Beyond IgE—When Do IgE-Crosslinking and Effector Cell Activation Lead to Clinical Anaphylaxis?

Abstract

Anaphylaxis in humans is inherently difficult to study due to the acuteness of symptoms and the lack of biomarkers serving as risk predictors. Most cases are related to IgE sensitizations to foods, insect venoms, and drugs with mastocytosis patients forming a smaller risk group. However, identifying the relatively small fraction of persons at risk has been exceedingly difficult. In this review, we propose to describe anaphylaxis in a broader context than defined by IgE sensitization alone. Exposure to a trigger, such as an allergen, may lead to anaphylaxis, but in particular, the internal dose sensed by the immune system needs to be established. Moreover, intrinsic patient factors as well as the specific circumstances of the exposure, i.e., the extrinsic factors, need to be thoroughly accounted for. More controversially, other triggers of anaphylaxis, such as increased sensitivity to or reduced catabolism of histamine (“histamine intolerance”) or mast cell activation syndrome also named mast cell activation disorder have been suggested, but still with very limited epidemiological evidence that a significant proportion of the observed reactions are caused by these alleged conditions. Thus, when all conditions are considered, it seems as if IgE-mediated reactions are responsible for the vast majority of anaphylactic conditions.

The TNF-like weak inducer of the apoptosis/fibroblast growth factor–inducible molecule 14 axis mediates histamine and platelet-activating factor–induced subcutaneous vascular leakage and anaphylactic shock

“…[4][5][6] The action of released mediators produces changes in homeostasis, pulmonary vasodilation, vascular permeability, and altered contractile function in the main organs involved in anaphylaxis, causing respiratory and cardiovascular anomalies that can lead to life-threating episodes. 7,8 One of the most relevant downstream immune effects observed is endothelial layer breakdown. Growing evidence points to the endothelium as a key player in anaphylactic reactions because this active layer is highly involved in maintaining the vascular barrier and controlling homeostatic stability.…”

PGE2 deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness

“…This has led to the concept of cofactors or augmentation factors, which can be intrinsic or extrinsic in nature. 5 Intrinsic factors encompass older age, male sex, and concomitant mastocytosis, all of which facilitate an anaphylaxis episode or aggravate its outcome, 6 whereas exercise, psychological stress, and drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) (ie, COX inhibitors) are frequent extrinsic factors. 6 In fact, around 40% of severe anaphylactic reactions occur in the presence of extrinsic factors.…”

IgE-Mediated Peanut Allergy: Current and Novel Predictive Biomarkers for Clinical Phenotypes Using Multi-Omics Approaches

“…Those peptide structures might be novel candidates for serological assays, be it as antigens in immunoassays or as references for peptide identification in patient blood. In fact, upon ingestion, peanut allergens are degraded, followed by absorption across biological barriers and distribution via the bloodstream ( 20 , 60 , 104 – 106 ). The analysis of allergen residues in human samples after peanut ingestion has been recognized as an important challenge ( 60 , 61 ).…”

“…The organ involvement may relate to the skin and/or gastrointestinal tract, but also respiratory/ cardiovascular symptoms in the case of potentially lifethreatening anaphylaxis. Although most patients suffer from stereotypic symptoms, threshold doses depend on multiple factors under real-life conditions (atopic comorbidities; cofactors eg, exercise, alcohol, nonsteroidal anti-inflammatory drugs) (19)(20)(21). Disease prognosis and progression may also vary depending on the food allergy, such as in milk or egg allergy, which is commonly outgrown, compared to peanut allergy, which often persists lifelong (22).…”