Mast Cell Migration in Inflammatory Diseases

Abstract: 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 TH1- and TH2-cytokines) and to recombinant cytokines (transforming growth factor -? (TGF-?) 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-?. We also show that MC chemotactic activity during pollen season is significantly increased compared to before pollen season. Furthermore, we demonstrate that TGF-? isoforms, CCL5, TNF-? and IL-4 act as MC chemoattractants in a bellshaped dose- dependent manner. TGF-? proved to be an extremely potent attractant giving an optimal migratory response at 40fM and TGF-?3 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-? produced by TH1-lymphocytes and IL-4 produced by TH2-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.