Citation | Austen is renowned for his fundamental cellular and molecular characterisation of mast cells and their products, key components of allergic inflammation and asthma. After major early work on the complement system, his insightful and rigorous studies have elucidated biosynthesis of the cysteinyl leukotrienes (slow reacting substance of anaphylaxis/SRS-A) and the diversity of mast cell phenotypes. Austen's commitment to this field is validated by the efficacy in management of clinical asthma of the recently available leukotriene inhibitory drugs. He defined the local cellular inactivation of cysteinyl leukotrienes; the energy dependent carrier mediated export of LTC4, which gives rise to LTD4 and LTE4; the products and function when the initial substrate is fish oil eicosapentaenoic acid; and the logs greater potency of cysteinyl leukotrienes relative to histamine for the human airway. He cloned the CDNA for human LTC4 synthase, defined the residues R51 and Y93 as essential for the conjugation of LTA4 with reduced glutathione and characterised the gene at 5q35 distal to the gene cluster for the Th2 cytokines. Basal transcription of this TATA-less gene involved an initiator and a SP-1 site, with cell specificity through tandem motifs for Kruppel-like factors. Austen discovered that a single mast cell gene, designated serglycin, encloded the peptide core of secretory granule proteoglycan in T cell driven mast cells. He cloned eight different mouse secretory granule proteases, providing the probes that defined tissue specific mast cell phenotypes. He defined a new class of counter-regulatory receptors on mouse mast cells, and showed that co-ligation of gp49B1 to FceRI inhibited IgE mediated activitation through recruitment of SHP-1. The co-mitogenic activity of Th2 cytokines for human mast cells highlights the relationship of Th2 cells, submucosal eosinophils, and intraepithelial mast cells, a combination which dominates allergic and asthmatic inflammation. |