CHILDHOOD ANAPHYLAXIS: NEW DEVELOPMENTS IN DIAGNOSIS AND TREATMENT

CHILDHOOD_ANAPHYLAXIS_NEW_DEVELOPMENTS _IN_DIAGNOSIS_AND_TREATMENT_kapak

IMMUNOLOGICAL AND NON-IMMUNOLOGICAL ANAPHYLAXIS

Tuba Karakurt

İstanbul Medeniyet University, Faculty of Medicine, Department of Pediatric Immunology and Allergic Diseases, İstanbul, Türkiye

Karakurt T. Immunological and Non-Immunological Anaphylaxis. In: Harmancı K, editor. Childhood Anaphylaxis: New Developments in Diagnosis and Treatment. 1st ed. Ankara: Türkiye Klinikleri; 2025. p.37-48.

ABSTRACT

Anaphylaxis is a severe, systemic, and potentially life-threatening hypersensitivity reaction that requires immediate recognition and treatment. Mast cells and/or basophils are key effector cells involved in the complex and interconnected mechanisms of anaphylactic reactions. Understanding their roles and examining their activation pathways is essential. Activation of these cells can occur through both immunological and non-immunological pathways. Immunological mechanisms include the classical Immunglobulin (Ig) E-mediated pathway and an IgG-mediated pathway, while non-immunological pathways involve direct mast cell activation through various receptors. At the core of immunologic anaphylaxis is the activation of mast cells and basophils, predominantly via antigen-specific IgE antibodies binding to high-affinity FceRI receptors. Cross-linking of these receptors by allergens initiates a cascade of intracellular signaling events, culminating in degranulation and the release of potent mediators such as histamine, tryptase, prostaglandins, and leukotrienes. These mediators modulate the classical clinical manifestations of anaphylaxis, including vasodilation, bronchoconstriction, increased vascular permeability, and cardiovascular collapse. However, non-IgE-mediated pathways, particularly those involving IgG immune complexes and complement activation, have also been implicated in anaphylactic responses, especially in experimental models and certain clinical settings. IgG-mediated anaphylaxis involves the activation of macrophages, basophils, and neutrophils, with platelet-activating factor, rather than histamine, as the principal mediator. The mechanisms observed with various pharmacological agents such as dextran and von Willebrand factor, immune complexes have been shown to activate the complement system and subsequently produce anaphylatoxins (C3a, C5a) that activate mast cells and other cells, causing increased vascular permeability and smooth muscle contraction. Mas-related G protein-coupled receptor member X2 (MRGPRX2), expressed on mast cells, can be activated by various agents such as icatibant, ciprofloxacin, mivacurium and cisatracurium, as well as selected opioids and local anesthetics, leading to degranulation and anaphylaxis-like symptoms. The contact system, comprising factor XII, prekallikrein, high-molecular-weight kininogen, and kallikrein, plays a role in anaphylaxis through the generation of bradykinin, a potent vasoactive peptide, that contributes to hypotension and angioedema in anaphylaxis. In addition to all these mechanisms, various factors -such as genetic predisposition, hormonal influences, certain medications, age-related health conditions, mast cell-related disorders, physical exertion, infections, and pre-existing conditions affecting the heart, mental health, or chronic respiratory diseasescan all contribute to the progression and severity of anaphylactic reactions. Understanding the diverse mechanisms underlying anaphylaxis is crucial for accurate diagnosis, effective management, and the development of targeted therapies.

Keywords: Childhood anaphylaxis; IgE-mediated; IgG-mediated; The complement system; MRGPRX2; The contact system

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