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- Fuchs, B, et al.
(författare)
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Mast cell engraftment of the peripheral lung enhances airway hyperresponsiveness in a mouse asthma model
- 2012
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Ingår i: American journal of physiology. Lung cellular and molecular physiology. - : American Physiological Society. - 1522-1504 .- 1040-0605. ; 303:12, s. L1027-L1036
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Tidskriftsartikel (refereegranskat)abstract
- Allergic asthma is a chronic inflammatory disease, characterized by airway hyperresponsiveness (AHR), inflammation, and tissue remodeling, in which mast cells play a central role. In the present study, we analyzed how mast cell numbers and localization influence the AHR in a chronic murine model of asthma. C57BL/6 (wild-type) and mast cell-deficient B6.Cg- KitW−shmice without (Wsh) and with (Wsh+MC) mast cell engraftment were sensitized to and subsequently challenged with ovalbumin for a 91-day period. In wild-type mice, pulmonary mast cells were localized in the submucosa of the central airways, whereas the more abundant mast cells in Wsh+MC mice were found mainly in the alveolar parenchyma. In Wsh+MC, ovalbumin challenge induced a relocation of mast cells from the perivascular space and central airways to the parenchyma. Allergen challenge caused a similar AHR in wild-type and Wsh mice in the resistance of the airways and the pulmonary tissue. In Wsh+MC mice the AHR was more pronounced. The elevated functional responses were partly related to the numbers and localization of connective tissue-type mast cells in the peripheral pulmonary compartments. A mast cell-dependent increase in IgE and IL-33 together with impairment of the IL-23/IL-17 axis was evoked in Wsh and Wsh+MC mice by allergen challenge. This study shows that within the same chronic murine asthma model the development of AHR can be both dependent and independent of mast cells. Moreover, the spatial distribution and number of pulmonary mast cells determine severity and localization of the AHR.
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- Ekoff, M, et al.
(författare)
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Coaggregation of FcepsilonRI with FcgammaRIIB Inhibits Degranulation but Not Induction of Bcl-2 Family Members A1 and Bim in Mast Cells
- 2006
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Ingår i: Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology. - : Springer Science and Business Media LLC. - 1710-1492. ; 2:3, s. 87-97
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Tidskriftsartikel (refereegranskat)abstract
- The aggregation of high-affinity immunoglobulin E (IgE) receptors (FcεRI) on mast cells is a critical event in the initiation of an allergic reaction. Coengagement of FcεRI with immunoglobulin G (IgG) low-affinity receptor FcγRIIB/CD32 inhibits degranulation and the release of inflammatory mediators from mast cells and has therefore been proposed as a new therapeutic approach for the treatment of allergies. In this study, we investigated whether FcγRIIB, besides inhibiting degranulation, negatively regulates other signalling pathways downstream of FcεRI. For this, we determined the phosphorylation and/or expression of proteins involved in the regulation of mast-cell apoptosis. Coaggregation led to an attenuation of Akt phosphorylation but did not inhibit phosphorylation of transcription factor Foxo3a or its proapoptotic target, Bim. Similarly, FcεRI-dependent expression of the prosurvival gene A1 was not affected by coaggregation. Our data demonstrate that coengagement of FcεRI and FcγRIIB inhibits degranulation but not the signalling pathways regulating Bcl-2 family members Bim and A1.
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- Ekoff, M, et al.
(författare)
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FcepsilonRI aggregation promotes survival of connective tissue-like mast cells but not mucosal-like mast cells
- 2007
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Ingår i: Journal of immunology (Baltimore, Md. : 1950). - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 178:7, s. 4177-4183
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Tidskriftsartikel (refereegranskat)abstract
- Mast cells play a critical role in IgE-dependent immediate hypersensitivity reactions. This is facilitated by their capacity to release inflammatory mediators and to undergo activation-induced survival upon cross-linking of the high-affinity IgE-receptor (FcεRI). Due to their heterogeneity, mast cells can be divided into two major groups: the connective tissue mast cells and the mucosal mast cells. We have previously shown that IL-3-dependent bone marrow-derived mast cells can undergo activation-induced survival that is dependent on the prosurvival gene A1. In this study, we have used two different protocols to develop murine connective tissue-like mast cells (CTLMC) and mucosal-like mast cells (MLMC) to investigate their capacity to survive an allergic reaction in vitro. In this study, we demonstrate that FcεRI stimulation promotes survival of CTLMC but not MLMC. Similarly, a prominent induction of A1 is observed only in CTLMC but not MLMC. MLMC have a higher basal level of the proapoptotic protein Bim compared with CTLMC. These findings demonstrate a difference among mast cell populations in their ability to undergo activation-induced survival after FcεRI stimulation, which might explain the slower turnover of CTMC in IgE-dependent reactions.
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- Ekoff, M, et al.
(författare)
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Mast cell apoptosis and survival
- 2011
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Ingår i: Advances in experimental medicine and biology. - Boston, MA : Springer US. - 0065-2598. ; 716, s. 47-60
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Tidskriftsartikel (refereegranskat)
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- Gela, Anele, et al.
(författare)
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Eotaxin-3 (CCL26) exerts innate host defense activities that are modulated by mast cell proteases
- 2015
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Ingår i: Allergy. - : Wiley. - 1398-9995 .- 0105-4538. ; 70:2, s. 161-170
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundDuring bacterial infections of the airways, a Th1-profiled inflammation promotes the production of several host defense proteins and peptides with antibacterial activities including -defensins, ELR-negative CXC chemokines, and the cathelicidin LL-37. These are downregulated by Th2 cytokines of the allergic response. Instead, the eosinophil-recruiting chemokines eotaxin-1/CCL11, eotaxin-2/CCL24, and eotaxin-3/CCL26 are expressed. This study set out to investigate whether these chemokines could serve as innate host defense molecules during allergic inflammation. MethodsAntibacterial activities of the eotaxins were investigated using viable count assays, electron microscopy, and methods assessing bacterial permeabilization. Fragments generated by mast cell proteases were characterized, and their potential antibacterial, receptor-activating, and lipopolysaccharide-neutralizing activities were investigated. ResultsCCL11, CCL24, and CCL26 all showed potent bactericidal activity, mediated through membrane disruption, against the airway pathogens Streptococcus pneumoniae, Staphylococcus aureus, Nontypeable Haemophilus influenzae, and Pseudomonas aeruginosa. CCL26 retained bactericidal activity in the presence of salt at physiologic concentrations, and the region holding the highest bactericidal activity was the cationic and amphipathic COOH-terminus. Proteolysis of CCL26 by chymase and tryptase, respectively, released distinct fragments of the COOH- and NH2-terminal regions. The COOH-terminal fragment retained antibacterial activity while the NH2-terminal had potent LPS-neutralizing properties in the order of CCL26 full-length protein. An identical fragment to NH2-terminal fragment generated by tryptase was obtained after incubation with supernatants from activated mast cells. None of the fragments activated the CCR3-receptor. ConclusionsTaken together, the findings show that the eotaxins can contribute to host defense against common airway pathogens and that their activities are modulated by mast cell proteases.
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- Gülen, T, et al.
(författare)
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Assessment of in vivo mast cell reactivity in patients with systemic mastocytosis.
- 2017
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Ingår i: Clinical and Experimental Allergy. - : Wiley. - 0954-7894 .- 1365-2222. ; 47:7, s. 909-917
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Patients with systemic mastocytosis (SM) have clinical signs of mast cell (MC) activation and increased levels of MC mediators. It is unclear whether the increased mediator levels are caused by increased numbers of tissue MCs, or whether these cells in affected individuals have a hyperactive phenotype.OBJECTIVE: To determine reactivity of the skin and the airways to directly acting mediators and indirectly acting mast cell secretagogues in subjects with SM.METHODS: were measured, as well as ex vivo basophil histamine release.RESULTS: Mast cell mediators in the blood and urine were significantly higher in patients with SM than in HC and A controls. Responsiveness to local activation of skin MCs (by morphine) and airway MCs (by mannitol) was similar in SM and HC groups. Likewise, end-organ responsiveness in the skin to histamine, and in the airways to methacholine, was similar in all three subject groups. There was no evidence of increased basophil reactivity in SM patients.CONCLUSIONS AND CLINICAL RELEVANCE: Mast cells in the skin and airways of subjects with SM do not exhibit hyper-reactivity towards the MC-activating stimuli morphine and mannitol, respectively. Therefore, the highly elevated baseline levels of MC mediators in SM are most likely due to increased MC numbers, rather than altered MC responsiveness. The underlying mechanisms could involve leakage of MC mediators, or dysfunctions in mediator synthesis, storage and release. One clinical implication of our study is that there is no contraindication to perform skin tests using morphine in subjects with mastocytosis.
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- Rydell, Niclas, et al.
(författare)
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Measurement of Serum IgG Anti-Integrin alpha v beta 6 Autoantibodies Is a Promising Tool in the Diagnosis of Ulcerative Colitis
- 2022
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Ingår i: Journal of Clinical Medicine. - : MDPI. - 2077-0383. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- IgG anti-integrin alpha v beta 6 autoantibodies (IgG anti-alpha v beta 6) have been described as highly sensitive and specific markers of ulcerative colitis (UC) in the sera of Japanese inflammatory bowel disease (IBD) patients. We aimed to evaluate the diagnostic performance of IgG anti-alpha v beta 6 as a biomarker in Swedish patients with IBD or irritable bowel syndrome (IBS). The study included adult UC (n = 59), Crohn's disease (CD, n = 38), and IBS patients (n = 100). Partial Mayo score and Harvey-Bradshaw index were used to assess disease severity for UC and CD, respectively. Serum levels of IgG anti-alpha v beta 6, reported as absorbance units (AU), were measured using an in-house ELISA where the 95th percentile of 76 healthy controls defined positivity. Faecal calprotectin (fCP) was measured using a commercial assay. The majority of the IBD patients were on medical treatment, and many were in remission (UC: 40.7%; CD: 47.4%). Seventy-one percent of the UC patients, 74.2% of CD patients, and 23.1% of the IBS patients had fCP test results >50 mg/kg. The UC group had significantly higher IgG anti-alpha v beta 6 levels (median: 1.76 AU) than the CD and IBS groups (0.34 and 0.31 AU, both p < 0.0001). The diagnostic sensitivity of IgG anti-alpha v beta 6 in UC was 76.3%, and the specificities were 79.0% (vs. CD) and 96.0% (vs. IBS). The IgG anti-alpha v beta 6 levels related to disease severity of the UC patients (p < 0.01-0.05). Our study shows that IgG anti-alpha v beta 6 is associated with UC in Swedish IBD patients and that the levels of the autoantibodies reflect disease severity. IgG anti-alpha v beta 6 could be an attractive complement to fCP in the diagnostic work up of IBD patients.
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| 22. |
- Westerberg, CM, et al.
(författare)
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Regulation of mast cell survival and apoptosis
- 2015
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Ingår i: Methods in molecular biology (Clifton, N.J.). - New York, NY : Springer New York. - 1940-6029. ; 1220, s. 257-67
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Tidskriftsartikel (refereegranskat)
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| 23. |
- Wu, Chenyan, et al.
(författare)
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Single-cell transcriptomics reveals the identity and regulators of human mast cell progenitors
- 2022
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 6:15, s. 4439-4449
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Tidskriftsartikel (refereegranskat)abstract
- Mast cell accumulation is a hallmark of a number of diseases, including allergic asthma and systemic mastocytosis. Immunoglobulin E-mediated crosslinking of the Fc epsilon RI receptors causes mast cell activation and contributes to disease pathogenesis. The mast cell lineage is one of the least studied among the hematopoietic cell lineages, and controversies remain about whether Fc epsilon RI expression appears during the mast cell progenitor stage or during terminal mast cell maturation. Here, we used single-cell transcriptomics analysis to reveal a temporal association between the appearance of Fc epsilon RI and the mast cell gene signature in CD341 hematopoietic progenitors in adult peripheral blood. In agreement with these data, the Fc epsilon RI+ hematopoietic progenitors formed morphologically, phenotypically, and functionally mature mast cells in long-term culture assays. Single-cell transcriptomics analysis further revealed the expression patterns of prospective cytokine receptors regulating development of mast cell progenitors. Culture assays showed that interleukin-3 (IL-3) and IL-5 promoted disparate effects on progenitor cell proliferation and survival, respectively, whereas IL-33 caused robust Fc epsilon RI downregulation. Taken together, we showed that FceRI expression appears at the progenitor stage of mast cell differentiation in peripheral blood. We also showed that external stimuli regulate Fc epsilon RI expression of mast cell progenitors, providing a possible explanation for the variable Fc epsilon RI expression levels during mast cell development.
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| 24. |
- Zhang, Liying, et al.
(författare)
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Cannabinoid non-cannabidiol site modulation of TRPV2 structure and function
- 2022
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- TRPV2 is a ligand-operated temperature sensor with poorly defined pharmacology. Here, we combine calcium imaging and patch-clamp electrophysiology with cryo-electron microscopy (cryo-EM) to explore how TRPV2 activity is modulated by the phytocannabinoid Δ9-tetrahydrocannabiorcol (C16) and by probenecid. C16 and probenecid act in concert to stimulate TRPV2 responses including histamine release from rat and human mast cells. Each ligand causes distinct conformational changes in TRPV2 as revealed by cryo-EM. Although the binding for probenecid remains elusive, C16 associates within the vanilloid pocket. As such, the C16 binding location is distinct from that of cannabidiol, partially overlapping with the binding site of the TRPV2 inhibitor piperlongumine. Taken together, we discover a new cannabinoid binding site in TRPV2 that is under the influence of allosteric control by probenecid. This molecular insight into ligand modulation enhances our understanding of TRPV2 in normal and pathophysiology.
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