing both protective and detrimental activities.
Here, the current knowledge of how the MC-restricted proteases impact on asthma is reviewed.
Mast Cells and Their Progenitors in Allergic Asthma
Erika MĂŠndez-EnrĂquez and Jenny Hallgren*
Mast cells and their mediators have been implicated in the pathogenesis of asthma and allergy for decades. Allergic asthma is a complex chronic lung disease in which several different immune cells, genetic factors and environmental exposures influence the pathology.
Mast cells are key players in the asthmatic response through secretion of a multitude of mediators with pro-inflammatory and airway-constrictive effects.
Well-known mast cell mediators, such as histamine and bioactive lipids are responsible for many of the physiological effects observed in the acute phase of allergic reactions.
The accumulation of mast cells at particular sites of the allergic lung is likely relevant to the asthma phenotype, severity and progression.
Mast cells located in different compartments in the lung and airways have different characteristics and express different mediators.
According to in vivo experiments in mice, lung mast cells develop from mast cell progenitors induced by inflammatory stimuli to migrate to the airways.
Human mast cell progenitors have been identified in the blood circulation. A high frequency of circulating human mast cell progenitors may reflect ongoing pathological changes in the allergic lung.
In allergic asthma, mast cells become activated mainly via IgE-mediated crosslinking of the high affinity receptor for IgE (FcÎľRI) with allergens.
However, mast cells can also be activated by numerous other stimuli e.g. toll-like receptors and MAS-related G protein-coupled receptor X2.
In this review, we summarize research with implications on the role and development of mast cells and their progenitors in allergic asthma and cover selected activation pathways and mast cell mediators that have been implicated in the pathogenesis.
The review places an emphasis on describing mechanisms identified using in vivo mouse models and data obtained by analysis of clinical samples.
This information page is for the use of the mast cell disorders community for disseminating research, education and information only.
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Blueprint Medicines Corporation
(NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, today announced positive top-line results from the Phase 1 EXPLORER and Phase 2 PATHFINDER clinical trials of AYVAKIT⢠(avapritinib) in patients with advanced systemic mastocytosis (SM).
Consistent with previously reported EXPLORER trial results, the registrational data for AYVAKIT showed profound reductions in mast cell burden, high overall response and complete remission rates, and durable clinical benefit, including prolonged median overall survival (OS).
AYVAKIT was generally well-tolerated, with an improved safety profile at the 200 mg once daily (QD) dose.
Based on these data, Blueprint Medicines plans to submit a supplemental new drug application (sNDA) to the U.S. Food and Drug Administration (FDA) for AYVAKIT for the treatment of advanced SM in the fourth quarter of 2020.
What Have Mast Cells To Do with Edema Formation, the Consecutive Repair and Fibrinolysis?
Valent P. ¡ Sillaber C. ¡ Baghestanian M. ¡ Bankl H.C. ¡ Kiener H.P. ¡ Lechner K. ¡ Binder B.R.
Int Arch Allergy Immunol 1998;115:2â8
(DOI:10.1159/000023823)
Mast cells (MC) have been implicated in the activation of vascular endothelial cells, capillary leak formation, transmigration of white blood cells, and translocation of fibrinogen (and other plasma molecules) into the tissues, with consecutive edema formation.
However, the mechanisms of repair that lead to tissue reconstitution after MC activation and edema formation have not been defined so far. In the present article, the possible contribution of MC to repair, in particular fibrinolysis, is discussed. Thus, accumulating evidence exists that human MC express and release the tissue-type plasminogen activator (tPA) in a constitutive manner.
MC also express the urokinase receptor (uPAR) and heparin. Most importantly, however, MC lack plasminogen activator inhibitors (PAI-1, PAI-2, PAI-3). In line with this âpro-fibrinolyticâ profile of antigens, MC supernatants induce plasminogen-to-plasmin conversion and fibrin clot lysis in vitro.
The c-kit ligand SCF upregulates uPAR expression, and the release of tPA from MC. These observations point to an important role of MC in endogenous fibrinolysis, a hitherto unrecognized (repair) function of this cell.
Mast cells (MCs) promote a wide range of localized and systemic inflammatory responses. Their involvement in immediate as well as chronic inflammatory reactions at both local and distal sites points to an extraordinarily powerful immunoregulatory capacity with spatial and temporal versatility.
MCs are preferentially found in close proximity to both vascular and lymphatic vessels.
On activation, they undergo a biphasic secretory response involving the rapid release of prestored vasoactive mediators followed by de novo synthesized products.
Many actions of MCs are related to their capacity to regulate vascular flow and permeability and to the recruitment of various inflammatory cells from the vasculature into inflammatory sites.
These mediators often work in an additive fashion and achieve their inflammatory effects locally by directly acting on the vascular and lymphatic endothelia, but they also can affect distal sites.
Along these lines, the lymphatic and endothelial vasculatures of the host act as a conduit for the dissemination of MC signals during inflammation.
The central role of the MC-endothelial cell axis to immune homeostasis is emphasized by the fact that some of the most effective current treatments for inflammatory disorders are directed at interfering with this interaction.
The close proximity of MCs to the hostâs vascular and lymphatic endothelia enables their products to act directly on ECs and also to enter the vasculature and spread to distal sites, promoting local and long-distance effects. Activation of vascular ECs is required for the timely recruitment of circulating leukocytes to a site of inflammation and for the regulation of vascular permeability and blood flow to the site. MCs produce many mediators that functionally overlap in
The Role of Mast Cells Mediators in Angioedema Without Wheals
Anna Sala-Cunill M.D, PhD & M. Guilarte M.D, Ph.D
Current Treatment Options in Allergy volume 2, pages294â306(2015)
Angioedema is defined as localized and transient edema of the deep skin layers or the upper respiratory or gastrointestinal mucosa.
Although the most common sites of involvement are the tongue, lips, face, and throat, angioedema may also occur in the extremities, genitalia, and viscera, and it can be life-threatening when affecting the upper airway.
Angioedema is due to a temporary increase of the vascular permeability caused by vasoactive mediators. However, the mechanisms and the mediators involved in angioedema without wheals vary depending on the type of angioedema. The purpose of this review is to give new insights on angioedema without wheals.
To facilitate the understanding of the different types of angioedema, a modified classification of angioedema without wheals from the Hereditary Angioedema International Working Group consensus is proposed. It also summarizes the pathophysiology of the main types of AE and describes the current knowledge regarding the role of the mast cell mediators involved.
Finally, given that the treatment of angioedema has changed greatly in the last years, this review also describes the specific treatment options of angioedema without wheals. Gaining knowledge into these pathophysiologic mechanisms of angioedema and into the gaps in the diagnosis will allow to improve the management of these patients, avoiding fatal outcomes.
In 2013, the Hereditary Angioedema International Working (HAWK) group proposed a new classification of angioedema distinguishing hereditary from nonhereditary forms [2â˘â˘]. The term BK-mediated was avoided because of the lack of evidence of the implication of BK (BK) in most types of angioedema. Moreover, other vasoactive substances such as substance P, cystenil, Cla
ssically, angioedema without wheals had been classified as bradykinin (BK) or histamine-mediated. Nevertheless, the implication of these vasoactive substances has only been demonstrated in a few patients. An increase of plasma BK has been observed locally during angioedema attacks in hereditary angioedema with C1 inhibitor deficiency (HAE-C1INH), acquired angioedema with C1 inhibitor deficiency (AAE-C1INH) and in angioedema due to angiotensin converting enzyme inhibitors (ACEi) [5, 6]. The
term histamine-mediated angioedema was established on the basis of the therapeutic response to antihistamines. In 2013, the Hereditary Angioedema International Working (HAWK) group proposed a new classification of angioedema distinguishing hereditary from nonhereditary forms [2â˘â˘]. The term BK-mediated was avoided because of the lack of evidence of the implication of BK (BK) in most types of angioedema. Moreover, other vasoactive substances such as substance P, cystenil leukotrienes, or prostaglandins are also implicated in the generation of angioedema. On the other hand, mast cell heparin can activate contact system and the release of BK [7â˘â˘, 8].
Recently, a new classification based on endotypes has been proposed [9]. In this classification, the different types of angioedema are divided into three groups: those due to an excess of BK, those due to mast cell and basophil degranulation, and a third group (idiopathic). This classification includes other types of angioedema such as NSAID induced or exacerbated angioedema, allergic angioedema, or drug-induced angioedema. However, BK involvement in hereditary angioedema with normal C1 inhibitor (HAE-nC1INH) has not been demonstrated, although it is assumed because of the clinical similarity to angioedema due to C1INH deficiency and the response to drugs targeting BK.
