scholarly journals A Challenge for Allergologist: Application of Allergy Diagnostic Methods in Mast Cell Disorders

2021 ◽  
Vol 22 (3) ◽  
pp. 1454
Author(s):  
Jan Romantowski ◽  
Aleksandra Górska ◽  
Marek Niedoszytko ◽  
Theo Gulen ◽  
Marta Gruchała-Niedoszytko ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Clinical Symptoms ◽  
Allergic Diseases ◽  
Diagnostic Methods ◽  
Mast Cell Activation ◽  
Recombinant Allergen ◽  
Organ Systems

Primary and secondary mast cell activation syndromes (MCAS) can occur in patients with mastocytosis. During the past few years our knowledge about the pathogenesis and disease-triggering mechanisms in MCAS and mastocytosis have increased substantially. Whereas mastocytosis is characterized by an accumulation of neoplastic (clonal) mast cells (MC) in various organ systems, MCAS is defined by a massive and systemic activation of these cells. Mast cells are crucial effector cells in allergic diseases, thus their elevated number and activation can cause severe anaphylactic reactions and MCAS in patients with mastocytosis. However, these cells may also degranulate spontaneously or degranulate in response to non-allergic triggers leading to clinical symptoms. In mastocytosis patients, such symptoms may lead to the diagnosis of a primary MCAS. The diagnosis of a concomitant allergy in mastocytosis patients is challenging. In these patients, a mixed form (primary and secondary) of MCAS may be diagnosed. These patients may also suffer from life-threatening anaphylactic reactions when exposed to allergens. In these cases, the possibility of severe side effects of in vivo provocations can sometimes also limit diagnostic evaluations. In the current article, we discuss the diagnosis and management of patients suffering from mastocytosis and concomitant MCAS, with special emphasis on novel diagnostic tests and management, including allergen microarrays, recombinant allergen analysis, basophil activation tests, optimal prophylaxis, and specific therapies.

scholarly journals S100A4 Is Critical for a Mouse Model of Allergic Asthma by Impacting Mast Cell Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Tongqian Wu ◽  
Lan Ma ◽  
Xiaoqian Jin ◽  
Jingjing He ◽  
Ke Chen ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Calcium Binding ◽  
Cell Activation ◽  
Allergic Diseases ◽  
Lavage Fluid ◽  
Mast Cell Activation ◽  
Asthma Model

BackgroundThe calcium-binding protein S100A4 demonstrates important regulatory roles in many biological processes including tumorigenesis and inflammatory disorders such as allergy. However, the specific mechanism of the contribution of S100A4 to allergic diseases awaits further clarification.ObjectiveTo address the effect of S100A4 on the regulation of mast cell activation and its impact on allergy.MethodsBone marrow-derived cultured mast cells (BMMCs) were derived from wild-type (WT) or S100A4-/- mice for in vitro investigation. WT and S100A4-/- mice were induced to develop a passive cutaneous anaphylaxis (PCA) model, a passive systemic anaphylaxis (PSA) model, and an ovalbumin (OVA)-mediated mouse asthma model.ResultsFollowing OVA/alum-based sensitization and provocation, S100A4-/- mice demonstrated overall suppressed levels of serum anti-OVA IgE and IgG antibodies and proinflammatory cytokines in serum, bronchoalveolar lavage fluid (BALF), and lung exudates. S100A4-/- mice exhibited less severe asthma signs which included inflammatory cell infiltration in the lung tissue and BALF, and suppressed mast cell recruitment in the lungs. Reduced levels of antigen reencounter-induced splenocyte proliferation in vitro were recorded in splenocytes from OVA-sensitized and challenged mice that lacked S100A4-/-. Furthermore, deficiency in the S100A4 gene could dampen mast cell activation both in vitro and in vivo, evidenced by reduced β-hexosaminidase release and compromised PCA and PSA reaction. We also provided evidence supporting the expression of S100A4 by mast cells.ConclusionS100A4 is required for mast cell functional activation, and S100A4 may participate in the regulation of allergic responses at least partly through regulating the activation of mast cells.

scholarly journals Mast cell activation is not required for induction of airway hyperresponsiveness by ozone in mice

1999 ◽  
Vol 86 (1) ◽  
pp. 202-210 ◽  
Author(s):  
N. Noviski ◽  
J. P. Brewer ◽  
W. A. Skornik ◽  
S. J. Galli ◽  
J. M. Drazen ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Airway Hyperresponsiveness ◽  
Essential Role ◽  
Cell Activation ◽  
Mast Cell Degranulation ◽  
Mast Cell Activation ◽  
Polymorphonuclear Cell ◽  
Pulmonary Parenchyma

Exposure to ambient ozone (O3) is associated with increased exacerbations of asthma. We sought to determine whether mast cell degranulation is induced by in vivo exposure to O3in mice and whether mast cells play an essential role in the development of pulmonary pathophysiological alterations induced by O3. For this we exposed mast cell-deficient WBB6F1- kitW/ kitW-v( kitW/ kitW-v) mice and the congenic normal WBB6F1(+/+) mice to air or to 1 or 3 parts/million O3for 4 h and studied them at different intervals from 4 to 72 h later. We found evidence of O3-induced cutaneous, as well as bronchial, mast cell degranulation. Polymorphonuclear cell influx into the pulmonary parenchyma was observed after exposure to 1 part/milllion O3only in mice that possessed mast cells. Airway hyperresponsiveness to intravenous methacholine measured in vivo under pentobarbital anesthesia was observed in both kitW/ kitW-vand +/+ mice after exposure to O3. Thus, although mast cells are activated in vivo by O3and participate in O3-induced polymorphonuclear cell infiltration into the pulmonary parenchyma, they do not participate detectably in the development of O3-induced airway hyperresponsiveness in mice.

scholarly journals The rat c-kit ligand, stem cell factor, induces c-kit receptor-dependent mouse mast cell activation in vivo. Evidence that signaling through the c-kit receptor can induce expression of cellular function.

1992 ◽  
Vol 175 (1) ◽  
pp. 245-255 ◽  
Author(s):  
B K Wershil ◽  
M Tsai ◽  
E N Geissler ◽  
K M Zsebo ◽  
S J Galli
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Stem Cell Factor ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Tyrosine Kinase Receptor ◽  
Kit Ligand ◽  
Kit Receptor

Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and occurs at doses of SCF at least 10-fold lower on a molar basis than the minimally effective dose of the classical dermal mast cell-activating agent substance P. These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function.

scholarly journals The Role Played by Mitochondria in FcεRI-Dependent Mast Cell Activation

2020 ◽  
Vol 11 ◽  
Author(s):  
Maria A. Chelombitko ◽  
Boris V. Chernyak ◽  
Artem V. Fedorov ◽  
Roman A. Zinovkin ◽  
Ehud Razin ◽  
...  
Keyword(s):  
Mast Cell ◽  
Transcription Factors ◽  
Mast Cells ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Mitochondrial Dynamics ◽  
Allergic Diseases ◽  
Mast Cell Activation ◽  
Basic Knowledge ◽  
Mitochondrial Activity

Mast cells play a key role in the regulation of innate and adaptive immunity and are involved in pathogenesis of many inflammatory and allergic diseases. The most studied mechanism of mast cell activation is mediated by the interaction of antigens with immunoglobulin E (IgE) and a subsequent binding with the high-affinity receptor Fc epsilon RI (FcεRI). Increasing evidences indicated that mitochondria are actively involved in the FcεRI-dependent activation of this type of cells. Here, we discuss changes in energy metabolism and mitochondrial dynamics during IgE-antigen stimulation of mast cells. We reviewed the recent data with regards to the role played by mitochondrial membrane potential, mitochondrial calcium ions (Ca2+) influx and reactive oxygen species (ROS) in mast cell FcεRI-dependent activation. Additionally, in the present review we have discussed the crucial role played by the pyruvate dehydrogenase (PDH) complex, transcription factors signal transducer and activator of transcription 3 (STAT3) and microphthalmia-associated transcription factor (MITF) in the development and function of mast cells. These two transcription factors besides their nuclear localization were also found to translocate in to the mitochondria and functions as direct modulators of mitochondrial activity. Studying the role played by mast cell mitochondria following their activation is essential for expanding our basic knowledge about mast cell physiological functions and would help to design mitochondria-targeted anti-allergic and anti-inflammatory drugs.

scholarly journals Resveratrol inhibits IL-33–mediated mast cell activation by targeting the MK2/3–PI3K/Akt axis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Shotaro Nakajima ◽  
Kayoko Ishimaru ◽  
Anna Kobayashi ◽  
Guannan Yu ◽  
Yuki Nakamura ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Cytokine Production ◽  
Allergic Diseases ◽  
Mast Cell Activation ◽  
Akt Pathway ◽  
Mouse Lung ◽  
Mouse Bone Marrow ◽  
Interleukin 33

AbstractInterleukin-33 (IL-33)/ST2–mediated mast cell activation plays important roles in the pathophysiology of allergic diseases. Hence, pharmacologically targeting the IL-33/ST2 pathway in mast cells could help to treat such diseases. We found that resveratrol inhibits IL-33/ST2–mediated mast cell activation. Resveratrol suppressed IL-33–induced IL-6, IL-13, and TNF-α production in mouse bone marrow–derived mast cells (BMMCs), mouse fetal skin–derived mast cells, and human basophils. Resveratrol also attenuated cytokine expression induced by intranasal administration of IL-33 in mouse lung. IL-33–mediated cytokine production in mast cells requires activation of the NF-κB and MAPK p38–MAPK-activated protein kinase-2/3 (MK2/3)–PI3K/Akt pathway, and resveratrol clearly inhibited IL-33–induced activation of the MK2/3–PI3K/Akt pathway, but not the NF-κB pathway, without affecting p38 in BMMCs. Importantly, resveratrol inhibited the kinase activity of MK2, and an MK2/3 inhibitor recapitulated the suppressive effects of resveratrol. Resveratrol and an MK2/3 inhibitor also inhibited IgE-dependent degranulation and cytokine production in BMMCs, concomitant with suppression of the MK2/3–PI3K/Akt pathway. These findings indicate that resveratrol inhibits both IL-33/ST2–mediated and IgE-dependent mast cell activation principally by targeting the MK2/3–PI3K/Akt axis downstream of p38. Thus, resveratrol may have potential for the prevention and treatment of broad ranges of allergic diseases.

scholarly journals Direct Inhibition of the Allergic Effector Response by Raw Cow’s Milk—An Extensive In Vitro Assessment

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1258
Author(s):  
Suzanne Abbring ◽  
Bart R. J. Blokhuis ◽  
Julie L. Miltenburg ◽  
Kiri G. J. Romano Olmedo ◽  
Johan Garssen ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Allergic Diseases ◽  
Raw Milk ◽  
Mast Cell Activation ◽  
Cow’S Milk ◽  
Cow's Milk ◽  
Ige Mediated ◽  
Raw Cow’S Milk

The mechanisms underlying the allergy-protective effects of raw cow’s milk are poorly understood. The current focus is mainly on the modulation of T cell responses. In the present study, we investigated whether raw cow’s milk can also directly inhibit mast cells, the key effector cells in IgE-mediated allergic responses. Primary murine bone marrow-derived mast cells (BMMC) and peritoneal mast cells (PMC), were incubated with raw milk, heated raw milk, or shop milk, prior to IgE-mediated activation. The effects on mast cell activation and underlying signaling events were assessed. Raw milk was furthermore fractionated based on molecular size and obtained fractions were tested for their capacity to reduce IgE-mediated mast cell activation. Coincubation of BMMC and PMC with raw milk prior to activation reduced β-hexosaminidase release and IL-6 and IL-13 production, while heated raw milk or shop milk had no effect. The reduced mast cell activation coincided with a reduced intracellular calcium influx. In addition, SYK and ERK phosphorylation levels, both downstream signaling events of the FcεRI, were lower in raw milk-treated BMMC compared to control BMMC, although differences did not reach full significance. Raw milk-treated BMMC furthermore retained membrane-bound IgE expression after allergen stimulation. Raw milk fractionation showed that the heat-sensitive raw milk components responsible for the reduced mast cell activation are likely to have a molecular weight of > 37 kDa. The present study demonstrates that raw cow’s milk can also directly affect mast cell activation. These results extend the current knowledge on mechanisms via which raw cow’s milk prevents allergic diseases, which is crucial for the development of new, microbiologically safe, nutritional strategies to reduce allergic diseases.

scholarly journals IgE Enhances Mouse Mast Cell FcεRI Expression In Vitro and In Vivo: Evidence for a Novel Amplification Mechanism in IgE-dependent Reactions

1997 ◽  
Vol 185 (4) ◽  
pp. 663-672 ◽  
Author(s):  
Masao Yamaguchi ◽  
Chris S. Lantz ◽  
Hans C. Oettgen ◽  
Ildy M. Katona ◽  
Tony Fleming ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Specific Antigen ◽  
Mast Cell Activation ◽  
Proinflammatory Mediators ◽  
Mouse Mast Cell

The binding of immunoglobulin E (IgE) to high affinity IgE receptors (FcεRI) expressed on the surface of mast cells primes these cells to secrete, upon subsequent exposure to specific antigen, a panel of proinflammatory mediators, which includes cytokines that can also have immunoregulatory activities. This IgE- and antigen-specific mast cell activation and mediator production is thought to be critical to the pathogenesis of allergic disorders, such as anaphylaxis and asthma, and also contributes to host defense against parasites. We now report that exposure to IgE results in a striking (up to 32-fold) upregulation of surface expression of FcεRI on mouse mast cells in vitro or in vivo. Moreover, baseline levels of FcεRI expression on peritoneal mast cells from genetically IgE-deficient (IgE −/−) mice are dramatically reduced (by ∼83%) compared with those on cells from the corresponding normal mice. In vitro studies indicate that the IgE-dependent upregulation of mouse mast cell FcεRI expression has two components: an early cycloheximide-insensitive phase, followed by a later and more sustained component that is highly sensitive to inhibition by cycloheximide. In turn, IgE-dependent upregulation of FcεRI expression significantly enhances the ability of mouse mast cells to release serotonin, interleukin-6 (IL-6), and IL-4 in response to challenge with IgE and specific antigen. The demonstration that IgE-dependent enhancement of mast cell FcεRI expression permits mast cells to respond to antigen challenge with increased production of proinflammatory and immunoregulatory mediators provides new insights into both the pathogenesis of allergic diseases and the regulation of protective host responses to parasites.

Spiraeoside inhibits mast cells activation and IgE-mediated allergic responses by suppressing phospholipase C-γ-mediated signaling

2015 ◽  
Vol 93 (3) ◽  
pp. 227-235 ◽  
Author(s):  
Jung Kuk Kim ◽  
Young-Kyo Seo ◽  
Sehoon Park ◽  
Soo-Ah Park ◽  
Seyoung Lim ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Phospholipase C ◽  
Cell Activation ◽  
Mapk Signaling ◽  
Mast Cell Activation ◽  
Tnf Α ◽  
Ige Mediated ◽  
Subsequent Activation

Mast cells are responsible for IgE-mediated allergic responses through the secretion of various inflammatory cytokines and mediators. Therefore, the pharmacological regulation of mast cell activation is an important goal in the development of novel anti-allergic drugs. In this study, we found that spiraeoside (SP) inhibits mast cell activation and allergic responses in vivo. SP dose-dependently inhibited the degranulation induced by IgE-antigen (Ag) stimulation in RBL-2H3 mast cells without cytotoxic effects. At the molecular level, SP reduced the Ag-induced phosphorylation and subsequent activation of phospholipase C-γ2 (PLC-γ2). Moreover, SP inhibited the phosphorylation of spleen tyrosine kinase (Syk), linker for activation of T cells (LAT), and downstream MAPKs, such as ERK1/2, p38, and JNK, eventually attenuating expression of TNF-α and IL-4. Finally, we found that SP significantly inhibited IgE-mediated passive cutaneous anaphylaxis (PCA) in mice. Taken together, our results strongly suggest that SP suppresses IgE-mediated mast cell activation and allergic responses by inhibiting Lyn-induced PLC-γ2/MAPK signaling in mast cells.

scholarly journals The pLysRS-Ap4A Pathway in Mast Cells Regulates the Switch from Host Defense to a Pathological State

2021 ◽  
Vol 22 (11) ◽  
pp. 5620
Author(s):  
Sharmila Govindaraj ◽  
Lakshmi Bhargavi Paruchuru ◽  
Ehud Razin
Keyword(s):  
Mast Cell ◽  
Immune System ◽  
Mast Cells ◽  
Host Defense ◽  
Cell Activation ◽  
Adaptive Immune System ◽  
Allergic Diseases ◽  
Mast Cell Activation ◽  
Pathological State ◽  
Adaptive Immune

The innate and adaptive immune systems play an essential role in host defense against pathogens. Various signal transduction pathways monitor and balance the immune system since an imbalance may promote pathological states such as allergy, inflammation, and cancer. Mast cells have a central role in the regulation of the innate/adaptive immune system and are involved in the pathogenesis of many inflammatory and allergic diseases by releasing inflammatory mediators such as histamines, proteases, chemotactic factors, and cytokines. Although various signaling pathways are associated with mast cell activation, our discovery and characterization of the pLysRS-Ap4A signaling pathway in these cells provided an additional important step towards a full understanding of the intracellular mechanisms involved in mast cell activation. In the present review, we will discuss in depth this signaling pathway’s contribution to host defense and the pathological state.

scholarly journals ORMDL3 Functions as a Negative Regulator of Antigen-Mediated Mast Cell Activation via an ATF6-UPR-Autophagy–Dependent Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Jia Li ◽  
Md Ashik Ullah ◽  
Hongping Jin ◽  
Yuting Liang ◽  
Lihui Lin ◽  
...  
Keyword(s):  
Mast Cell ◽  
Cell Activation ◽  
Critical Role ◽  
Allergic Diseases ◽  
Negative Regulator ◽  
Mast Cell Activation ◽  
Chemokine Production ◽  
Autophagy Pathway ◽  
Dependent Pathway

Antigen (Ag)-mediated mast cell activation plays a critical role in the immunopathology of IgE-dependent allergic diseases. Restraining the signaling cascade that regulates the release of mast cell-derived inflammatory mediators is an attractive therapeutic strategy to treat allergic diseases. Orosomucoid-like-3 (ORMDL3) regulates the endoplasmic reticulum stress (ERS)-induced unfolded protein response (UPR) and autophagy. Although ERS/UPR/autophagy pathway is crucial in Ag-induced mast cell activation, it is unknown whether ORMDL3 regulates the ERS/UPR/autophagy pathway during mast cell activation. In this study, we found that ORMDL3 expression was downregulated in Ag-activated MC/9 cells. Overexpression of ORMDL3 significantly inhibited degranulation, and cytokine/chemokine production, while the opposite effect was observed with ORMDL3 knockdown in MC/9 cells. Importantly, ORMDL3 overexpression upregulated mediators of ERS-UPR (SERCA2b, ATF6) and autophagy (Beclin 1 and LC3BII). Knockdown of ATF6 and/or inhibition of autophagy reversed the decreased degranulation and cytokine/chemokine expression caused by ORMDL3 overexpression. Moreover, in vivo knockdown of ORMDL3 and/or ATF6 enhanced passive cutaneous anaphylaxis (PCA) reactions in mouse ears. These data indicate that ORMDL3 suppresses Ag-mediated mast cell activation via an ATF6 UPR-autophagy dependent pathway and thus, attenuates anaphylactic reaction. This highlights a potential mechanism to intervene in mast cell mediated diseases.

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