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Mast Cell Progenitor Trafficking in Allergic Airway Inflammation
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. , 41 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 932
Keyword [en]
Mast cells, mast cell progenitors, allergy, asthma, allergic airway inflammation, IgE, lung, CD11c
National Category
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-206608ISBN: 978-91-554-8741-6 (print)OAI: oai:DiVA.org:uu-206608DiVA: diva2:644732
Public defence
2013-10-17, C8:301, BMC, Husargatan 3, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2013-09-24 Created: 2013-09-02 Last updated: 2014-01-23
List of papers
1. IgE Immune Complexes Stimulate an Increase in Lung Mast Cell Progenitors in a Mouse Model of Allergic Airway Inflammation
Open this publication in new window or tab >>IgE Immune Complexes Stimulate an Increase in Lung Mast Cell Progenitors in a Mouse Model of Allergic Airway Inflammation
2011 (English)In: PLoS One, ISSN 1932-6203, Vol. 6, no 5, e20261- p.Article in journal (Refereed) Published
Abstract [en]

Mast cell numbers and allergen specific IgE are increased in the lungs of patients with allergic asthma and this can be reproduced in mouse models. The increased number of mast cells is likely due to recruitment of mast cell progenitors that mature in situ. We hypothesized that formation of IgE immune complexes in the lungs of sensitized mice increase the migration of mast cell progenitors to this organ. To study this, a model of allergic airway inflammation where mice were immunized with ovalbumin (OVA) in alum twice followed by three daily intranasal challenges of either OVA coupled to trinitrophenyl (TNP) alone or as immune complexes with IgE-anti-TNP, was used. Mast cell progenitors were quantified by a limiting dilution assay. IgE immune complex challenge of sensitized mice elicited three times more mast cell progenitors per lung than challenge with the same dose of antigen alone. This dose of antigen challenge alone did not increase the levels of mast cell progenitors compared to unchallenged mice. IgE immune complex challenge of sensitized mice also enhanced the frequency of mast cell progenitors per 10 6 mononuclear cells by 2.1-fold. The enhancement of lung mast cell progenitors by IgE immune complex challenge was lost in FcR gamma deficient mice but not in CD23 deficient mice. Our data show that IgE immune complex challenge enhances the number of mast cell progenitors in the lung through activation of an Fc receptor associated with the FcR gamma chain. This most likely takes place via activation of Fc epsilon RI, although activation via Fc gamma RIV or a combination of the two receptors cannot be excluded. IgE immune complex-mediated enhancement of lung MCp numbers is a new reason to target IgE in therapies against allergic asthma.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-154525 (URN)10.1371/journal.pone.0020261 (DOI)000290771200055 ()21625525 (PubMedID)
Available from: 2011-06-07 Created: 2011-06-07 Last updated: 2014-01-23Bibliographically approved
2. CD11c(+) Cells Are Required for Antigen-Induced Increase of Mast Cells in the Lung
Open this publication in new window or tab >>CD11c(+) Cells Are Required for Antigen-Induced Increase of Mast Cells in the Lung
Show others...
2012 (English)In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 189, no 8, 3869-3877 p.Article in journal (Refereed) Published
Abstract [en]

Patients with allergic asthma have more lung mast cells, which likely worsens the symptoms. In experimental asthma, CD11c(+) cells have to be present during the challenge phase for several features of allergic inflammation to occur. Whether CD11c(+) cells play a role for Ag-induced increases of lung mast cells is unknown. In this study, we used diphtheria toxin treatment of sensitized CD11c-diphtheria toxin receptor transgenic mice to deplete CD11c(+) cells. We demonstrate that recruitment of mast cell progenitors to the lung is substantially reduced when CD11c(+) cells are depleted during the challenge phase. This correlated with an impaired induction of endothelial VCAM-1 and led to a significantly reduced number of mature mast cells 1 wk after challenge. Collectively, these data suggest that Ag challenge stimulates CD11c(+) cells to produce cytokines and/or chemokines required for VCAM-1 upregulation on the lung endothelium, which in turn is crucial for the Ag-induced mast cell progenitor recruitment and the increase in mast cell numbers.

National Category
Immunology Immunology in the medical area
Research subject
Immunology
Identifiers
urn:nbn:se:uu:diva-184515 (URN)10.4049/jimmunol.1201200 (DOI)000309590900014 ()22972929 (PubMedID)
Funder
Swedish Research Council
Available from: 2012-11-07 Created: 2012-11-07 Last updated: 2017-12-07Bibliographically approved
3. Committed mast cell progenitors in mouse blood differ in maturity between Th1 and Th2 strains
Open this publication in new window or tab >>Committed mast cell progenitors in mouse blood differ in maturity between Th1 and Th2 strains
2013 (English)In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 68, no 10, 1333-1337 p.Article in journal (Refereed) Published
Abstract [en]

Mast cell progenitors (MCp) leave the bone marrow and migrate to peripheral tissues where they mature. Although the existence of committed MCp in adult mouse and human blood has been postulated, they have never been found. We have isolated a rare population of cells in adult mouse blood, committed to the mast cell lineage. These were identified as lineage c-kithi ST2+ integrin β7hi CD16/32hi cells. Moreover, a major difference in maturity of these cells based on FcεRI expression was observed between the Th2-prone BALB/c strain and the Th1-prone C57BL/6 strain (66% vs 25% FcεRI+, respectively). Therefore, the choice of mouse strain is critical when studying disease models such as experimental asthma where mast cells and their progenitors are involved.

National Category
Immunology Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-205507 (URN)10.1111/all.12223 (DOI)000326024300015 ()
Available from: 2013-09-02 Created: 2013-08-19 Last updated: 2017-12-06Bibliographically approved

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