Anaphylaxis: Mediators, Biomarkers, and Microenvironments

Abstract

The life-threating nature of the anaphylactic reactions promotes a growing interest to discover new biomarkers that could support their better diagnosis and prevention. However, both the clinical features and the etiopathology of anaphylaxis are very diverse, hindering the elucidation of valuable molecular indicators of disease. Most studies of anaphylaxis have focused on the immune system. Precisely, anaphylactic reactions are characterized primarily by IgE-mediated activation of mast cells and basophils and the release of several mediators. Among them, determinations of the serum tryptase levels is the main in vitro test used to confirm the reaction and there are no available biomarkers with predictive capacity for this pathological event. However, recent research has postulated that alternative pathways, cell types and systems are involved. Consequently, different molecular products have been explored and indicated as potential biomarkers, but none of them have been translated into the clinical practice yet. Precisely, vasoactive agents, proteases, proteoglycans, lipids, interleukins, cytokines, products of the complement-contact and coagulation systems, circulating proteins, extracellular vesicles, microRNAs and metabolites have been found to be altered in patients with anaphylaxis. The recognition of biological processes and molecular pathways interacting in the magnitude of the microenvironments switched on in anaphylaxis will notably nourish the clinical practice and the recognition of better molecular markers. Therefore, this article covers a broad review of the different mediators described in anaphylaxis and their proposal as biomarkers of this pathological event, as well as their role in the molecular basis of the reaction.

Novel mediator in anaphylaxis: decreased levels of miR-375-3p in serum and within extracellular vesicles of patients

“…However, other IgE-independent molecular processes and cells are involved in this pathological event ( 8 ). Overall, there is a release of mediators that gives rise to signs and symptoms of anaphylaxis ( 9 ). Among them, the cutaneous ones are the most frequent, although the respiratory and cardiovascular systems mark the development of the most severe cases ( 10 ).…”

Circulating serum profile of small non-coding RNAs in patients with anaphylaxis beyond microRNAs

“…The life-threatening nature of anaphylaxis fosters a growing interest in the improvement of its clinical management, as well as in the finding of new molecular markers that allows an accurate diagnosis of this pathological event. However, for this purpose, it is necessary to simultaneously increase the molecular knowledge underlying the clinical reaction ( 13 ). Precisely, circulating serum sncRNAs are emerging agents that have been described as non-invasive biomarkers and as messengers in the pathophysiology of different diseases ( 25 , 26 ).…”

“…Unfortunately, their molecular function has not been fully defined yet ( 40 , 41 ). Nevertheless, one study showed that YRFs regulate cell death and inflammation in monocytes/macrophages ( 42 ), which are relevant cells for the development of anaphylaxis, especially in non-IgE-mediated reactions ( 12 , 13 ). Therefore, the increase of YRFs could be related to a modulation of monocyte and macrophage activation in anaphylaxis.…”

“…Therefore, it has been suggested that there exists other signaling pathways independent or complementary to IgE participating in the reaction ( 8 , 12 ). Precisely, over time, more molecules and mediators involved in the underlying molecular mechanisms of anaphylaxis have been identified ( 13 ).…”

Extracellular vesicles and melanoma: New perspectives on tumor microenvironment and metastasis

“…There is plenty of evidence for the importance of extracellular vesicles in pathological states. From cancer interaction with the immune system ( Pelissier Vatter et al, 2021 ) to cancer resistance to therapy ( Palazzolo et al, 2022 ), from cardiovascular disease ( de Abreu et al, 2020 ) to anaphylaxis ( Fernández-Bravo et al, 2022 ), the EV role in pathogenesis and its potential use as biomarker have been well characterized, albeit there are still many questions to answer. However, EVs role in normal physiology or cellular and tissue homeostasis presents multiple pending questions.…”