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Title: Studies investigating peripheral blood derived cells that express the high affinity receptor for immunoglobulin E (FceRI) in allergic disorders
Author: Sihra, Bhupinder Singh
ISNI:       0000 0004 2672 2212
Awarding Body: University of Southampton
Current Institution: University of Southampton
Date of Award: 2008
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It is just forty years since the identification of immunoglobulin E (IgE) as the reagin responsible for allergen induced immediate hypersensitivity reactions. IgE exerts its biological actions through the binding of its Fc fragment to specific Fc receptors on effector cells. There are two predominant Fc receptors for IgE – FcεRI, which has a very high affinity for IgE and FcεRII, which shows less avid binding. For much of the first two decades after the identification of IgE, it was thought that FcεRI expression was limited to mast cells and basophils and that IgE binding to other cell types such as Blymphocytes and antigen presenting cells (APCs) was mainly due to FcεRII. However with major advances in characterisation and functional knowledge of FcεRI, particularly in the last fifteen years, it has become apparent that FcεRI can be expressed on several more cell types that may be involved in initiation and maintenance of allergic inflammation – including APCs (monocytes and dendritic cells) and possibly eosinophils. The research described in the four papers forming this thesis was completed during this period and evaluated FcεRI expression on different cell types, their potential roles in allergen induced inflammatory responses and whether successful therapeutic strategies for allergic disorders may involve actions on FcεRI+ cells. The relative expression of FcεRI on peripheral blood basophils, monocytes and eosinophils from atopic and non-atopic subjects and any relationship with serum IgE concentrations was assessed in the first paper. The second study examined a potentially important role for basophils as a cellular source of rapidly releasable IL-4 which may help initiate allergen induced TH2 responses. The next study investigated the possible effects on allergen induced early and late asthmatic responses of the immunosuppressive drug cyclosporin A which had been shown both to inhibit mast cell and basophil degranulation and cytokine secretion (particularly by CD4+ T-cells). The final study evaluated FcεRI expression on these cell types as well humoral factors (e.g. seasonal changes in allergen specific IgG and IgE) in subjects who, after 3 to 4 years of grass pollen immunotherapy, had continued on either active or placebo immunotherapy for a further 3 years. A historical perspective explaining some of the reasons the studies were done is provided in the introductory chapter whilst the discussion chapter at the end reviews how many of the findings of the study have evolved in subsequent years right up to the present day and finishes off with a brief synopsis of how rapidly increasing knowledge of the regulatory functions of dendritic cells (expressing FcεRI and often monocyte derived) has resulted in better understanding of the mechanisms of allergen specific immunotherapy and is leading to more effective treatment modalities.
Supervisor: Roberts, Graham Sponsor: Department of Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College School of Medicine, London, UK
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QR180 Immunology ; RM Therapeutics. Pharmacology