Perivascular dendritic cells elicit anaphylaxis by relaying allergens to mast cells via microvesicles

Abstract

Anaphylactic reactions are triggered when allergens enter the blood circulation and activate IgE-sensitized mast cells (MCs) causing systemic discharge of prestored proinflammatory mediators. Since MCs are extravascular, how they perceive circulating allergens remains a conundrum. Here, we describe the existence of a CD301b+ perivascular dendritic cell (DC) subset that continuously samples blood and relays antigens to neighboring MCs, which vigorously degranulate and trigger anaphylaxis. DC antigen-transfer involves the active discharge of surface-associated antigens on 0.5-1.0-μm microvesicles (MVs) generated by vacuolar protein sorting 4 (VPS4). Antigen sharing by DCs is not limited to MCs, as neighboring DCs also acquire antigen-bearing MVs. This capacity of DCs to distribute antigens-bearing MVs to various immune cells in the perivascular space potentiates inflammatory and immune responses to blood-borne antigens.

Platelets trigger perivascular mast cell degranulation to cause inflammatory responses and tissue injury

“…To confirm that significant MC activation occurred following platelet activation, we examined collagen and epinephrine-treated mice for signs of shock, a classical manifestation of systemic MC activation. It is known that when mice are subjected to immunoglobulin E (IgE)-mediated MC activation, they experience anaphylaxis, which is indicated by a sharp drop in core body temperature (13). We observed that collagen and epinephrine-treated mice experienced a sharp drop in core body temperature, which was attributable to MC activation based on the high levels of chymase-a major prestored MC mediator (10)-detected in the plasma of these mice ( Fig.…”

“…Because the genetic elements of Mcpt5 drive tdTomato expression in MCs, red fluorescence is mostly cytoplasmic and does not readily denote degranulation. Therefore, to evaluate the actual degranulation of MCs, we stained MC granules by using avidin, which is routinely used for MC granule staining (8,13), and found that several of these MCs showed signs of degranulation ( Fig. 1F).…”

“…Mcpt5-cre + iDTR + mice were from A. Roers, University of Technology, Dresden (21). In these mice, MCs were conditionally depleted through intravenous injections of 200 ng of diphtheria toxin per mouse every other day for 2 weeks (13). Pla2 −/− (17) and Pafr −/− (18) mice were provided by Shimizu (University of Tokyo) through the RIKEN BioResource Research Center (RBRC01733 and RBRC05641) and were rederived by the Division of Laboratory Animal Resources, Duke University Medical Center.…”

A Shocking Type of Communication

“…In allergic patients, small amounts of allergen activate mast cells and trigger an immune cascade that can result in anaphylactic shock. In a recent issue of Science, Choi et al (2018) show that dendritic cells sample the lumen of blood vessels and use microvesicles to trigger mast cell degranulation and anaphylaxis.…”

“…Therefore, research that addresses the current gaps in understanding of how minor amounts of allergen can trigger IgE-mediated immune responses that result in anaphylactic shock has become imperative to develop effective novel treatment strategies for allergic patients. In a recent article in Science, Choi et al describe a novel form of innate immune communication that provides an explanation of how minor amounts of antigen in circulation efficiently induces massive mast cell degranulation (Choi et al, 2018).…”