Title:Recent Knowledge and Insights on the Mechanisms of Immediate Hypersensitivity
and Anaphylaxis: IgE/FcεRI- and Non-IgE/FcεRI-Dependent Anaphylaxis
Volume: 29
Issue: 3
Author(s): Didier G. Ebo*, Michiel Beyens, Kevin Heremans, Marie-Line M. van der Poorten, Athina L. Van Gasse, Christel Mertens, Michel Van Houdt, Vito Sabato and Jessy Elst
Affiliation:
- Department of Immunology, Allergology and Rheumatology and the Infla-Med Centre of Excellence, University Antwerp, Antwerp
University Hospital, Antwerpen, Belgium
- Department of Immunology and Allergology, AZ Jan Palfijn Gent, Ghent, Belgium
Keywords:
Anaphylaxis, mast cells, basophils, IgE, MRGPRX2, pathomechanisms.
Abstract: Immediate hypersensitivity reactions can pose a clinical and diagnostic challenge, mainly because of
the multifarious clinical presentation and distinct underlying - frequently uncertain - mechanisms. Anaphylaxis
encompasses all rapidly developing and life-threatening signs and may cause death. Evidence has accumulated
that immediate hypersensitivity and anaphylaxis do not necessarily involve an allergen-specific immune response
with cross-linking of specific IgE (sIgE) antibodies bound to their high-affinity IgE receptor (FcεRI) on
the surface of mast cells (MCs) and basophils. Immediate hypersensitivity and anaphylaxis can also result from
alternative specific and nonspecific MC and basophils activation and degranulation, such as complementderived
anaphylatoxins and off-target occupancy of MC and/or basophil surface receptors such as the Masrelated
G protein-coupled receptor X2 (MRGPRX2). Degranulation of MCs and basophils results in the release
of inflammatory mediators, which can be, depending on the underlying trigger, in a different spatiotemporal
manner. In addition, hypersensitivity and anaphylaxis can occur entirely independently of MC and basophil
degranulation, as observed in hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) that divert
normal arachidonic acid metabolism by inhibiting the cyclooxygenase (COX)-1 isoenzyme. Finally, one should
remember that anaphylaxis might be part of the phenotype of particular - sometimes poorly recognizable - conditions
such as clonal MC diseases (e.g. mastocytosis) and MC activation syndrome. This review provides a status
update on the molecular mechanisms involved in both sIgE/FcεRI- and non-sIgE/FcεRI-dependent immediate
hypersensitivity and anaphylaxis. In conclusion, there is increasing evidence for alternative pathophysiological
hypersensitivity and anaphylaxis endotypes that are phenotypically and biologically indistinguishable,
which are frequently difficult to diagnose, mainly because of uncertainties associated with diagnostic tests that
might not enable to unveil the underlying mechanism.
