FcαRI: a case of multiple personality disorder?

IgA and its receptor FcαRI have multifaceted anti-inflammatory, noninflammatory, and proinflammatory functions. In this issue of Blood, Kanamaru and colleagues introduce a new level of complexity by showing that monomeric targeting of FcαRI can induce apoptosis in monocytes.

Immunoglobulin A (IgA) is the most prominent antibody (Ab) class present in mucosal areas. The specific characteristics of these sites, as a vast interface that separates the interior of the body and the outside world, require a tight balance between mounting an effective immunologic defense against pathogenic microorganisms, and avoiding responses against commensal microbial and environmental antigens. In general, IgA is—erroneously—considered a noninflammatory Ab without activating properties, but one which helps to neutralize adherence of microorganisms to the mucosal wall and virus entry.¹  This notion, however, holds true only for IgA that is present in mucosal secretions (secretory IgA [SIgA]), which consists of a dimeric IgA molecule, J chain, and secretory component (SC). SIgA is presumably a poor opsonin due to blockage of the receptor-binding site on IgA by the SC,²  which precludes activation of immune cells. In contrast, invading Escherichia coli bacteria that are opsonized with serum IgA are vigorously ingested by FcαRI-expressing phagocytes like neutrophils and Kupffer cells.³  Thus, IgA can be involved in either noninflammatory or proinflammatory responses.

The mode of interaction between serum IgA and FcαRI adds a next level of duality. Cross-linking of the receptor (multimeric aggregation with complexed serum IgA) initiates superoxide production, release of cytokines, phagocytosis, and antigen presentation. However, FcαRI targeting with monomeric serum IgA triggers inhibitory signals.⁴  Interestingly, both activating and inhibitory signals depend on the immunoreceptor tyrosine-based activation (ITAM) motif of the associating FcR γ chain by either Syk phosphorylation or recruitment of SHP-1, respectively.

Kanamaru and colleagues now describe yet another intricacy as they report that monomeric occupancy of FcαRI can lead to apoptosis, which is also dependent on FcR γ chain ITAM. Downstream signaling proteins have not yet been identified, but apoptosis seems to be suppressed by SHP-1. Furthermore, apoptosis induction presumably requires a second signal, as monomeric targeting of FcαRI triggers programmed cell death only in low-serum conditions. In high-serum conditions, inhibitory signals are initiated. This makes sense, as blood cells are continuously in contact with monomeric serum IgA, and apoptosis needs to be suppressed in order to circumvent unwarranted death of circulating monocytes. The authors hypothesize that IgA-induced apoptosis may come into play in inflammatory sites where stress conditions and ischemia can provide ample additional signals. As such, it can be envisioned that this process may help to limit disproportionate inflammatory reactions. Although it is currently unclear to what extent this phenomenon will play a role in physiologic or pathologic situations, it remains intriguing that 1 receptor can trigger at least 3 different outcomes depending on the mode of interaction with its ligand (see figure).

Finally, the authors demonstrate that development of FcαRI-transfected mast cell tumors can effectively be prevented by monomeric triggering of FcαRI with anti-FcαRI Fabs, and propose that this may constitute a new approach for treating tumors. Since most malignancies do not express FcαRI, this treatment modality will be limited. Still, as myeloid precursor cells express FcαRI,⁵  patients with acute or chronic myeloid leukemia may benefit from this approach.

In conclusion, these findings emphasize once more the complexity of IgA-FcαRI–mediated immune responses, which extend far beyond the old-fashioned concept of IgA as merely a noninflammatory protector by forming an “antiseptic” coating of the mucosal wall.