{"doi":"10.1111/cea.14610","title":"Anaphylaxis: Spotlight on Inflammation","abstract":"Anaphylaxis is a medical condition for which several definitions have been proposed (Table 1 is available in the repository information at https://osf.io/sc2ey/?view_only=f66e841be31b42418eecf639caa0b24d). Charles Richet and Paul Portier coined the term ‘anaphylaxis’ in 1902. If discovered earlier, it might have invigorated the ongoing scientific debate in the late 19th century between Rudolf Virchow and Iliá Méchnikov on the detrimental versus beneficial nature of inflammation [1]. While inflammation typically serves as a response to tissue damage or infection, to restore homeostasis, anaphylaxis is a classic example of an immunopathological reaction in which an exaggerated and inappropriate response can lead, although rarely, to potentially fatal outcomes. Precisely, the role of inflammation has been underlined as central in several atopic diseases, but, surprisingly, not in anaphylaxis. The most common triggers of anaphylaxis are foods, insect stings and medications, but the aetiology may be unknown in some cases (idiopathic). This reaction is a multisystem condition that may involve different findings from the skin/mucosal, respiratory, cardiovascular and/or gastrointestinal systems. However, patients may rarely present isolated respiratory or cardiovascular involvement, and skin/mucosal participation may be absent. In addition, anxiety about the possibility of a new episode of anaphylaxis significantly impairs the quality of life of patients and their relatives, restricting daily activities and increasing the state of constant alertness [2]. The foundations of acute anaphylaxis management are removing the trigger, proper patient positioning, immediate administration of adrenaline and repeat adrenaline injections if severe clinical manifestations do not resolve. Moreover, this treatment can be supplemented with the use of second-line medications (e.g., β2-adrenergic agonists), as well as with the administration of supportive treatments (e.g., oxygen) [2, 3]. Most patients treated with adrenaline experience prompt resolution of symptoms and signs. However, a minority of patients may require three or more doses of adrenaline (refractory anaphylaxis) or have recurrence after an asymptomatic period (biphasic anaphylaxis) [4, 5]. Different signalling pathways can mediate anaphylaxis (Figure 1). Among them, the classical one is mediated by immunoglobulin (Ig)E. In sensitised individuals, secreted IgE binds to its high-affinity receptor (FcεRI) on effector cells (mainly mast cells and basophils), which store preformed pro-inflammatory granules. Then, allergen binding by cell-bound IgE triggers effector cell activation, leading to the immediate release of potent pro-inflammatory mediators, such as histamine, tryptase, platelet-activating factor (PAF), prostaglandins, leukotrienes and TNF-α, which are responsible for the rapid clinical manifestations of anaphylaxis [6]. However, in some cases, anaphylaxis occurs without detectable levels of specific IgE, suggesting the presence of alternative molecular pathways contributing to the inflammatory response of the reaction, such as IgG-mediated anaphylaxis. Although this pathway is well characterised in murine models [7], clinical evidence for its contribution to human anaphylaxis is limited and plausibly restricted to clinical settings involving systemic administration of drugs (e.g., protamine, dextran) because it seems to require a higher concentration of antigen compared to the classical pathway [8, 9]. Nevertheless, antigen-IgG binding to FcγR on myeloid cells (such as mast cells, basophils, neutrophils, monocytes and macrophages) can lead to their activation and the release of pro-inflammatory mediators. In addition, Ig-independent mechanisms can trigger anaphylaxis. For example, certain medications, such as neuromuscular blocking agents or contrast media, can directly induce the release of inflammatory mediators from mast cells by binding to the Mas-related G protein-coupled rece","journal":"Clinical & Experimental Allergy","year":2025,"id":530890,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9625,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":623159,"name":"Timothy E. Dribin","orcid":"0000-0002-7483-1750","position":1,"is_corresponding":false},{"id":1049717,"name":"Pablo Rodríguez del Río","orcid":"0000-0002-0783-1988","position":2,"is_corresponding":false},{"id":242827,"name":"Carlos A. Camargo","orcid":"0000-0002-5071-7654","position":3,"is_corresponding":false},{"id":1410836,"name":"Vanesa Esteban","orcid":"0000-0002-7500-6277","position":4,"is_corresponding":false},{"id":247760,"name":"George Du Toit","orcid":"0000-0002-0321-2928","position":5,"is_corresponding":false},{"id":881210,"name":"Rodrigo Jiménez‐Saiz","orcid":"0000-0002-0606-3251","position":6,"is_corresponding":false},{"id":1014674,"name":"Mattia Giovannini","orcid":"0000-0001-9568-6882","position":7,"is_corresponding":false},{"id":1410835,"name":"Emilio Nuñez‐Borque","orcid":"0000-0003-2928-410X","position":0,"is_corresponding":true}],"reference_count":8,"raw_metadata":null,"created_at":"2026-07-19T02:51:10.077559Z","pmid":"39777926","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}