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

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