New aspects of tissue mast cells in inflammatory airway diseases

Abstract: Mast cell are found throughout the body, but are especially prominent in tissues that have direct contact with the external milieu such as the skin, gastrointestinal tract and lungs. Mast cells are commonly recognized for their detrimental role in allergic reactions and can, upon activation through the high-affinity receptor for IgE (FcεRI), rapidly produce and secrete many of the mediators responsible for the typical symptoms in urticaria, asthma and rhinitis. However, increasing amount of data show that mast cells have important, even vital, roles in host defence against bacteria, viruses, parasites and venoms. Mast cells exist as two different subtypes, MCT (mucosal mast cells) and MCTC (connective tissue mast cells). These two subtypes differ in their molecular expression and distribution in the body. MCT are for example the dominating subtype in the lungs, while MCTC are most common in the skin and the gastrointestinal tract. Since mast cells (unlike the majority of other immune cells) only mature inside the tissue, their final phenotype is highly dependent on the local tissue milieu. This gives rise to a pronounced heterogeneity within the populations. The mast cell populations differ between human and rodents. In this thesis mast cells were, henceforth, studied in human tissue from patients suffering from allergic and non-allergic inflammatory airway diseases. A variety of histological methods are used to study the balance between MCT and MCTC, mast cell morphology and mediator and receptor expression patterns in different lung compartments. Under healthy baseline conditions, mast cells were abundant at all airway levels with a gradually increasing numbers towards the alveolar parenchyma. The MCT and MCTC populations could be further divided into site-specific subpopulations with regard to expression of mediators and morphology. A main finding was that the alveolar mast cell population had low expression of FcεRI in the healthy human lung. In COPD, CF and IPF, a significant increase in the proportion and density of MCTC with increased expression of CD88, IL-6 and TGF-β were found. Several mast cell alterations correlated to patient lung function and to the degree of remodelling compared to healthy controls. Mast cell numbers did not differ in healthy controls, patients with mild asthma or rhinitis with or without bronchial hyperreactivity. In patients with uncontrolled asthma despite treatment with inhaled corticosteroids, an increase of MCTC was found in the bronchi and alveolar parenchyma. In mild and uncontrolled asthma a significant increase of the expression of FcεRI was found in the alveolar parenchyma In conclusion, the prevailing MCT and MCTC populations could be further divided into site-specific subpopulations dependent on the local microenvironment already at healthy conditions. Mast cell alterations are present in patients with COPD, CF and IPF, diseases characterised by increases in the density of MCTC with increased expression of pro-inflammatory and pro-fibrotic molecules. Uncontrolled atopic asthma patients have expanded MCT and MCTC populations in the alveolar parenchyma. The increase in alveolar mast cell expression of FcεRI might be specific to atopic asthma since we could detect similar changes in mild asthma, but not in patients with allergic rhinitis, CF and COPD.