Alternative Anaphylactic Routes: The Potential Role of Macrophages

Abstract

Anaphylaxis is an acute, life-threatening, multisystem syndrome resulting from the sudden release of mediators from effector cells. There are two potential pathways for anaphylaxis. The first one, IgE-dependent anaphylaxis, is induced by antigen (Ag) cross-linking of Ag-specific IgE bound to the high-affinity IgE receptor (FcεRI) on mast cells and basophils. The second one, IgG-dependent anaphylaxis is induced by Ag cross-linking of Ag-specific IgG bound to IgG receptors (FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, and FcγRIIIA) on macrophages, neutrophils, and basophils. Macrophages exhibit a huge functional plasticity and are capable of exerting their scavenging, bactericidal, and regulatory functions under a wide variety of tissue conditions. Herein, we will review their potential role in the triggering and development of anaphylaxis. Thereby, macrophages, among other immune cells, play a role in both anaphylactic pathways (1) by responding to anaphylactic mediators secreted by mast cells after specific IgE cross-linking or (2) by acting as effector cells in the anaphylactic response mediated by IgG. In this review, we will go over the cellular and molecular mechanisms that take place in the above-mentioned anaphylactic pathways and will discuss the clinical implications in human allergic reactions.

The Interplay Between Blood Proteins, Complement, and Macrophages on Nanomedicine Performance and Responses

“…Notwithstanding, two key factors could play critical roles in macrophage responses. The first is the nature of the responding macrophage receptor, and its associated signaling threshold, that may regulate the transitional link between robust internalization and kinetics of bioactive molecule release from macrophages (Escribese et al, 2017;Moghimi, 2018). For example, a plausible role for low-affinity Fc-receptor-mediated response to nanomedicine anaphylaxis has been proposed (Moghimi, 2018).…”

“…Indeed, Fc receptors (FcgRI, FcgRIIA, FcgRIIB, FcgRIIC, FcRIIIA, and FcgRIIIB) show different affinities for antibodies and exhibit different expression patterns and downstream signaling (Strait et al, 2002). Fc receptors also contribute to desensitization (Strait et al, 2002;Escribese et al, 2017). Nevertheless, the location of responding macrophages, their number, and accessibility to nanoparticles play a role as a rate-limiting factor.…”

A biotinylated peptide, BP21, alleviates hypotension in anaphylactic mice

“…The first limitation is that it is still unknown whether BP21 could be an effective therapeutic agent for human anaphylaxis as well as mouse anaphylaxis. There are two potential pathways (IgE‐dependent and IgE‐independent) for anaphylaxis . IgE‐dependent anaphylaxis is the classical and main pathway induced by an antigen (at low concentration) cross‐linked by its specific IgE bound to the high‐affinity IgE receptor (FcεRI) on mast cells and basophils, followed by the release of histamine.…”

“…IgG‐dependent (IgE‐independent) anaphylaxis is an alternative pathway induced by an antigen (at high concentrations of antigen and IgG) cross‐linked by its specific IgG bound to IgG receptors (FcγRI, FcγRIIA, FcγRIIB, FcγRIIC, and FcγRIIIA) rather than IgE, which are present on macrophages and neutrophils instead of mast cells, followed by the release of mainly PAF instead of histamine. Mouse models of anaphylaxis indicated that both the IgG‐dependent pathway as well as IgE‐dependent pathway are important for anaphylaxis, but their importance in human anaphylaxis is not yet clear . However, in humans, recent studies have shown that PAF induces wheal‐and‐flare reactions in skin and that circulating PAF levels are direct and the activities of circulating PAF‐AH, which degrades PAF to inactive lyso‐PAF, are inversely correlated with the severity of anaphylaxis in humans .…”

Factor XII-Driven Inflammatory Reactions with Implications for Anaphylaxis

“…One explanation could be that mast cells can selectively release serotonin without releasing histamine ( 52 ) via high-affinity serotonin-binding proteins used to sequester serotonin from secretory vesicles ( 53 ). Serotonin functions as a regulator of immune and inflammatory responses and is partially mediated through direct interactions with macrophages ( 54 ).…”