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

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 (FcRI) on neutrophils. It was furthermore described that FcRI 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 FcRI-mediated activation may dampen inflammation in these patients. This process also opens up the possibility of targeting FcRI in antibody immunotherapy of cancer. Thus, interfering with IgA-mediated FcRI activation may represent an attractive novel therapeutic strategy for multiple maladies.