The era of the immunoglobulin A Fc receptor FcαRI; its function and potential as target in disease

Abstract

Immunoglobulin A (IgA) is the most prevalent antibody at mucosal sites, and has an important role in defense by preventing invasion of pathogens. Traditionally, IgA has been thought of as a non-inflammatory antibody that helps to maintain homeostasis in the mucosa. However, in the last decade it has become clear that IgA is a very potent stimulus to initiate pro-inflammatory cellular processes, especially after triggering the IgA Fc receptor (FcαRI) on neutrophils. It was furthermore described that FcαRI acts as a regulator between anti- and pro-inflammatory responses of IgA. Although neutrophil activation is beneficial in (mucosal) infections, abnormal or excessive IgA immune complexes can induce disproportionate neutrophil migration and in this way initiate a perpetuating neutrophil recruitment and activation loop, which will result in severe tissue damage. Increasing evidence on this process plays a detrimental role in several diseases, including autoimmune IgA blistering diseases, a subtype of rheumatoid arthritis and ulcerative colitis. Inhibiting FcαRI-mediated activation may dampen inflammation in these patients. This process also opens up the possibility of targeting FcαRI in antibody immunotherapy of cancer. Thus, interfering with IgA-mediated FcαRI activation may represent an attractive novel therapeutic strategy for multiple maladies.

Immunoglobulin A: magic bullet or Trojan horse?

“…Multivalent ligands such as IgA-immune complexes induce full phosphorylation of the ITAMs by Src-kinases. Subsequently, Syk is recruited and multiple signalling pathways are induced, resulting in cell activation [4]. Monovalent ligands such as serum IgA cannot cross-link FcaRI and induce anti-inflammatory responses via inhibitory ITAM (ITAMi) signalling [15].…”

“…IgA autoantibodies are detrimental during the course of autoimmune skin diseases by binding to FcaRI on neutrophils. This may also play a role in other diseases characterized by increased (auto-) IgA serum levels, such as rheumatoid arthritis, IgA nephropathy, coeliac disease, inflammatory bowel disease and IgA vasculitis [4]. Several approaches can be taken to intervene with this disadvantageous process.…”

“…Antibodies, secreted by plasma cells, are able to opsonize pathogens and subsequently bind to and activate Fc receptors. One of the most significant receptors on neutrophils is the prototypic IgA Fc receptor (CD89, FcaRI) [4].…”

“…Stimulation of neutrophils by IgA-immune complexes, however, induces multiple proinflammatory functions, including phagocytosis, antibodydependent cellular cytotoxicity (ADCC), degranulation, release of cytokines and chemokines, production of reactive oxygen species (ROS) and the release of NETs (Fig. 1b) [4,7]. Previously, our group showed that FcaRI triggering leads to the release of the chemoattractant leukotriene B4 (LTB4), thereby inducing neutrophil migration and recruitment [8].…”

Immunoglobulin A nephropathy: a pathophysiology view

“…S-IgA prevents penetration of the mucosal wall by pathogenic microorganisms or foreign antigens, serving as an antiseptic barrier [27]. S-IgA can surround microorganisms and be repelled by mucosal surfaces, can agglutinate microbes and interfere with bacterial motility and can interact with and neutralize bacterial products such as enzymes and toxins [28]. Moreover, if antigens achieve the lamina propria, dIgA can interact and transport them back to the lumen via the pIgR route, before recognition by inflammatory cells.…”