Allergy 1998: 53: 15-21 Printed zyxwvutsrqponml in UK zyxwvutsrqponm - zyxwvutsrq all rights reserved Copyright zyxw 0 Munksgaard 1998 ISSN 0105-4538 zyx ALLERGY Molecular concepts of IgE-initiated inflammation in atopic and nonatopic asthma Menz G, Ying S, Durham SR, Comgan CJ, Robinson DS, Hamid Q, F’fister R, Humbert M, Kav AB. Molecular concepts of IgE-initiated zyxw G. Menz’, S. Ying’, S. R. Durham‘, C. J. Corrigan’, D. S. Robinson‘, inflammation in atopic and nonatopic asthma. Allergy 1998: 53: 15-21. 0 Munksgaard 1998. * The identification of reaginic antibody as IgE was one of the most important discoveries in the field of immunology. It opened the door to the appli- cation of molecular biologic and immunopatho- logic techniques to the study of allergic tissue reactions. However, even to this day, it is still unclear as to how much of the asthma process is IgE-mediated - as opposed to pathways which are dependent largely on cell-mediated hypersensitivity re act ions. In addition to immediate-type (type I) hypersen- sitivity reactions, asthmatics undergoing inhala- tional challenge with specific allergen frequently develop an additional delayed-in-time late-phase reaction (LPR) (1). The LPR has been used exten- sively as a model of chronic allergic inflammation, especially as mucosal inflammation is recognized as an integral feature of ongoing perennial atopic diseases such as asthma and allergic rhinitis. There has been considerable debate as to whether the LPR is dependent on IgE-mediated release of mast-cell-derived mediators zyxwvut (2), or whether it is a form of cell-mediated hypersensitivity, or both. Biopsies of allergen-induced LPR elicited in the skin of atopic subjects revealed a strong inflamma- tory component, with eosinophils and CD4’ T cells being prominent (3). Allergen-induced late-phase responses in several organs and tissues, including the bronchi and nose as well as the skin, all had Q. Hamid3,R. Pfister’, M. H~mbe&~, A. B. Kaf ‘Hochgebirgsklinik Davos-Wolfgang, Switzerland; *Department of Allergy and Clinical Immunology, National Heart and Lung Institute, Imperial College School of Medicine, London, UK; 3Meakins-Christie Laboratories, McGill University, Montreal, Canada; 4H6pital Antoine Beclere, Clamart, France Key words: asthma; atopy; cytokines. Professor A. B. Kay Allergy and Clinical Immunology National Heart and Lung Institute Imperial College School of Medicine Dovehouse Street London SW3 6LY UK the appearance of an “eosinophilic cell-mediated hypersensitivity” response with a preponderance of cells mRNA* for Th2-type cytokines (4-6). These features have also been observed in biopsies from on-going chronic allergic asthma (7-10) as well as atopic dermatitis. The mechanisms by which eosinophils accumu- late in allergic tissue reactions can be summarized briefly as follows. Terminal differentiation of the eosinophil precursor and mobilization of mature eosinophils from the bone marrow (11) are largely under the control of interleukin (1L)-5. IL-5, together with GM-CSF and IL-3, promotes hyper- adherence of eosinophils to vascular endothelium (12). The C-C chemokines, e.g., eotaxin, RANTES, MCP-3, and MCP-4 (13, 14), promote selective directional migration of eosinophils across the ves- sel wall. IL-5, GM-CSF, and IL-3 also contribute to local eosinophil accumulation by acting as sur- vival factors (whereby programmed cell death, or apoptosis, is delayed [15]). Eosinophils produce tissue damage, particularly at mucosal surfaces, through the release of basic proteins and lipid mediators (16). Atopic (or “allergic”) asthma In immunologic terms, the allergic asthma process can be considered a combination of Gel1 and 15