IgA and FcαRI: Versatile Players in Homeostasis, Infection, and Autoimmunity

Mucosal surfaces constitute the frontiers of the body and are the biggest barriers of our body for the outside world. Immunoglobulin A (IgA) is the most abundant antibody class present at these sites. It passively contributes to mucosal homeostasis via immune exclusion maintaining a tight balance between tolerating commensals and providing protection against pathogens. Once pathogens have succeeded in invading the epithelial barriers, IgA has an active role in host-pathogen defense by activating myeloid cells through divers receptors, including its Fc receptor, Fc alpha RI (CD89). To evade elimination, several pathogens secrete proteins that interfere with either IgA neutralization or Fc alpha RI-mediated immune responses, emphasizing the importance of IgA-Fc alpha RI interactions in preventing infection. Depending on the IgA form, either anti- or pro-inflammatory responses can be induced. Moreover, the presence of excessive IgA immune complexes can result in continuous Fc alpha RI-mediated activation of myeloid cells, potentially leading to severe tissue damage. On the one hand, enhancing pathogen-specific mucosal and systemic IgA by vaccination may increase protective immunity against infectious diseases. On the other hand, interfering with the IgA-Fc alpha RI axis by monovalent targeting or blocking Fc alpha RI may resolve IgA-induced inflammation and tissue damage. This review describes the multifaceted role of Fc alpha RI as immune regulator between anti- and pro-inflammatory responses of IgA, and addresses potential novel therapeutic strategies that target Fc alpha RI in disease.