Rozprawy doktorskie: „Mast cells”

1

Dacre, Kirstie Jane. "Involvement of mast cells and mast cell serine proteinases in equine heaves". Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/29721.

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Mast cells release potent mediators upon degranulation, including serine proteinases. These proteinases play a pivotal role in the pathogenesis of human asthma. Due to the similarities between human asthma and equine heaves, a similar role for the mast cell in equine heaves is proposed. Clinical heaves horses had significantly increased BALF tryptase concentrations compared to controls or heaves horses in remission, whereas BALF tryptase concentrations of controls and heaves horses in remission did not significantly differ. Horses with other pulmonary diseases also had significantly elevated BALF tryptase concentrations compared to controls. Cloning and sequencing of these proteinases revealed an alanine 216 substitution in equine tryptase, which confers increased arginine substrate specificity and may restrict fibrinogenolysis in vivo. Probing of tryptase mRNA transcript regulation in control and heaves susceptible horses revealed no significant change in airway liminal cell pellet tryptase expression following hay/straw challenge of control or heaves horses. However, bronchiolar tissues from heaves horses in early resolution phase had significantly down-regulated tryptase transcripts compared to controls. Furthermore, immunohistochemistry revealed significant intra-epithelial recruitment of tryptase positive mast cells in heaves horses compared to controls, suggesting involvement of tissue mast cells in response to challenge. In vitro hay dust suspension (HDS) challenge induced significant airway luminal mast cell degranulation in heaves susceptible horses, however a similar dose response trend was also evident in control horses. The increased number of intra-epithelial mast cells in heaves horses may explain the divergent mast cell response to in vivo and in vitro challenges. HDS-induced mast cell degranulation in both control and heaves horses may suggest non-IgE mediated degranulation. Alternatively, both control and heaves horses may have been sensitised to HDS allergens and phenotypic diversity may ultimately determine response to challenge.

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2

Leskinen, Markus. "Mast cell-mediated apoptosis of smooth muscle cells and endothelial cells". Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/kliin/vk/leskinen/.

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3

Crummy, F. "Adenosine, mast cells and asthma". Thesis, Queen's University Belfast, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403238.

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Huntley, John Frederick. "Mast cells and intestinal nematodiasis". Thesis, University of Edinburgh, 1991. http://hdl.handle.net/1842/15070.

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Specific enzyme-linked immunosorbent assays (ELISA) for rat mast cell proteinase I and II (RMCP I and II), intestinal mast cell proteinase (IMCP) and sheep mast cell proteinase (SMCP) were developed. Sheep serum or lymph contained potent inhibitory factors which interfered with the ELISA for SMCP, whereas little or no effect was demonstrated in the rodent ELISA by homologous serum. Secretion of SMCP into gastric lymph was noted in immune sheep following oral challenge with Ostertagia circumcincta. Development of immunity to Haemonchus contortus in sheep, expressed as the ability to exclude larvae from the mucosal surface, was characterised by an increase in mucosal mast cells (MMC) and increased abomasal tissue concentrations of SMCP. Increased concentrations of SMCP were demonstrated in serum and mucus in immune, but not in naive, sheep following direct abomasal challenge with 1 x 10⁶ L₃ Haemonchus larvae. The abrogation of immune exclusion by treatment with corticosteroids was associated with a significant reduction in the number of MMC and concentrations of SMCP in abomasal tissue. Immune exclusion persisted for 6 weeks but had declined by 12 weeks following the cessation of larval challenge. This decline was associated with a significant reduction in the number of MMC and concentrations of SMCP in abomasal tissue. Ovine mast cells derived from in vitro culture of bone marrow cells (BMMC) were compared with MMC. BMMC contained similar constituents to MMC including SMCP, histamine, dopamine and arylsulphatase. BMMC contained an additional ³[H]-DFP reactive protein not demonstrated in MMC. In the mouse, the major source of IMCP was the gastrointestinal tract. During infection with Trichinella spiralis, secretion of IMCP was demonstrated. Murine mast cells of the gastrointestinal tract exhibited heterogeneity in their proteinase phenotype, with many cells apparently containing a mixture of proteinases. Heterogeneity in the proteinase expression of mast cells in the rat was also demonstrated, with mast cells containing either RMCP I, RMCP II or RMCP I and II. Cells expressing dual proteinase phenotype were observed in some non-mucosal locations. During a primary infection of Nippostrongylus brasiliensis, changes in the RMCP I and II concentrations occurred in almost all tissues of the rat. These included significant increases in RMCP II concentrations in mesenteric lymph node, lung and intestinal tract 12 days after infection. Other changes, including those of RMCP I concentrations in bone marrow, are described.

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5

Alswied, Abdullah M. "Calcium signalling in mast cells". Thesis, University of Oxford, 2015. https://ora.ox.ac.uk/objects/uuid:cc8f5f8b-5cab-4391-bce3-9541ab371002.

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Mast cells play a central role in many allergic and in ammatory conditions. These cells are activated following an intracellular rise in calcium, such as that which occurs after the activation of cell-surface receptors. One such important receptor is cysteinyl leukotriene (CysLT) receptor type 1 (CysLT1), which is activated by lipid mediators such as CysLTs LTC4, LTD4, and LTE4. CysLT1 stimulation leads to the hydrolysis of membrane phospholipids such as phosphatidylinositol 4 5-bisphosphate (PIP2) via phospholipase C-β , which results in the generation of diacylglycerol and inositol trisphosphate. Inositol trisphosphate transiently increases cytosolic calcium levels by releasing calcium from its internal stores. This transient phase is followed by an influx of external calcium caused by the opening of store-operated calcium release-activated calcium (CRAC) channels in the plasma membrane. To understand how CRAC channels are involved in receptor- driven calcium responses, I investigated whether the opening of CRAC channels regulates the production of cellular phosphoinositide. Using cytoplasmic calcium ion (Ca2+) imaging in the mast cell line RBL-2H3, I found that LTC4 induced repetitive calcium oscillations that ran down in the absence of external calcium and were sustained by calcium entry through CRAC channels. The molecular characterisation of CRAC channel components in RBL-2H3 cells revealed that LTC4 -mediated calcium oscillations were maintained through calcium entry via Orai1 and that the calcium signal could not be maintained by Orai3 or other calcium- permeable channels. Furthermore, STIM1 (but not STIM2) was the only homologue that supported calcium oscillations in RBL-2H3 cells. The inhibition of the cellular phosphoinositide pool by lithium chloride (LiCl) reduces calcium oscillations. Adding the substrate inositol rescued these oscillations, but only when external calcium was present. Pharmacologically blocking CRAC channels with a low concentration of CRAC channel blockers prevented the recovery of oscillations in LiCl-treated cells, even when inositol was present. To further understand how calcium entry contributes to the production of PIP2, I investigated whether PI4P- or PI5P-specific pools support the oscillatory calcium signal induced by LTC4. Accordingly, by using pharmacological blockers, concluded that PIP2 used in LTC4 -mediated calcium signalling is produced via the conversion of PI4P into PIP2 by PI5K1 kinases and that the cellular PI5P pool does not contribute to the calcium signal. Moreover, the conversion of PI4P into PIP2 was possible only when there was calcium entry via CRAC channels. Characterisation of the expressed PI5K1 kinases in RBL-2H3 cells revealed expression of only PIP5K1a and PIP5K1? and that both kinases are needed to maintain the oscillatory calcium signal induced by LTC4 and to provide an overlapping function. To further expand current understanding of how calcium regulates PI5K1 kinases, I specifically investigated how calcium entry regulates PIP5K1?. This was accomplished by looking into PIP5K1?-regulating proteins, of which talin is a focal adhesion protein shown to activate PIP5K1?. In this thesis, I show that the cleavage and activation of talin depend on calcium entry via CRAC channels, thereby elucidating a possible mechanism in how CRAC channels mediating calcium entry are involved in phosphoinositide production. This thesis identifies a new role for CRAC channels in mast cell activation. The opening of CRAC channels and calcium entry are required for PIP2 production and thus the maintenance of agonist-mediated calcium signalling.

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6

Roy, Ananya. "Mast Cells as Sentinels : Role of serglycin and mast cell proteases in infection and inflammation". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-173508.

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Mast cells (MCs), normally classified into connective tissue MCs and mucosal MCs, are highly granulated cells found in the interface between the interior and the exterior environment of our body, e.g. skin, airways and gastro-intestinal tract. They react to bacteria, parasites, viruses, and allergens by degranulation and release of premade and newly synthesized inflammatory mediators. The MC-proteases (tryptases, chymases and carboxypeptidase A), histamine and serglycin (SG) proteoglycans are premade mediators. Among these, SG is also expressed in a variety of other immune and non-immune cells. Heparin and chondroitin sulphate glycosaminoglycan chains confer highly negative charge to SG, by which MC-proteases are retained in secretory granules. Deletion of SG cause impaired packing and storage of most MC-proteases. During challenge with Toxoplasma gondii the SG-deficient mice showed significant lower inflammatory cytokine levels in comparison to wild-type mice. Results were consistently similar in vitro, bringing forward the importance of SG in inflammatory cytokine and innate immune responses towards T. gondii. Infection with Trichinella spiralis in SG-/- mice caused increased intestinal enteropathy, a tendency of delayed worm expulsion and increased larval burden in the muscle tissue as compared to wild-type animals. An altered TH2 cytokine response was also observed, and all these effects were not repaired by wild-type MC reconstitution of the SG-/- mice. Altogether, our results suggest that SG is important for tissue homeostasis, and that SG expressing cells seem capable of switching from a SG-dependent storage mode to a SG-independent secretory mode upon infection. The chymase (MCPT4) expressed by connective tissue MC has been implicated to have a protective role during infection and in limiting inflammation. We explored a protective role by inducing T. gondii infection in the Mcpt4-null mice, and found MCPT4-mediated recruitment of neutrophils and eosinophils via control of cytokine signaling. Endogenous proteins “alarmins” released by dead cells can trigger tissue and cell damage. We conclusively show that chymase efficiently degrades Hsp70 both in vitro and in vivo and that the degradation of other alarmins, e.g. HMGB1, biglycan and IL-33 may also depend on chymase.

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7

Friend, Reuben. "SNARE proteins in human mast cells". Thesis, University of Sheffield, 2013. http://etheses.whiterose.ac.uk/5177/.

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Mast cells form an integral part of both innate and adaptive immunity; they help to orchestrate the inflammatory immune response through the release of a variety of inflammatory mediators. Adverse reaction to allergens can lead to activation of mast cells, causing degranulation and release of a range of pro-inflammatory mediators contributing to the onset of allergy. The most studied activation pathway in the adaptive immune response of mast cells is through the Immunoglobulin E (IgE) cell surface receptor FceRI. Crosslinking of FceRI leads to degranulation and de novo synthesis of mediators. Every eukaryotic cell undergoes constitutive secretion. Alongside this general process, cells such as neuronal endocrine and immune cells, including mast cells, perform regulated secretion. This enables the cell to rapidly release mediators stored in secretory granules upon stimulation by a particular extracellular ligand. Mediators released fall into two categories; pre-formed, contained within these secretory granules; monoamines such as histamine as well as many proteases, and de novo synthesized that are released through the constitutive secretory pathway, including prostaglandins, leukotrienes, cytokines and chemokines. Elucidating the mechanisms of mast cell mediator release is imperative for understanding many disease processes; however, knowledge of the precise mechanisms by which mast cell exocytosis is controlled remains elusive. The aim of this study was to identify and characterise Soluble NSF attachment protein receptor (SNARE) proteins involved in the release of inflammatory mediators in human mast cells. Using LAD 2 human mast cells and primary human lung mast cells (HLMCS), expression of a variety of syntaxins and Vesicle associated membrane proteins (VAMPs), as well as the ubiquitously expressed SNAP-23 were found. To study the roles of individual VAMPs in exocytosis a novel technique utilising pH sensitive pHluorins was developed. Using VAMPs tagged with pHluorins, the cellular distribution of VAMP-3 and VAMP-8 containing vesicles and their behaviour upon IgE stimulation in live cells was monitored. In unstimulated cells, VAMP- 3 and 8 were found to have distinct cellular distributions. Upon IgE stimulation both VAMP-3 and VAMP-8 containing vesicles translocated to the membrane and underwent membrane fusion, consistent with roles in exocytosis. However, their responses showed distinct time courses and calcium dependences. Importantly the VAMP-3 vesicle pool could be selectively targeted with a botulinum neurotoxin serotype B (BoNT)/B LC construct and in doing so inhibited the release of IL-6. The findings in this study support the notion that distinct vesicle pools, defined in part by expression of VAMP-3 and VAMP-8, regulate the release of inflammatory mediators from mast cells and that BoNTs might provide a novel means of targeting the release of chronic inflammatory mediators from mast cells for treatment of chronic inflammatory diseases.

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8

Tree-Booker, Claire. "TRPC channels in human mast cells". Thesis, University of Sheffield, 2011. http://etheses.whiterose.ac.uk/1927/.

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Mast cells have an important role in the immune system, but they are centrally involved in the pathophysiology of asthma, along with a number of other allergic diseases including rhinitis, eczema and irritable bowel disease (Metcalfe et al., 1997; Beaven, 2009). In the allergic response they are activated by IgE binding to high affinity receptors and subsequent crosslinking by antigen. A rise in intracellular Ca2+ is required for mast cells to become activated and release mediators into the surrounding areas, which give rise to the symptoms of allergic disease (Gilfillan & Tkaczyk, 2006). Elucidating the ion channels responsible for mast cell Ca2+ entry may unveil new therapeutic targets for the treatment of asthma and other allergic diseases. Store-operated Ca2+ entry (SOCE) is a major mechanism for mast cell Ca2+ influx and is known to involve highly Ca2+-selective Orai1 channels. TRPC channels are non-selective Ca2+ channels; TRPC1, 4 and 5 are thought to be involved in SOCE, whereas TRPC3, 6 and 7 are activated by diacylglycerol (DAG). Whilst a limited number of studies carried out in rodent mast cells suggest that TRPC channels could be important for Ca2+ entry and mediator release, their functional expression and roles in human mast cells have not been characterised. This study showed that the LAD 2 human mast cell line and primary human lung mast cells (HLMCs) express mRNA for TRPC6. TRPC6-like currents were demonstrated for the first time in HLMCs, in response to direct activation by the DAG analogue OAG, and downstream of Gq protein-coupled P2Y1 receptor stimulation by ADP. This study also revealed for the first time that TRPC1 channels are expressed in both LAD 2 cells and HLMCs, and that both TRPC1 and Orai1 channels are likely to be involved in SOCE. Importantly, this study also indicated that TRPC1 channels could be involved in Ca2+ entry and mediator release downstream of IgE receptor activation. TRPC channels could thus contribute to Ca2+ entry required for mast cell activation in allergic disease, and could represent a therapeutic target for the modulation of diseases such as asthma.

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9

Lin, Tzu-Yin. "The world according to mast cells – the role of Kit in normal and neoplastic canine mast cells". The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1189098916.

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10

Wang, Yiyu [Verfasser]. "Analysis of mast cells and mast cell-mediator-related histological features in cholinergic urticaria / Yiyu Wang". Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/1189139715/34.

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11

Noma, Naruto. "Inhibition of MMP-2-Mediated Mast Cell Invasion by NF-κB Inhibitor DHMEQ in Mast Cells". 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225446.

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Kinoshita, Makoto. "Mast cell tryptase in mast cell granules enhances MCP-1 and interleukin-8 production in human endothelial cells". Kyoto University, 2006. http://hdl.handle.net/2433/144319.

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13

Möller, Christine. "Regulation of mast cell survival /". Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-4703.

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Lin, Tzu-yin. "The world according to mast cells the role of Kit in normal and neoplastic canine mast cells /". Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1189098916.

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15

Offiah, I. "Cross-talk between human T cells, mast cells and conjunctival epithelial cells". Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1348498/.

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The ocular surface is continually exposed to the outside environment and is a common site of inflammation. Conjunctival epithelial cells are thought to play a role in innate responses at the ocular surface. The hypothesis of my study is that conjunctival epithelial cells also contribute to T cell and mast cell effector mechanisms in chronic allergic eye disease via secretion of cytokines. In this study we initially demonstrate that the conjunctiva expresses TLRs, and that the TLR3 ligand (poly I:C) activates conjunctival epithelial cells in vitro to secrete inflammatory mediators as part of the innate immune response. Conjunctival tissues were also shown to express the Th2 associated cytokine, IL-13 as well as TSLP – a cytokine thought to be involved in Th2 differentiation. Conjunctival tissues from chronic allergic eye disease subjects were found to have increased IL-13 and TSLP expression compared to normal controls. Using a human conjunctival epithelial cell line, cells could be induced to express increased levels of TSLP following exposure to poly I:C or pro-inflammatory cytokines. Th17 cells, identified by coexpression of CD4 and IL-17, were also detected in CAED tissues and a high level of expression of IL-17A was localised to the epithelium. However, although capable of secreting IL- 25, IL-17A was not secreted by conjunctival epithelial cells, indicating that the IL-17 observed histologically may have been IL-17 binding to the surface of the epithelium. IL-17 receptor C (IL-17RC) expression was found to be increased in CAED tissues whilst IL-17RA was upregulated when conjunctival epithelial cells were stimulated with pro-inflammatory cytokines together with poly I:C. Blockade of IL-17RA and subsequent stimulation with IL-17 led to increased IL-8 and decreased TGF-β secretion. Although being implicated in the immunopathogenesis of certain diseases, IL-17 and its other family members may potentially serve to play an immunoregulatory role in immunity at the ocular surface.

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16

Shende, Vishvesh H. "Role of mast cells in ischaemic stroke". Thesis, University of Strathclyde, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.502318.

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The purpose of the project was to investigate the role of mast cells and oestrogen in ischaemic stroke. Inflammatory cells and mediators may prove to be novel targets for stroke. In addition studies carried out on animals clearly signify that biological and endogenous sex steroids play a role in experimental stroke outcome. Histological staining (toluidine blue) of coronal sections from SHRSP and WKY rats post-middle cerebral artery occlusion (MCAO, an experimental stroke model) was used to observe cerebral mast cells and their anatomical localisation. Mast cells were found in the brain at 2 hours, 24 hours, 8 days and 30 days post-MCAO in the SHRSP with the peak levels at the earlier time points. The majority of mast cells were localised in thalamic and hippocampus regions. Mast cells were also seen in cortex region, a region within the MCA territory.

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17

Elkovich, Andrea J. "Mast Cells In Kainate Receptor Knockout Mice". VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3944.

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Kainate receptor knockout mice have unique differences within their immune system. They exhibit an attenuated TH2 branch, while maintaining a robust TH1 response. Specifically, blocking the formation of functional kainate receptors affects mast cells and their related pathologies. While they seem to develop and activate normally in vivo and in vitro, KAR KO mast cells release more inflammatory mediators upon degranulation. These mice experience severe anaphylactic shock due to two compounding abnormalities. First, KAR KO mast cells release significantly more histamine in vivo upon IgE-mediated activation. Second, the animals over-respond to exogenous histamine with drastic temperature drops compared to WT. This report shows that the kainate receptor plays an important role in mast cell-mediated immune responses.

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18

Compton, Steven John. "The proinflammatory actions of mast cell tryptase on human endothelial cells". Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245046.

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Sundström, Magnus. "Signal transduction in mast cell migration /". Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5130-6/.

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Peng, Qi. "The heterogeneity, mechanism of regulation and function of human mast cell tryptase". Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285784.

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Takano, Hirotsugi. "Terminal differentiation of connective tissue-type mast cells". 京都大学 (Kyoto University), 2008. http://hdl.handle.net/2433/137162.

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Zhu, Fu-Gang. "Mechanisms of inflammatory cytokine secretion by mast cells". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0029/NQ66688.pdf.

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Crisp, A. J. "Mast cells and their products in rheumatoid arthritis". Thesis, University of Cambridge, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598149.

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Cross, Laurence Joseph Mark. "Mast cells and their role in disease states". Thesis, Queen's University Belfast, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336723.

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Hooi, Peh Kheng. "Actions of balsalazide and sulphasalazine on mast cells". Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294805.

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Okayama, Yoshimichi. "Immunopharmacological studies on human mast cells and basophils". Thesis, University of Southampton, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296403.

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Wang, Yenfeng. "The role of mast cells in foam cell formation, growth inhibition, and apoptosis of smooth muscle cells". Helsinki : University of Helsinki, 1999. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/wang/.

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Collmann, Emilie. "Role of phosphoindositide 3-kinases in mast cell activation /". [S.l.] : [s.n.], 2009. http://edoc.unibas.ch/diss/DissB_8779.

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Chugunova, Elena. "Biological function of mast cell chymase : in vitro and in vivo studies: a thorny pathway /". Uppsala : Dept. of Molecular Biosciences, Swedish Univ. of Agricultural Sciences, 2004. http://epsilon.slu.se/v181.pdf.

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Serra, Pagès Mariona. "Selective EP2 agonism attenuates hdm-induced murine airway pathology and mast cell activity, and triggers intracellular inhibitory signaling in mast cells". Doctoral thesis, Universitat Autònoma de Barcelona, 2012. http://hdl.handle.net/10803/84009.

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L'asma al lèrgica és una malaltia respiratòria crònica amb una alta prevalença en els països desenvolupats. Els tractaments actuals no aturen el procés al lèrgic subjacent ni aconsegueixen el control dels símptomes de la malaltia. El tractament més eficaç és l'ús de corticoesteroids, que es basen en modificacions químiques de potents hormones endògenes antiinflamatòries. L'estudi de vies antiinflamatòries endògenes és una estratègia experimental eficaç per descobrir noves dianes terapèutiques potencials contra l'asma. Una d'aquestes vies endògenes és la de la ciclooxigenasa (COX). Prostaglandina (PG) PGE2, un producte de la COX, s'ha suggerit que exerceixen un efecte protector en els pulmons. En particular, els estudis experimentals en pacients amb asma van revelar que la PGE2 inhalada redueix la hiperreactivitat bronquial i la inflamació. Aquest efecte de protecció de la PGE2 també s'ha demostrat, directament i indirectament, en ratolins sensibilitzats amb OVA o HDM. Els mecanismes subjacents als efectes beneficiosos de la PGE2 en l'asma no es coneixen. Una de les característiques més constants de la PGE2 és la seva capacitat de modular l’activitat dels mastòcits in vitro. Els nostres darrers estudis in vivo van mostrar que la PGE2 també inhibeix l’activitat dels mastòcits en ratolins sensibilitzats a HDM i que aquest efecte modulador sobre els mastòcits és paral lel a la sobreexpressió del receptor EP2. D’aquests resultats sorgeix la hipòtesi que la PGE2 podria interactuar amb els receptors EP2 dels mastòcits de la superfície bronquials i així exercir una acció protectora enfront la patologia impulsada pels al lèrgens en contactar amb les vies respiratòries. El coneixement precís d’aquests mecanismes sens dubte ajudarà a descobrir potencials molècules diana contra l'asma. L'objectiu general d'aquesta tesi és establir preclínicament la rellevança del receptor EP2 mastocitari en l’efecte beneficiós de la PGE2 en l'asma al lèrgica, i descobrir els mecanismes moleculars que resulten d’aquesta activació selectiva del receptor. Per aconseguir aquest objectiu hem dut a terme diversos abordatges in vitro i in vivo. En primer lloc, determinar el patró d’expressió dels receptors EP de la PGE2 en diferents poblacions de mastòcits humans i murins, i es va avaluar a partir de llavors (a) si aquestes diferències en l’expressió relativa dels receptors de EP 1-4 influïa en la capacitat de PGE2 per modular la degranulació dels mastòcits i la mobilització del calci i (b) si els mastòcits humans es van comportar de manera similar als murins en diferents escenaris d'expressió dels receptors EP. Els resultats van apuntar a EP2 com el principal contribuent a l’efecte inhibitori de la PGE2 sobre els mastòcits murins i humans. Quan EP2 es va suggerir com a el receptor primari de protecció, vam abordar la importància de l’activació selectiva d’EP2 (a) en la protecció de la patologia de les vies respiratòries induïda per HDM en ratolins, i (b) la correlació d’aquesta patologia amb la capacitat de l’agonista selectiu EP2 en prevenir l’activitat de mastòcits in vivo. Hem demostrat que un agonista selectiu d’EP2 impedia el desenvolupament de l’AHR i la inflamació, i que aquest efecte estava relacionat amb la capacitat d'aquesta acció de l’agonista selectiu per atenuar l’activitat dels mastòcits de les vies respiratòries. A continuació, es van estudiar possibles mecanismes inhibitoris de senyalització implicats en aquest efecte de bloqueig intervingut per EP2. Hem observat que l’agonisme d’EP2 inhibeix in vivo i in vitro, l'activitat dels mastòcits. Hem descrit que la interacció amb PGE2-EP2 inhibeix la degranulació mastocitària a través de la supressió de la mobilització de calci intervinguda per la inhibició de la via Src-Fyn, i cAMP/PKA. Les nostres observacions ressalten que l’eix "la PGE2" - "l’EP2 mastocitari" - "les vies respiratòries" és una via endògena que condueix a una protecció natural contra la patologia de les vies respiratòries induïda pels aeroal lergens i ajuda a dilucidar els mecanismes precisos que descobreixen molècules diana objectiu de possibles nous tractaments antiasmàtics.
Allergic asthma is a chronic respiratory disease with a high prevalence in developed countries. Current treatments do not halt the underlying allergic process and do not always control the symthomps of the disease. The most effective treatment is the use of glucocorticoids, which are based on chemical modifications of potent natural endogenous anti-inflammatory hormones. Studying endogenous anti-inflammatory pathways to explore new therapeutic targets is an efficient experimental strategy to uncover potential novel targets against asthma. One of such endogeneous pathways are cyclooxygenase (COX)-mediated. Prostaglandin (PG) PGE2, a COX product, has been suggested to exert a protective effect in the lungs. Notably, experimental studies with asthma patients revealed that inhaled PGE2 reduces airway hyperresponsiveness and inflammation. This protective PGE2 effect has also been demonstrated, directly and indirectly, in mice sensitized to OVA or HDM. The mechanisms underlying the beneficial effect of PGE2 in asthma are not understood. One of the most consistent features of PGE2 is its ability to modulate mast cell activity in vitro. Our recent in vivo studies showed that PGE2 also prevents mast cell activity in HDM sensitized mice and that this mast cell modulatory effect was paralleled by EP2 receptor overexpression. These results brought up the hypothesis that PGE2 might interact with EP2 receptor on the bronchial mast cells surface to exert a protective action against allergen-driven airway pathology. The precise understanding of such mechanisms will certainly help uncover potential anti-asthma target molecules along the way. The general objective of this thesis was to establish preclinically the relevance of the mast cell EP2 receptor to PGE2 beneficial effect in allergic asthma, and to uncover molecular mechanisms resulting from this receptor selective activation. To achieve this objective we have undertaken several in vitro and in vivo approaches. We first determined the PGE2 EP receptors expression pattern on different human and murine mast cell population, and thereafter assessed (a) whether such differences in the relative expression of EP receptors 1 to 4 influenced the ability of PGE2 to modulate mast cells degranulation and calcium mobilization, and (b) whether human mast cells behaved similarly to murine mast cells under different EP receptors expression scenarios. The results pointed at EP2 as the main contributor to mediate the inhibitory effect of PGE2 on both murine and human mast cells. Once EP2 had been suggested to be the primary protective receptor, we addressed the relevance of selective EP2 activation to (a) protection against HDMinduced airway pathology in mice, and (b) correlation of such pathology to the ability of selective EP2 agonism to prevent mast cells activity in vivo. We showed that a selective EP2 agonist prevented AHR and inflammation from developing, and that such effect was linked to the ability of such selective agonistic action to attenuate airway mast cell activity. We then studied potential inhibitory signaling mechanisms involved in such EP2-mediated blocking effect. We observed that EP2 agonism inhibited in vivo and in vitro, mast cell activity. We described that the PGE2-EP2 interaction on mast cells inhibiting mast cell degranulation through the supression of calcium influxes mediated by an inhibition of the Src-Fyn pathway, and cAMP/PKA. Our observations highlight that the “PGE2”-“mast cells EP2”-“airway” axis is an endogeneous pathway leading to natural protection against aeroallergens-induced airway pathology, and helps elucidate the precise mechanisms that will uncover clue molecules to be targeted by potential novel antiasthma treatments.

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Meleski, Melissa. "The role of mast cells in fetal wound healing". Connect to resource, 2010. http://hdl.handle.net/1811/45043.

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Ghouse, Shanawaz Mohammed. "Role of Mast cells in HPV-induced skin cancer". Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-229004.

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Mast cells (MCs) are long-lived immune cells, which were reported to play an important role in initiating innate and adaptive immune responses against various infections. MCs accumulate in high numbers in the stroma and at the invasion front of various human cancers, suggesting a possible contribution by MCs to tumour growth. Experimental studies using crosses of MC-deficient Kit-mutant mouse strains with mouse models of epithelial cancers have provided evidence for important MC tumour-promoting functions. However, the complex alterations of the immune system that characterize Kit-mutant mice in addition to their MC deficiency, limit the interpretation of these findings. Numerous key observations made in Kit mutant mice were not reproduced in novel, Kit-independent mouse models of MC deficiency. Thus, the impact of MCs on tumour biology remains unclear. The aim of this study is to clarify the contribution of MCs to the biology of Human papilloma virus (HPV)-induced skin cancer in a Kit-independent mouse model of MC deficiency. In K14-HPV16 transgenic mice, HPV oncogenes are constitutively expressed in the epidermis resulting in epidermal hyperplasia with 100% penetrance and squamous cell carcinoma in about 50% of the animals. A cross to a Kit-mutant line suggested that MCs are important tumour promoters in this model. We crossed K14-HPV16 mice to M5Cre R-DTA line, in which MCs are constitutively depleted with high efficiency and selectivity. Unexpectedly, the loss of MCs neither affected keratinocyte proliferation indices nor altered keratinocyte apoptosis at any stage of HPV-induced neoplasia. Furthermore, the loss of MCs did not result in any detectable changes in composition and gene expression of the inflammatory hematopoietic cell infiltrate in the tumour stroma. This shows that, contrary to current belief, MCs have no important function in orchestrating the tumour micro milieu. In keeping with this finding, MC deficiency resulted in no detectable difference in the incidence growth or grading of SSC in K14-HPV16 transgenic mice. Collectively, these results show that, despite their high density in HPV-induced neoplasia, MC have no role in cancerogenesis or neoplastic progression in the K14-HPV16 mouse model. Our findings also emphasize the importance of novel Kitindependent mouse models in the investigation of MC in vivo functions.

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Price, Leo Sebastian. "Secretion and the actin cytoskeleton in rat mast cells". Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307776.

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Williams, Cara Margaret May. "Cytokine expression in mast cells and rat lung tissue". Thesis, University of Liverpool, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295818.

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COSTANZA, MASSIMO. "Mast cells in the pathogenesis of experimental multiple sclerosis". Doctoral thesis, Università degli Studi di Milano-Bicocca, 2012. http://hdl.handle.net/10281/29633.

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Mast cell (MC)-deficient c-Kit mutant KitW/W-v mice are protected against experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, suggesting a detrimental role for MCs in this disease. However studies performed so far on this topic relied on a single model of MC-deficiency, the KitW/W-v, which bears several c-Kit dependent phenotypic abnormalities other than MC-deficiency, such as neutropenia and anaemia. Also, it is not clear how MCs shape the central nervous system (CNS) autoimmune response occurring in EAE. In the first work, we focused on evaluating the contribution of MCs to EAE in both KitW/W-v mice and in a newly characterized MC-deficient strain, KitW-sh/W-sh, which seems to bear fewer c-Kit dependent hematopoietic alterations. We also aimed at characterizing the T cell response to myelin antigen in a context of MC-deficiency. The comprehension of how mast cells intervene in the pathology of EAE and MS might help designing better therapies for these diseases. Histamine is one of the main preformed mediators stored in MC granules. In the second part of the thesis we evaluated the ability of histamine to modulate the response of myelin-activated T cells. We explored the effect of histamine and specific agonists of histamine receptors 1 and 2 on activation and migratory capacity of myelin-autoreactive T cells through the inflamed BBB.

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Dahlin, Joakim. "Mast Cell Progenitor Trafficking in Allergic Airway Inflammation". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-206608.

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Mast cell progenitors originate from the bone marrow and migrate to the lungs via the blood. During maturation, these cells acquire granules that contain a potent array of bronchoconstrictive mediators. The number of pulmonary mast cells is augmented in asthmatic patients and in mice with allergic airway inflammation, possibly contributing to airway hyperreactivity. An increase in mast cells is likely due to an increased recruitment of committed mast cell progenitors from the blood. However, until now a committed mast cell progenitor population has not been found in adult peripheral blood. We isolated Lin- c-kithi ST2+ integrin β7hi CD16/32hi progenitors from murine blood and showed that these cells were committed to the mast cell lineage. Based on the expression of FcεRI, these cells were less mature in Th1-prone C57BL/6 mice than in Th2-prone BALB/c mice. Asthma is associated with elevated levels of IgE. Upon exposure to allergens, IgE immune complexes are formed. In a mouse model of allergic airway inflammation, we showed that intranasal administration of IgE immune complexes to antigen-sensitized mice resulted in an increased number of mast cell progenitors compared with antigen administration alone. The increase in mast cell progenitors was independent of the low-affinity IgE receptor CD23. Rather, signaling through the common FcRγ-chain was required to enhance the number of lung mast cell progenitors. Signaling through FcεRI was likely responsible for the increase. However a role for FcγRIV could not be excluded. CD11c+ cells, such as dendritic cells, are important for antigen sensitization. In a mouse model of allergic airway inflammation, these cells are also important for the development of airway hyperreactivity, eosinophilia and Th2 cytokine production in response to antigen challenge. We showed that CD11c+ cells are critical for the recruitment of lung mast cell progenitors and the subsequent increase in mast cells. These CD11c+ cells were needed for the upregulation of endothelial vascular cell adhesion molecule-1 (VCAM-1), which is a prerequisite for the antigen-induced recruitment of lung mast cell progenitors.

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Olsson, Niclas. "Mast Cell Migration in Inflammatory Diseases". Doctoral thesis, Uppsala University, Department of Genetics and Pathology, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3615.

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Mast cells (MCs) are forceful multifunctional effector cells of the immune system. MCs are normally distributed throughout connective and mucosal tissues, but in several pathological conditions accumulation of MCs occur. This accumulation is probable due to directed migration of MCs and they are subjects for migration at least two different occations: 1) when they are recruited as progenitor cells from the blood into the tissue; and 2) when they as mature MCs are recruited to sites of inflammation. The aim of this study was to investigate MC migration to chemoattractants released in vivo or in vitro (body fluids collected from patients with asthma or rheumatoid arthritis and T_H1- and T_H2-cytokines) and to recombinant cytokines (transforming growth factor -β (TGF-β) and CCL5/RANTES).

This thesis shows that bronchoalveolar lavage (BAL) fluid from asthmatic patients and synovial fluid from patients with rheumatiod arthritis contain MC chemoattractants, and that part of the chemotactic activity can be related to the presence of stem cell factor (SCF) and TGF-β. We also show that MC chemotactic activity during pollen season is significantly increased compared to before pollen season. Furthermore, we demonstrate that TGF-β isoforms, CCL5, TNF-α and IL-4 act as MC chemoattractants in a bellshaped dose- dependent manner. TGF-β proved to be an extremely potent attractant giving an optimal migratory response at 40fM and TGF-β3 being the most effective isoform. The chemokine CCL5 induced migration through interaction with the receptors CCR1 and CCR4 expressed on MC. Furthermore, we also found that TNF-α produced by T_H1-lymphocytes and IL-4 produced by T_H2-lymphocytes are MC chemoattractants.

In conclusion, with this thesis we have identified six new human mast cell chemoattractants and provide evidence that BAL fluid and synovial fluid from patients with asthma and rheumatoid arthritis, respectivly, contain MC chemoattractants. This information provides important clues in understanding the mechanisms behind MC recruitment to sites of inflammation.

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Zarnegar, Behdad. "Mechanisms triggering the recruitment of mast cell progenitors to the lung and regulation of mast cell degranulation". Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-306115.

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Mast cells stem from the bone marrow and migrate via the blood as mast cell progenitors. Upon arrival in peripheral tissues, they develop into mast cells. These rare immune cells have numerous granules that contain large amounts of pro-inflammatory mediators. Mast cells accumulate at certain sites in the asthmatic lung, and once activated they release mediators that are thought to induce symptoms. In mouse models of allergic airway inflammation, the increase in lung mast cells in asthma can be mimicked and is mainly caused by the recruitment of mast cell progenitors to the lung. However, whether other types of lung inflammation stimulate the recruitment of mast cell progenitors to the lung was unknown until now. Here, using a murine model of influenza A virus infection, this type of virus was demonstrated to trigger an extensive recruitment of mast cell progenitors to the lung, most likely through the induction of VCAM-1 expression in the lung endothelium. Thereafter, some influenza-induced mast cell progenitors developed into an intermediate mast cell stage before they matured into mast cells. However, upon the resolution of inflammation, the mast cells that accumulated in the lung upon influenza infection were gradually lost. Because the recruitment of mast cell progenitors started early after influenza infection, the role of innate immune signals in inducing the recruitment of mast cell progenitors was addressed. The intranasal administration of either Poly I:C or IL-33 was sufficient to induce an increase in lung mast cell progenitors in a TLR3- or ST2-dependent fashion. However, the influenza-induced recruitment of mast cell progenitors to the lung occurred independently of TLR3 and ST2. VAAT/SLC10A4 is a member of the solute carrier family of proteins that is expressed in nerve cells and mast cells. In this study, murine VAAT was localized to mast cell granules and regulated the IgE/antigen-mediated release of granule-associated mediators and ATP. However, the absence of VAAT did not affect IgE/antigen-mediated de novo synthesis of cytokines and lipid mediators. Additionally, mice lacking VAAT had attenuated passive cutaneous anaphylaxis reactions and scratched less frequently in response to compound 48/80 injections, suggesting that VAAT regulates reactions for which mast cells are implicated in vivo.

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GacÌ§a, Marianna Danuta Aleksandria. "The bi-directional relationship between mast cells and hepatic stellate cells in liver fibrosis". Thesis, University of Southampton, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323958.

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Hara, Masatake. "Mast cells cause apoptosis of cardiomyocytes and proliferation of order intramyocardial cells in vitro". Kyoto University, 2000. http://hdl.handle.net/2433/180841.

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Stelekati, Erietta [Verfasser]. "The role of mast cells in CD8+ T cell-mediated immune responses / Erietta Stelekati". Kiel : Universitätsbibliothek Kiel, 2010. http://d-nb.info/1019951877/34.

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Kranenburg, Tanya Ann School of Medicine UNSW. "Isolation and characterisation of intact RBL-2H3 mast cell granules ~ phosphorylation events during secretion". Awarded by:University of New South Wales. School of Medicine, 2005. http://handle.unsw.edu.au/1959.4/23445.

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Mediators released from the granules of antigen-activated mast cells contribute to allergies, inflammation and diseases such as asthma. One of the major models used to study mucosal mast cells is the RBL-2H3 mast cell line. While there has been considerable research on the initial signalling events following IgE receptor (Fc??RI) cross-linking, the movement of granules to sites of exocytosis is poorly understood. Understanding the mechanisms that control granule movement to and fusion with the plasma membrane could provide novel targets for improved asthma and allergy therapeutics. To this end, an isolated intact population of granules from the RBL-2H3 mast cell provides a powerful research tool and as such the primary aim of this work was to isolate intact granules from the RBL-2H3 mast cell. Using iso-osmotic Percoll gradients we have isolated an intact granule population from RBL-2H3 mast cells. This granule population contained three granule markers: ??- hexosaminidase, serotonin and chymase. Triton X-100 pre-lysis resulted in loss of granule markers from this main peak, indicating that the isolated granules are in fact intact. Further analysis of the granule population showed that it is free from bulk contamination with other organelles and plasma membrane. The granules were estimated to have a density of 1.055 ??? 1.092g/mL, significantly less dense than that of rat peritoneal mast cell granules (1.2g/mL; [1]). Using an intact versus lysed approach, granule-associated proteins and phosphoproteins, from unactivated RBL-2H3 cells, were determined. Nine unknown granule-associated proteins were found using silver staining of gradient fractions separated on a SDSPAGE gel. In addition, four unknown serine or threonine granule-associated phosphoproteins were found. Molecular weight comparison suggested overlap in some of the unknown proteins and phosphoproteins. Probing for protein kinase C (PKC) isoforms confirmed previous results suggesting that a small population of PKC?? localised to the granules [2], and extended these results to include a population of PKC??I. The serine/threonine phosphatase PP1 does not appear to be granule associated. However, there was a small loss of PP2A from the granules (upon lysis), suggesting that perhaps a subpopulation of PP2A is granule-associated. The main granule peak represents a secretion competent population as Fc??RI-mediated activation of the cells resulted in a significant loss of granule markers from this peak. At the peak rate of antigen-induced secretion a number of changes occur in the phosphorylation of granule-associated phosphoproteins. In addition to an increase in the phosphorylation of three of the phosphoproteins seen in resting mast cell granules, eight new proteins were seen. Whether these proteins are granule-associated is currently unknown. PKC?? was found to translocate away from the granules at the peak rate of secretion, perhaps representing an important control mechanism in granule exocytosis. None of the tested PKC isoforms were found to translocate to the granules, providing little clue as to the identity of the kinase that may be involved in these phosphorylation events. However, as PKC??I is granule-associated and does not translocate off the granules, it would suggest that this kinase might be important for some of the observed phosphorylations. Overall the studies in this thesis show for the first time a rapid gradient-based method for the isolation of intact granules from unactivated and activated RBL-2H3 mast cells. These granules were used to determine granule-associated proteins and phosphoproteins, as well as to investigate changes that occur during the secretory process. In addition, the results show that a number of proteins have increased serine/threonine phosphorylation at the peak rate of antigen-stimulated secretion. This implies that phosphorylation is likely to play a role in the control of granule exocytosis. The identity of these proteins deserves further investigation. Thus, isolated intact RBL- 2H3 mast cell granules provide a powerful research tool to further investigate the mechanism and control of granule exocytosis.

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Eskandari, Nahid. "Characterisation of phosphodiesterases in human lung mast cells and basophils". Thesis, University of Sheffield, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434577.

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Alfaiz, Faiz Abdulaziz. "Evaluation of the role of mast cells in parasitic infection". Thesis, University of Strathclyde, 2017. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=29560.

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Mast cells (MCs) are important for controlling both bacterial and parasitic infections, including those caused by helminths. However, their role in combatting these infections is unclear. MCs have been shown to be essential for the successful expulsion of Trichinella spiralis worms and play a role in mounting the immune response towards a T helper 2 type. Intestinal infection with parasitic worms is associated with mastocytosis and the activation and release of specific mediators and cytokines. In this case, MCs play an essential role in the successful expulsion of gastrointestinal worms via their release of mediators that serve the central function of protecting a host from these parasites. Specifically, the functions of MCs in the expulsion of T. spiralis were investigated using MC deficient c-kit mutant KitW/W-v(W/W-v) models. However, in addition to MC deficiency, these mice have a number of other abnormalities, including anaemia and a lack of interstitial cells of Cajal. Hence, there is a need to identify a model of MC deficiency that is not associated with other abnormalities that could affect the interpretation of results. The aim of the present study was to investigate the role of MCs in the immune response of mice to a parasitic infection of T. spiralis. Immune responses were explored in two recently developed strains of MC-deficient mice, the c-kit model C57BL/6-KitW-sh/W-sh (Wsh/Wsh) mice and an inducible mast cell-deficient model, Mas-TRECK, to determine the role of mast cells in protection against the parasite. These mice were infected with T. spiralis larvae, and the progression of the infection and the immune responses generated were examined via the enumeration of worms and the analysis of the associated intestinal pathology, cytokine production and antibody responses. The results obtained from mast cell deficient Wsh/Wsh mice with low-level infection resulted in a significant worm burden in these mice compared to wild-type mice that showed complete expulsion of the parasite. This suggests that the delay was potentially caused by dose dependent effect as a high dose did not show a significant delay in the expulsion of T. spiralis worms. In addition, the development of enteropathy and lengths of both villi and crypts were similar in both the lower and higher infection groups, in both wild-type and Wsh/Wsh mice. The immune responses were similar in wild-type and Wsh/Wsh mice as assessed by antigen-specific IgG1 levels, the total IgE levels and IL-4 levels. Moreover, Wsh/Wsh mice in both levels of infection were able to induce a significant marked mastocytosis, but they did not have significantly lower levels of mMCP-1 compared to wild-type mice. The results obtained from Mas-TRECK mice models showed no statistically significant differences between these mice and wild-type mice in the expulsion of T. spiralis worms. The enteropathy in Mas-TRECK mice following infection with T.spiralis was not significantly improved. In addition, the infection of Mas-TRECK mice did not induce a change in IgG2a levels compared with BALB/c mice, and no significant differences were observed in IgE levels or IL-4 levels in Mas-TRECK mice, compared with wild-type. In addition, Mas-TRECK were able to induce mastocytosis and did not have significantly lower levels of mMCP-1 following infection with T. spiralis, although they are considered to be MC-deficient, which suggests that MMCs may not be completely depleted in these mice. Mast cell activation was assessed using IgE-dependent MC activation to evaluate the ability of helminth antigens to activate mast cells through an immunoglobulin independent mechanism. An in vitro culture of bone marrow-derived mast cells(BMMCs) and peritoneal mast cells (PCMCs) used. Although cultured human MCs require stem cell factor (SCF) for growth, the expansion and growth of mouse MCs from bone marrow progenitors in the absence of SCF can be maintained with IL-3. It was found that stimulated PCMCs with Trichinella spiralis antigen (T. Ag) alone could activate mast cells to release IL-4 in all strains of mice. Moreover, the activation of PCMCs could be observed in the presence and absence of IgE, andC57BL/6 mice showed the greatest response to the stimulation and activation of PCMCs. BMMCs stimulated with helminth antigens led to similar secretions of mediators to those observed in wild-type mice, and all four strains of mice tended to secrete similar levels of mMCP-1. Overall, the present study concludes that MCs are crucial for protection against and expulsion of T. spiralis. However, it is evident that Wsh/Wsh and Mas-TRECK MC deficient mice are not entirely deficient in mucosal MC. Further studies are required to evaluate the benefits of different MC-deficient strains of mice and, particularly, to determine whether other abnormalities could have potentially affected the results of the present study.

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Panop, Wilainam Parnpen Viriyavejakul. "Response of mast cells in skin biopsy of falciparum malaria /". Abstract, 2003. http://mulinet3.li.mahidol.ac.th/thesis/2546/46E-Panop-W.pdf.

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Farrington, Jasmine. "Calcium release activated calcium channels in human lung mast cells". Thesis, University of Sheffield, 2014. http://etheses.whiterose.ac.uk/6609/.

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Taruselli, Marcela. "Fluvastatin and microRNA-146a alter interleukin-33 mediated mast cell functions". VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5859.

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Mast cells are tissue-resident immune cells known as effector cells for the innate and adaptive immune systems. Mast cells contribute to host defenses against parasites such as large roundworm parasites, bacterial pathogens, and toxins, and participate in wound healing, but they are mostly known for their role in allergic diseases. It has been well established that during allergic diseases, mast cells are stimulated by IgE cross-linkage to release proinflammatory mediators. However, a newly discovered cytokine, IL-33 has also been implicated in allergic disease. Recently, IL-33 has been implicated as a driver of several Type I sensitivities and previous studies have shown that IL-33 can stimulate mast cells in atopic inflammation. Although the importance of IL-33 has been established, there are still several things unknown about IL-33 signaling regulation or treatment. This dissertation will present two separate studies involving the modulation of IL-33-mediated mast cells function In the first study, the effects of fluvastatin are explored. In a previous study, fluvastatin was shown to inhibit proinflammatory functions of IgE crosslinked mast cells. Contrasting to IgE stimulation, fluvastatin augments IL-6 and TNF production in IL-33 stimulated mast cells, but suppressed MCP-1. This phenomenon was seen in mouse and human mast cells in vitro and replicated in a mast cell-dependent murine model of IL-33-induced inflammation in vivo. In the second study, IL-33 was found to induce miR-146a expression in mouse mast cells and mast cell-derived exosomes in vitro, and in plasma exosomes in vivo. IL-33 induced miR-146a was of interest because miR-146a is a known negative regulator of TLR signaling, which shares the MyD88 signaling pathway with IL-33. We found that miR-146a KO mast cells are hyperresponsive to IL-33 stimulation, data that were replicated by suppressing miR-146a-5p in WT mast cells. In an acute mast cell repopulation model, kitW-sh/W-sh mice containing miR-146a KO BMMC had increased IL-33 induced neutrophilia in comparison to their controls. Collectively, these data reveal new IL-33 signaling pathways and means of altering its inflammatory effects on mast cells. Because IL-33 has important roles in allergy and other Th2-mediated diseases, these results advance clinically relevant areas of immunology.

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Sime, Wondossen. "The diverse role of laminin isoforms in neuronal cells, human mast cells and blood platelets /". Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-122-7/.

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Kitawaki, Toshio. "IgE-activated mast cells in combination with pro-inflammatory factors induce Th2-promoting dendritic cells". Kyoto University, 2007. http://hdl.handle.net/2433/135901.

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Sundström, Magnus. "Signal Transduction in Mast Cell Migration". Doctoral thesis, Uppsala University, Department of Genetics and Pathology, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-1474.

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Mast cells are essential effector cells in the immune system as they release several inflammatory mediators. An accumulation of mast cells has been described in inflammatory conditions such as asthma and allergic rhinitis. Increased mast cell number, in the skin and other organs, is also a characteristic in mastocytosis, a disease without an effective treatment. One explanation for the increase in mast cell number is migration of mast cells in the tissue. In our studies we utilised mast cell lines, including HMC-1; cell lines transfected with the c-kit gene; and in vitro developed mast cells.

Our aim was to characterise, two variants of the HMC-1 cell line; the signalling pathways essential for mast cell migration towards TGF-β and SCF; and the mechanism regulating mast cell accumulation in mastocytosis.

Our results help to explain inconsistent findings regarding mast cell biology when HMC-1 cells have been used as a model system. The two variants, which we name HMC-1⁵⁶⁰ and HMC-1^{560, 816}, are used in different laboratories around the world. HMC-1⁵⁶⁰ and HMC-1^{560, 816} exhibited different characteristics regarding their karyotype, phenotype as well as their set of activating point mutations in the Kit receptor. Furthermore, divergent signalling pathways are of importance for mast cell migration towards TGF-β and SCF. The classical MAP kinase-signalling cascade was found to be of major relevance for TGF-β-induced migration. In contrast, this pathway had a modest impact on SCF-induced migration, which instead was highly dependent on p38 MAP kinase signalling. Finally, one mechanism for mast cell accumulation in mastocytosis appeared to be an activating point mutation in the gene for the Kit receptor. This mutation appeared to prone transfected cells and mast cell progenitors to a higher rate of migration towards SCF if compared with cells expressing wt Kit receptor.

In conclusion, our results show the importance of two different MAP kinase signalling pathways and mutations in the Kit receptor for mast cell migration induced by various types of stimuli. This knowledge helps us to understand the mechanism

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