Abstract
Basophils and eosinophils play important roles in various host defense mechanisms but also act as harmful effectors in allergic disorders. We generated novel basophil- and eosinophil-depletion mouse models by introducing the human diphtheria toxin (DT) receptor gene under the control of the mouse CD203c and the eosinophil peroxidase promoter, respectively, to study the critical roles of these cells in the immunological response. These mice exhibited selective depletion of the target cells upon DT administration. In the basophil-depletion model, DT administration attenuated a drop in body temperature in IgG-mediated systemic anaphylaxis in a dose-dependent manner and almost completely abolished the development of ear swelling in IgE-mediated chronic allergic inflammation (IgE-CAI), a typical skin swelling reaction with massive eosinophil infiltration. In contrast, in the eosinophil-depletion model, DT administration ameliorated the ear swelling in IgE-CAI whether DT was administered before, simultaneously, or after, antigen challenge, with significantly lower numbers of eosinophils infiltrating into the swelling site. These results confirm that basophils and eosinophils act as the initiator and the effector, respectively, in IgE-CAI. In addition, antibody array analysis suggested that eotaxin-2 is a principal chemokine that attracts proinflammatory cells, leading to chronic allergic inflammation. Thus, the two mouse models established in this study are potentially useful and powerful tools for studying the in vivo roles of basophils and eosinophils. The combination of basophil- and eosinophil-depletion mouse models provides a new approach to understanding the complicated mechanism of allergic inflammation in conditions such as atopic dermatitis and asthma.
Highlights
IgE, mast cells, basophils, and eosinophils are important elements in allergic inflammation
To develop a system in which basophil function could be studied in vivo, we used our toxin receptor-mediated conditional cell knockout (TRECK) method, a conditional ablation system mediated by the human diphtheria toxin (DT) receptor (hDTR) [29]
Because CD203c has been identified as a basophil activation marker [30,31] and because recent studies have revealed that the expression of CD203c on basophils is useful in the diagnosis of food allergies and asthma [31,32], the CD203c promoter was introduced in place of the alb promoter of the original TRECK cassette to facilitate the exclusive expression of hDTR on basophils (Fig. 1A)
Summary
IgE, mast cells, basophils, and eosinophils are important elements in allergic inflammation. Mast cells and basophils have long been considered primary effector cells in allergic disorders such as asthma, hay fever, and anaphylaxis. Allergen-specific IgE, synthesized in response to allergens in the environment, binds to FceRI on the surface of mast cells and basophils. Cross-linking of receptor-bound IgE molecules upon re-exposure to specific allergens results in the release of chemical mediators, such as histamine and leukotriene C4, that produce the allergic response [1,2,3,4,5]. The effector functions of eosinophils appear to be derived primarily from the release of lipid mediators and proteins, including cytokines and granule proteins. Eosinophil degranulation results in the release of several cytotoxic cationic granule proteins [6]. Cytotoxic eosinophils are harmful to foreign invaders within the body and can become detrimental to the host organs through an intricate immunological pathway [7]
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