Invited Symposium: Novel Cellular and Molecular Mechanisms in Allergic Inflammation
Allergic disease is characterised by a relatively selective accumulation of eosinophils and mononuclear cells without a marked increase in neutrophils. The molecular basis for this pattern of cell migration, at least in terms of eosinophils, is becoming understood. What has emerged is a complex picture with each step in the migration process involving a degree of selective pressure on eosinophil as oppose to neutrophil accumulation. Migration out of the bone marrow, at least in guinea pigs, involves IL-5 and eotaxin which can both stimulate egress of mature eosinophils, but are inactive on neutrophils. The tethering step of eosinophil adhesion to venular endothelium is largely mediated by PSGL-1/P-selectin with support from VLA-4/VCAM-1. Endothelial P-selectin expression is selectively induced by IL-4 and both histamine and LTC4 can recruit P-selectin from intracellular stores. Eosinophils bind to P-selectin with greater avidity than neutrophils and eosinophils, but not neutrophils can bind to IL-4 and IL13 stimulated HUVEC under flow conditions via both PSGL-1 and VLA-4 . The activation step that mediates CD18 integrin engagement is still unclear. Current evidence suggests that CCR3 binding chemokines play a minor role. Indeed there is limited evidence, unlike neutrophils, that any of the known chemoattractants mediate this step. The firm arrest/transmigration step is mediated by a combination of CD18 integrins and VLA-4/VCAM-1. It is likely that PECAM-1 and MMP-9 are required for progression through the basement membrane and that chemoattractants including CC chemokines control migration into tissue. Finally growth factors such as IL-5 delay apoptosis. It is the combined effects of each of these stages that lead to a tissue eosinophilia rather than any single event. It is however possible that each molecular event is required for successful migration so that blockade of any of them will effectively reduce eosinophil migration into tissue.
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|Wardlaw, AJ; (1998). Molecular Basis of Leucocyte Migration In Allergic Disease. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/denburg/wardlaw0479/index.html|
|© 1998 Author(s) Hold Copyright|