Abstract
Allergies and asthma are a major cause of chronic disease whose prevalence has been on the rise. Allergic disease including seasonal rhinitis, atopic dermatitis, urticaria, anaphylaxis, and asthma, are associated with activation of tissue-resident mast cells and circulating basophils. Although these cells can be activated in different ways, allergic reactions are normally associated with the crosslinking of the high affinity Fc receptor for Immunoglobulin E, FcεRI, with multivalent antigen. Inflammatory mediators released from cytoplasmic granules, or biosynthesized de novo, following FcεRI crosslinking induce immediate hypersensitivity reactions, including life-threatening anaphylaxis, and contribute to prolonged inflammation leading to chronic diseases like asthma. Thus, inappropriate or unregulated activation of mast cells and basophils through antigenic crosslinking of FcεRI can have deleterious, sometimes deadly, consequences. Accordingly, FcεRI has emerged as a viable target for the development of biologics that act to inhibit or attenuate the activation of mast cells and basophils. At the forefront of these strategies are (1) Anti-IgE monoclonal antibody, namely omalizumab, which has the secondary effect of reducing FcεRI surface expression, (2) Designed Ankyrin Repeat Proteins (DARPins), which take advantage of the most common structural motifs in nature involved in protein-protein interactions, to inhibit FcεRI-IgE interactions, and (3) Fusion proteins to co-aggregate FcεRI with the inhibitory FcγRIIb. This review presents the published research studies that support omalizumab, DARPins, and fusion proteins as, arguably, the three most currently viable strategies for inhibiting the expression and activation of the high affinity FcεRI on mast cells and basophils.
Highlights
Gregorio Gomez*Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States Ulrich Blank, Institut National de la Santé et de la Recherche Médicale (INSERM), France Specialty section: This article was submitted to Molecular Innate Immunity, a section of the journal
Allergic disease refers to a variety of disorders that include seasonal allergies, atopic dermatitis, urticaria, life-threatening anaphylaxis reactions to food, and allergic asthma
This study demonstrated that FcγRIIb-mediated inhibition of degranulation requires direct ligation with FcεRI, and that Designed Ankyrin Repeat Proteins (DARPins), at least D11_E53, could safely be applied to animals to inhibit anaphylaxis
Summary
Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States Ulrich Blank, Institut National de la Santé et de la Recherche Médicale (INSERM), France Specialty section: This article was submitted to Molecular Innate Immunity, a section of the journal
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