Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions

Abstract

Mast cells are primary effectors in allergic reactions, and may have significant roles in diseases by secreting histamine and various inflammatory and immunomodulatory substances1,2. While classically they are activated by IgE antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions1,3. Roles for these substances in pathology have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, MrgprB2, the orthologue of the human G-protein coupled receptor (GPCR) MrgprX2. Secretagogue-induced histamine release, inflammation, and airway contraction are abolished in MrgprB2 null mutant mice. Further, we show that most classes of FDA-approved peptidergic drugs associated with allergic-type injection-site reactions also activate MrgprB2 and MrgprX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that MrgprB2 and MrgprX2 are targets of many small molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice, and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MrgprX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

How do basic secretagogues activate mast cells?

“…McNeil did not discuss the possible physiological G-protein coupling of Mrgrb2 or MRGRX2. In addition, it was not explicitly reported by McNeil et al (2014) whether CADs exhibited stimulatory effects in non-transfected HEK293 cells.…”

“…The latter mechanism is also referred to as pseudo-allergy (Wang et al 2011). A recent letter published in Nature (McNeil et al 2014) rekindled the interest in the molecular mechanisms underlying pseudo-allergy.…”

“…The authors also report that the human ortholog of this receptor, MRGRX2, is activated by CADs. Based on these data, McNeil et al (2014) proposed that CADs mediate their pseudo-allergy-inducing effects via a mast cell-specific GPCR. Such a mechanism would open the door for the development of allergy-preventing antagonists, specifically in light of the fact that MRGRX2 is expressed only in mast cells but not peripheral white blood cells.…”

“…The concentrations of mastoparan used by McNeil et al (2014) to activate Mrgrb2 or MRGRX2 are in the same range as the concentrations typically used to activate Gproteins directly (Higashijima et al 1990), rendering discrimination of the two targets based on ligand-selectivity impossible. From the paper of McNeil et al (2014), it is not clear that all of the necessary control experiments with non-transfected cells, cells with just receptor, or G-protein alone and with complete concentration-response curves of CADs in control groups were performed to rule out receptor-independent Gprotein activation by CADs.…”

Evolving models of the immunopathogenesis of T cell–mediated drug allergy: The role of host, pathogens, and drug response

“…We now know that these reactions stem from specific off-target drug activity and include the immune-mediated ADRs (IM-ADRs) as well as off-target pharmacological drug effects such as that seen in non-IgE mediated mast cell activation syndrome (Figure 1). 11 IM-ADRs encompass a number of phenotypically distinct clinical diagnoses that comprise both B-cell (antibodymediated, Gell Coombs Types I-III) and purely T-cell mediated reactions (Gell-Coombs Type IV). The clinically relevant T-cell mediated drug reactions have been classified into delayed exanthema without systemic symptoms (maculopapular eruption or MPE), contact dermatitis, drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS)/hypersensitivity syndrome (HSS), Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), acute generalized exanthematous pustulosis (AGEP), fixed drug eruption, and single organ involvement pathologies such as drug-induced liver disease (DILI) and pancreatitis.…”