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New Aspects of Mast Cell Progenitors in Health and Disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Mast cells are tissue-resident immune cells that are well known for their involvement in asthma and allergy. They originate in the fetal yolk sac, or in the bone marrow. From the bone marrow, they are released as immature progenitors that are transported via the blood circulation to the peripheral tissue, where they mature. Human mast cells accumulate at certain sites in the airways of individuals with asthma, and in a mouse model of allergic airway inflammation, an influx of mast cell progenitors (MCp) to the lung has been demonstrated. We quantified MCp frequency by flow cytometry to determine if there is a correlation between MCp frequency and reduced lung function among allergic asthmatics and controls. We found that individuals with reduced lung function had an increased MCp frequency in the blood circulation. Additionally, women had a higher MCp frequency than men. 

In the second study, we identified a bone marrow counterpart to the human blood MCp. These two MCp populations had similar mast cell-related gene expression, morphology and proliferation capacity. However, the blood MCp expressed higher levels of the integrin β7 receptor, which in mice has been shown to be required for MCp transmigration into peripheral tissues. 

Mast cells can be activated by antigen crosslinking of IgE bound to FcεRI. Both human and mouse MCp express FcεRI, but it is unknown whether they can be activated via this receptor. In the third study, we demonstrated that human and mouse MCp can become activated in vitro via FcεRI by measuring tyrosine kinases phosphorylation by flow cytometry. Furthermore, we showed the activation in vivo by measuring IL-13 production in MCp in an allergic airway inflammation model.

In the final study, we investigated the chemokine receptor expression on mouse MCp. We found that MCp in the peritoneal cavity express CCR5 whereas bone marrow MCp express CCR1. 

To summarize, my thesis has provided novel insights into the significance of circulating human MCp, and reveled an MCp population in human bone marrow. Moreover, the data presented suggest that MCp can be activated and that their chemokine receptor expression depends on tissue localization. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 46
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1559
Keywords [en]
Mast cells, Mast cell progenitor, Lung function, Bone marrow, Blood, Activation, Chemotactic receptors
National Category
Immunology
Identifiers
URN: urn:nbn:se:uu:diva-379255ISBN: 978-91-513-0615-5 (print)OAI: oai:DiVA.org:uu-379255DiVA, id: diva2:1299405
Public defence
2019-05-16, C4:305, Husargatan 3, BMC, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2019-04-24 Created: 2019-03-26 Last updated: 2019-06-18
List of papers
1. Circulating mast cell progenitors correlate with reduced lung function in allergic asthma
Open this publication in new window or tab >>Circulating mast cell progenitors correlate with reduced lung function in allergic asthma
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2019 (English)In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 49, no 6, p. 874-882Article in journal (Refereed) Published
Abstract [en]

Background

Studies using mouse models have revealed that mast cell progenitors are recruited from the blood circulation to the lung during acute allergic airway inflammation. The discovery of a corresponding human mast cell progenitor population in the blood has enabled to study the relation of circulating mast cell progenitors in clinical settings.

Objectives

To explore the possible association between the frequency of mast cell progenitors in the blood circulation and allergic asthma, we assessed the relation of this recently identified cell population with asthma outcomes and inflammatory mediators in allergic asthmatic patients and controls.

Methods

Blood samples were obtained, and spirometry was performed on 38 well‐controlled allergic asthmatic patients and 29 controls. The frequency of blood mast cell progenitors, total serum IgE and 180 inflammation‐ and immune‐related plasma proteins were quantified.

Results

Allergic asthmatic patients and controls had a similar mean frequency of blood mast cell progenitors, but the frequency was higher in allergic asthmatic patients with reduced FEV1 and PEF (% of predicted) as well as in women. The level of fibroblast growth factor 21 (FGF‐21) correlated positively with the frequency of mast cell progenitors, independent of age and gender, and negatively with lung function. The expression of FcεRI on mast cell progenitors was higher in allergic asthmatic patients and correlated positively with the level of total IgE in the controls but not in the asthmatic patients.

Conclusion

Elevated levels of circulating mast cell progenitors are related to reduced lung function, female gender and high levels of FGF‐21 in young adults with allergic asthma.

Keywords
allergic asthma, asthma, lung function, mast cell progenitors, mast cells
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-379233 (URN)10.1111/cea.13388 (DOI)000475694600015 ()30892731 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20150379Swedish Asthma and Allergy Association, F2016-0045VinnovaSwedish Research Council, 2014-03293Swedish Research Council, 2016-00803Swedish Foundation for Strategic Research , RB13-0196Swedish Heart Lung Foundation, 20160618
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-09-20Bibliographically approved
2. Demonstration of human mast cell progenitors in the bone marrow
Open this publication in new window or tab >>Demonstration of human mast cell progenitors in the bone marrow
(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-379232 (URN)
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-03-26
3. Mast cell progenitors can be activated by IgE crosslinking
Open this publication in new window or tab >>Mast cell progenitors can be activated by IgE crosslinking
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-379231 (URN)
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-03-26
4. Differential expression of CCR1 and CCR5 on murine mast cell progenitors depending on tissue localization
Open this publication in new window or tab >>Differential expression of CCR1 and CCR5 on murine mast cell progenitors depending on tissue localization
(English)Manuscript (preprint) (Other academic)
National Category
Immunology
Identifiers
urn:nbn:se:uu:diva-379230 (URN)
Available from: 2019-03-26 Created: 2019-03-26 Last updated: 2019-03-26

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