The role of Rab27A in human eosinophil exocytosis (38.3)

Abstract

Abstract Eosinophils play an effector role in airway damage in asthma and related disorders, since their secreted granule-stored products can induce many of the clinical features of asthma. Degranulation of eosinophils requires the activity of several GTP-binding proteins, many of which remain unidentified. We hypothesized that Rab27A is one of these GTP-binding proteins because, in other cells, it interacts with effectors that regulate vesicle motility, docking and fusion. Humans with Rab27A-deficiency develop Griscelli syndrome which is characterized by immunodeficiency and partial albinism due to secretory defects in various cell types. We have established that Rab27A is expressed in human peripheral blood eosinophils as determined by RT-PCR and Western blotting. To asses Rab27A activation we developed a novel assay allowing the pulldown of the active, GTP-bound form. Rab27A was activated in several leukocyte populations upon cell stimulation with degranulatory stimuli. In human eosinophils, Rab27A was transiently activated by secretory-IgA stimulation. Rab27A activation followed a temporal pattern similar to that of degranulation, suggesting that Rab27A activation induces secretory granule movement and exocytosis. A clearer understanding of granulocyte exocytosis may contribute to novel therapeutic strategies in asthma, allergic inflammation and related conditions. Funding provided by the Canadian Institutes of Health Research and the Alberta Heritage Foundation for Medical Research