New Aspects of Mast Cell Progenitors in Health and Disease

Abstract: 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.