Chapter 3 New Insights on Mast Cell Activation via the High Affinity Receptor for IgE

Abstract

Mast cells are innate immune cells that function as regulatory or effector cells and serve to amplify adaptive immunity. These cells also function in adaptive immunity primarily through cell surface Fc receptors that bind immunoglobulin antibodies. The dysregulation of their adaptive role makes them central players in allergy and asthma. Upon encountering an allergen (antigen), which is recognized by immunoglobulin E (IgE) antibodies bound to the high affinity IgE receptor (FcεRI) expressed on their cell surface, mast cells secrete both preformed and newly synthesized mediators of the allergic response. Blocking of these responses is an objective in therapeutic intervention of allergic diseases. Thus, understanding the mechanisms by which antigens elicit mast cell activation (via FcεRI) holds promise towards identifying therapeutic targets. Here we review the most recent advances in understanding antigen-dependent mast cell activation. Specifically, we focus on the requirements for FcεRI activation; the regulation of calcium responses; co-stimulatory signals in FcεRI-mediated mast cell activation and function; and how genetics influences mast cell signaling and responses. These recent discoveries open new avenues of investigation with therapeutic potential.

Proteolytic Histone Modification by Mast Cell Tryptase, a Serglycin Proteoglycan-dependent Secretory Granule Protease

“…The general notion is that the preformed compounds present in immune cell granules predominantly carry out pro-inflammatory functions after their exocytosis in the context of various pathological situations, in particular during allergic conditions (1,7,8). However, we have recently shown that secretory granules and their contained serglycin-bound proteases in addition can influence cell death.…”

STIM1-Directed Reorganization of Microtubules in Activated Mast Cells

“…It is well established that an increase in [Ca 2+ ] i is a prerequisite for mast cell degranulation (1). To confirm the functional relevance of STIM1 KD, we determined the degree of degranulation by measuring the release of b-glucuronidase in cells activated by FcεRI aggregation or by thapsigargin.…”

“…After membrane anchoring and activation, phospholipase Cg produces inositol 1,4,5,-triphosphate that binds to its receptors in the endoplasmic reticulum (ER). This results in Ca 2+ efflux from the ER (1). Subsequently, depletion of Ca 2+ from ER lumen induces Ca 2+ influx across the plasma membrane through store-operated Ca 2+ channels (SOCs).…”

Mast cells form antibody-dependent degranulatory synapse for dedicated secretion and defence

“…Unlike FceRI, FcgRIIA cannot bind to monomeric antibodies in the absence of antigen but it can bind to antibodies as multivalent immune complexes with high avidity. Those receptors belong to the immunoreceptor tyrosine-based activation motif (ITAM)-containing superfamily of immunoreceptors and are coupled to a signalling cascade involving src-kinases triggering, [Ca 2 þ ] i increase and actin cytoskeleton remodelling [26][27][28] . Mast cell degranulation is classically studied using soluble stimuli such as secretagogues or antigen/antibody-mediated FcR crosslinking.…”