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Review
. 2021 Jan 5:9:351-372.
doi: 10.2147/ITT.S266242. eCollection 2020.

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

Melissa Maria Johanna van Gool  1   2 , Marjolein van Egmond  1   2   3
Affiliations
Review

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

Melissa Maria Johanna van Gool et al. Immunotargets Ther. .

Abstract

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, FcαRI (CD89). To evade elimination, several pathogens secrete proteins that interfere with either IgA neutralization or FcαRI-mediated immune responses, emphasizing the importance of IgA-FcαRI 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 FcαRI-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-FcαRI axis by monovalent targeting or blocking FcαRI may resolve IgA-induced inflammation and tissue damage. This review describes the multifaceted role of FcαRI as immune regulator between anti- and pro-inflammatory responses of IgA, and addresses potential novel therapeutic strategies that target FcαRI in disease.

Keywords: CD89; autoimmunity; infection; inflammation; mucosa; neutrophil.

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Conflict of interest statement

The authors report no conflicts of interest for this work.

Figures

Figure 1
Figure 1
Inhibitory and activating signaling via FcαRI after ligand binding. (A) Monomeric IgA (not complexed to an antigen) does not induce FcαRI cross-linking resulting in partial phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) and recruitment of Src homology region 2 domain‐containing phosphatase‐1 (SHP‐1). This results in inhibition of ITAM signaling, and impairs phosphorylation of spleen tyrosine kinase (Syk), LAT and ERK, which is initiated through signaling via other activating Fc receptors (like IgG-mediated Fcγ receptor activation). The exact binding of free dIgA to FcαRI, and concomitant signaling, has not yet been resolved. (B) IgA immune complexes (eg IgA-coated Escherichia coli) induce cross‐linking of FcαRI, resulting in ITAM phosphorylation of the associated FcR γ-chain. Phosphorylated ITAMs subsequently function as a docking site for signaling molecules such as Syk. Syk plays an essential role in initiating signaling pathways, including the Ras/Raf/MEK/MAPK pathway. Activation of signaling pathways results in pro‐inflammatory cellular functions such as phagocytosis, antibody‐dependent cellular cytotoxicity, respiratory burst, degranulation, antigen presentation, and release of NETS, cytokines and inflammatory mediators. Created with BioRender.com.
Figure 2
Figure 2
Roles of IgA and FcαRI in homeostasis and infection at mucosal sites. (A) Local plasma cells in the lamina propria produce dimeric IgA (dIgA), which is transported across the epithelium into luminal secretions by binding to the polymeric Ig receptor (pIgR). At the luminal side it is released as secretory IgA (SIgA) where it can neutralize pathogens and toxins. (B) On route of being secreted, dIgA can intercept viruses, which have infected epithelial cells and redirect them into the lumen. (C) Invading pathogens and antigens in the lamina propria are opsonized by dIgA and transported back into the lumen. (D) Microbes that are opsonized with SIgA are shuttled via microfold (M) cells to dendritic cells (DCs) in Peyer’s patches for sampling. Additionally, DCs can extend dendrites through the epithelial layer for sampling of the luminal content. (E) During infection, dIgA-opsonized pathogens are taken up by FcαRI-expressing DCs, and presented to T cells. Additionally, phagocytosis of dIgA-opsonized pathogens by neutrophils results in the release of leukotriene B4 (LTB4), which mediates the chemotaxis of more neutrophils to the site of infection, thereby functioning as a self-contained positive feedback loop of immune cell recruitment to clear invading pathogens. Created with BioRender.com.
Figure 3
Figure 3
Systemic protection by serum IgA and FcαRI-expressing Kupffer cells. Serum IgA-opsonized bacteria in the circulation are transported to the liver through the portal vein and phagocytosed by Kupffer cells (KC), which express FcαRI, providing protection against systemic infection. Cross-talk between FcαRI and pathogen recognition receptors (PRRs) may break the tolerance of Kupffer cells to bacterial structures. Created with BioRender.com.
Figure 4
Figure 4
IgA-FcαRI induced pathology in skin blistering diseases. Cross-linking of FcαRI on neutrophils with IgA immune complexes results in the release of leukotriene B4 (LTB4) inducing enhanced neutrophil influx, causing tissue damage in a variety of inflammatory- and autoimmune diseases. An example is the blister formation in linear IgA bullous disease (LABD). Created with BioRender.com.
Figure 5
Figure 5
IgA and FcαRI as therapeutic targets. Enhanced IgA complexes or autoantibodies result in excessive activation of immune cells contributing to chronic inflammation and tissue damage in autoimmune diseases. Blocking IgA-FcαRI interactions by either monoclonal antibodies or peptides may reduce inflammation and tissue damage in these diseases. Treatment with monomeric IgA or anti-FcαRI Fabs may dampen immune responses by inducing inhibitory ITAM signaling and inhibiting IgG-induced phagocytosis and IgE-mediated allergic diseases. To combat bacterial and viral infections, inducing pathogen-specific IgA via passive or active vaccination may result in enhanced protective immunity. Enhancing pro-inflammatory responses by FcαRI-expressing immune cells via IgA monoclonal antibody therapy, bi-specific antibodies, or cross-isotype hybrid antibodies may result in efficient killing of tumor cells and represent a promising therapeutic opportunity for cancer patients. Created with BioRender.com.
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References

    1. Belkaid Y, Harrison OJ. Homeostatic immunity and the microbiota. Immunity. 2017;46(4):562–576. doi:10.1016/j.immuni.2017.04.008 - DOI - PMC - PubMed
    1. Lu LL, Suscovich TJ, Fortune SM, Alter G. Beyond binding: antibody effector functions in infectious diseases. Nat Rev Immunol. 2018;18(1):46–61. doi:10.1038/nri.2017.106 - DOI - PMC - PubMed
    1. Dimitrov JD, Lacroix-Desmazes S. Noncanonical functions of antibodies. Trends Immunol. 2020;41(5):379–393. doi:10.1016/j.it.2020.03.006 - DOI - PubMed
    1. Bruhns P, Jonsson F. Mouse and human FcR effector functions. Immunol Rev. 2015;268(1):25–51. doi:10.1111/imr.12350 - DOI - PubMed
    1. Macpherson AJ, Yilmaz B, Limenitakis JP, Ganal-Vonarburg SC. IgA function in relation to the intestinal microbiota. Annu Rev Immunol. 2018;36(1):359–381. doi:10.1146/annurev-immunol-042617-053238 - DOI - PubMed