Background Studies with c- kit mutant mast cell (MC)–deficient mice and antibody-mediated depletion of basophils suggest that both MCs and basophils can contribute to peanut-induced anaphylaxis ...(PIA). However, interpretation of data obtained by using such approaches is complicated because c- kit mutant mice have several phenotypic abnormalities in addition to MC deficiency and because basophil-depleting antibodies can also react with MCs. Objective We analyzed (1) the changes in the features of PIA in mice after the selective and inducible ablation of MCs or basophils and (2) the possible importance of effector cells other than MCs and basophils in the PIA response. Methods Wild-type and various mutant mice were orally sensitized with peanut extract and cholera toxin weekly for 4 weeks and challenged intraperitoneally with peanut extract 2 weeks later. Results Peanut-challenged, MC-deficient Kit W-sh/W-sh mice had reduced immediate hypothermia, as well as a late-phase decrease in body temperature that was abrogated by antibody-mediated depletion of neutrophils. Diphtheria toxin–mediated selective depletion of MCs or basophils in Mcpt5-Cre ; iDTR and Mcpt8 DTR mice, respectively, and treatment of wild-type mice with the basophil-depleting antibody Ba103 significantly reduced peanut-induced hypothermia. Non–c- kit mutant MC- and basophil-deficient Cpa3-Cre;Mcl-1 fl/fl mice had reduced but still significant responses to peanut. Conclusion Inducible and selective ablation of MCs or basophils in non–c- kit mutant mice can significantly reduce PIA, but partial responses to peanut can still be observed in the virtual absence of both cell types. The neutrophilia in Kit W-sh/W-sh mice might influence the responses of these mice in this PIA model.
Overview
Systemic mastocytosis (SM) results from a clonal proliferation of abnormal mast cells (MC) in extra‐cutaneous organs.
Diagnosis
The major criterion is presence of multifocal clusters of ...spindled MC in the bone marrow. Minor diagnostic criteria include elevated serum tryptase level, abnormal MC CD25 expression, and presence of KITD816V mutation.
Risk Stratification
Establishing SM subtype as per the World Health Organization classification system is an important first step. Broadly, patients either have indolent/smoldering SM (ISM/SSM) or advanced SM, the latter includes aggressive SM (ASM), SM with associated hematological neoplasm (SM‐AHN), and mast cell leukemia (MCL). Identification of poor‐risk mutations (ie, ASXL1, RUNX1, SRSF2, NRAS) further refines the risk stratification. Recently, clinical and hybrid clinical‐molecular risk models have been developed to more accurately assign prognosis in SM patients.
Management
Treatment goals for ISM patients are primarily directed towards anaphylaxis prevention/symptom control/osteoporosis treatment. Patients with advanced SM frequently need MC cytoreductive therapy to ameliorate disease‐related organ dysfunction. High response rates have been seen with small‐molecule inhibitors that target mutant‐KIT, including midostaurin (Food and Drug Administration approved) or avapritinib (investigational). Other options for MC cytoreduction include cladribine or interferon‐α, although head‐to‐head comparisons are lacking. Treatment of SM‐AHN primarily targets the AHN component, particularly if an aggressive disease such as acute myeloid leukemia is present. Allogeneic stem cell transplant can be considered in such patients, or in those with relapsed/refractory advanced SM. Imatinib has a limited therapeutic role in SM; effective cytoreduction is limited to those with imatinib‐sensitive KIT mutations.
In patients given a diagnosis of chronic spontaneous urticaria (CSU), there are no obvious external triggers, and the factors that initiate the clinical symptoms of wheal, flare, and itch arise from ...within the patient. Most patients with CSU have an autoimmune cause: some patients produce IgE autoantibodies against autoantigens, such as thyroperoxidase or double-stranded DNA, whereas other patients make IgG autoantibodies against FcεRI, IgE, or both, which might chronically activate mast cells and basophils. In the remainder of patients with CSU, the nature of the abnormalities has not yet been identified. Accumulating evidence has shown that IgE, by binding to FcεRI on mast cells without FcεRI cross-linking, can promote the proliferation and survival of mast cells and thus maintain and expand the pool of mast cells. IgE and FcεRI engagement can also decrease the release threshold of mast cells and increase their sensitivity to various stimuli through either FcεRI or other receptors for the degranulation process. Furthermore, IgE-FcεRI engagement potentiates the ability of mast cells to store and synthesize de novo inflammatory mediators and cytokines. Administration of omalizumab, by virtue of its ability to deplete IgE, attenuates the multiple effects of IgE to maintain and enhance mast cell activities and hence reduces the ability of mast cells to manifest inflammatory mechanisms in patients with CSU.
Mast cells are tissue-resident immune cells that play a key role in inflammation and allergy. Here we show that interaction of mast cells with antibody-targeted cells induces the polarized exocytosis ...of their granules resulting in a sustained exposure of effector enzymes, such as tryptase and chymase, at the cell-cell contact site. This previously unidentified mast cell effector mechanism, which we name the antibody-dependent degranulatory synapse (ADDS), is triggered by both IgE- and IgG-targeted cells. ADDSs take place within an area of cortical actin cytoskeleton clearance in the absence of microtubule organizing centre and Golgi apparatus repositioning towards the stimulating cell. Remarkably, IgG-mediated degranulatory synapses also occur upon contact with opsonized Toxoplasma gondii tachyzoites resulting in tryptase-dependent parasite death. Our results broaden current views of mast cell degranulation by revealing that human mast cells form degranulatory synapses with antibody-targeted cells and pathogens for dedicated secretion and defence.
Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those ...derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1
Tac1
nociceptor-MRGPRB2
mast cell sensory clusters represents a key early event in the development of allergic skin reactions.
Mast Cell Function da Silva, Elaine Zayas Marcelino; Jamur, Maria Célia; Oliver, Constance
Journal of Histochemistry & Cytochemistry,
10/2014, Letnik:
62, Številka:
10
Book Review, Journal Article
Recenzirano
Odprti dostop
Since first described by Paul Ehrlich in 1878, mast cells have been mostly viewed as effectors of allergy. It has been only in the past two decades that mast cells have gained recognition for their ...involvement in other physiological and pathological processes. Mast cells have a widespread distribution and are found predominantly at the interface between the host and the external environment. Mast cell maturation, phenotype and function are a direct consequence of the local microenvironment and have a marked influence on their ability to specifically recognize and respond to various stimuli through the release of an array of biologically active mediators. These features enable mast cells to act as both first responders in harmful situations as well as to respond to changes in their environment by communicating with a variety of other cells implicated in physiological and immunological responses. Therefore, the critical role of mast cells in both innate and adaptive immunity, including immune tolerance, has gained increased prominence. Conversely, mast cell dysfunction has pointed to these cells as the main offenders in several chronic allergic/inflammatory disorders, cancer and autoimmune diseases. This review summarizes the current knowledge of mast cell function in both normal and pathological conditions with regards to their regulation, phenotype and role.
Non-IgE mediated mast cell activation Yu, Yingxin; Blokhuis, Bart R.; Garssen, Johan ...
European journal of pharmacology,
05/2016, Letnik:
778
Journal Article
Recenzirano
Odprti dostop
Mast cells are crucial effector cells in allergic reactions, where IgE is the best known mechanism to trigger their degranulation and release of a vast array of allergic mediators. However, IgE is ...not the only component to stimulate these cells to degranulate, while mast cell activation can also result in differential release of mediators. There is a plethora of stimuli, such as IgG, complement components, TLR ligands, neuropeptides, cytokines, chemokines and other inflammatory products, that can directly trigger mast cell degranulation, cause selective release of mediators, and stimulate proliferation, differentiation and/or migration. Moreover, some of these stimuli have a synergic effect on the IgE-mediated mast cell activation. Because of the ability to respond to a large repertoire of stimuli, mast cells may act as a versatile cell in various physiological and pathological conditions. In this review, we discuss current knowledge on non-IgE stimuli for (human) mast cells.
Mast cells can promote inflammation and other tissue changes in IgE-associated allergic disorders, as well as in certain innate and adaptive immune responses that are thought to be independent of ...IgE. However, mast cells can also have anti-inflammatory and immunosuppressive functions. Here, we review the evidence that mast cells can have negative, as well as positive, immunomodulatory roles in vivo, and we propose that mast cells can both enhance and later suppress certain features of an immune response.
Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances. Although they are ...classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.
Mast cell stabilisers Zhang, Tao; Finn, Deirdre Frances; Barlow, James William ...
European journal of pharmacology,
05/2016, Letnik:
778
Journal Article
Recenzirano
Mast cells play a critical role in type 1 hypersensitivity reactions. Indeed, mast cell mediators are implicated in many different conditions including allergic rhinitis, conjunctivitis, asthma, ...psoriasis, mastocytosis and the progression of many different cancers. Thus, there is intense interest in the development of agents which prevent mast cell mediator release or which inhibit the actions of such mediators once released into the environment of the cell. Much progress into the design of new agents has been made since the initial discovery of the mast cell stabilising properties of khellin from Ammi visnaga and the clinical approval of cromolyn sodium. This review critically examines the progress that has been made in the intervening years from the design of new agents that target a specific signalling event in the mast cell degranulation pathway to those agents which have been developed where the precise mechanism of action remains elusive. Particular emphasis is also placed on clinically used drugs for other indications that stabilise mast cells and how this additional action may be harnessed for their clinical use in disease processes where mast cells are implicated.
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