Controlling Mast Cell Activation and Homeostasis: Work Influenced by Bill Paul That Continues Today

Abstract

Mast cells are tissue resident, innate immune cells with heterogenous phenotypes tuned by cytokines and other microenvironmental stimuli. Playing a protective role in parasitic, bacterial, and viral infections, mast cells are also known for their role in the pathogenesis of allergy, asthma, and autoimmune diseases. Here, we review factors controlling mast cell activation, with a focus on receptor signaling and potential therapies for allergic disease. Specifically, we will discuss our work with FcεRI and FγR signaling, IL-4, IL-10, and TGF-β1 treatment, and Stat5. We conclude with potential therapeutics for allergic disease. Much of these efforts have been influenced by the work of Bill Paul. With many mechanistic targets for mast cell activation and different classes of therapeutics being studied, there is reason to be hopeful for continued clinical progress in this area.

Keywords: IL-10; IL-4; IgE; IgG; Stat5; TGF-β; allergy; mast cell.

Figure 1

Receptors that regulate mast cell function. The receptors shown are confirmed to regulate mast cell function. They are depicted at approximate scale. All except FcγRIIb are known to induce mast cell degranulation and/or cytokine secretion. FcγRIIb activates SHIP-1 and SHP-1, suppressing inositol and tyrosine kinase activity. c-Kit is a weak mast cell activator, but augments signals by other receptors. IL-3 receptor is modeled after work by Broughton et al. (20). Note that ligands for Mas-related G protein-coupled receptor-X2 (MRGPRX2)/B2 are not fully known, but include drug classes discussed in the accompanying text. In addition, we do not show “cytokinergic” IgE molecules. These form aggregates in the absence of antigen and elicit FcεRI signaling.