Crosslinking-mediated activation of the FcεRI: Does it need antigen for success?

Michael Huber,Sandro Capellmann

doi:10.32604/biocell.2022.018513

Abstract

Mast cells (MCs), hematopoietic cells of the myeloid lineage, are well-known for their pro-inflammatory nature contributing to the development of various allergic and autoimmune diseases. One of the characteristic receptors on MCs, the high-affinity receptor for IgE (FcεRI), is activated in its IgE-bound state via binding and crosslinking by polyvalent antigen. This results in its phosphorylation by the SRC family kinase LYN, initiating differential signaling pathways, eventually triggering immunological effector functions, such as degranulation and cytokine production. Few publications have reported on FcεRI-dependent but antigen-independent MC activation by antibody-mediated crosslinking of membrane molecules (e.g., transmembrane proteins and glycosphingolipids) that are both localized in membrane rafts and in close vicinity to the FcεRI. In this Viewpoint we will briefly introduce FcεRI-mediated MC stimulation, cite examples of FcεRI-proximal molecules, the crosslinking of which can cause FcεRI-dependent MC activation, and discuss the potential of certain viruses as well as auto-antibodies to act as indirect FcεRI-crosslinking agents. In latter cases, antigen-independent FcεRI-mediated pro-inflammatory MC activation could contribute to the development of detrimental cytokine storms.

Highlights

Mast cells (MCs) are innate immune cells and belong to the hematopoietic lineage
In an endeavor to find novel FcεRI-interacting proteins, potentially exerting co-receptor activities, we identified CD13/ aminopeptidase N as an FcεRI-interacting membrane protein and a negative regulator of MC activation (Zotz et al, 2016)
Few but thorough studies have demonstrated that antibodymediated crosslinking of raft-localized, FcεRI-proximal molecules, like transmembrane proteins or glycolipids, can result in FcεRI-dependent MC activation

Summary

Introduction

Mast cells (MCs) are innate immune cells and belong to the hematopoietic lineage. They are strategically located at the borders between self and environment of eukaryotic organisms, in skin, lung and gastrointestinal tract (Metz and Maurer, 2007; Huber et al, 2019). The FcεRI belongs to the family of multichain immune recognition receptors (MIRRs) It comprises an IgE-binding α-chain, a signal-modulating tetraspanin β-chain, and a disulfide-bridged signal-generating γ-chain homodimer. Both β- and γ-chains contain so-called ITAMs (immunoreceptor tyrosine-based activation motifs), which are phosphorylated by the tyrosine kinase LYN upon receptor stimulation (Fig. 1A). Concerning these initial tyrosine phosphorylation events that spark the downstream IgE-mediated signaling and effector processes, three models are discussed, which most likely are not mutually exclusive: i) the transactivation model,

A First Proof of Principle

Conclusion