FcαRI is a low affinity Fc receptor for monomeric IgA and dIgA (K_a = 10⁶ M⁻¹), while IgA immune complexes bind with high avidity and cross-link FcαRI (50). Monomeric IgA binds to the EC1 domain of FcαRI via its Cα2 and Cα3 domains in a 2:1 stoichiometry (i.e., one IgA molecule binds two FcαRI molecules) (Figure 1C) (51, 52). Presence of residues Pro440-Phe443 and Leu257-Leu258 in these domains is essential for IgA binding to FcαRI (53).

Dimeric IgA contains four FcαRI binding sites and can therefore theoretically bind four FcαRI, although this is presumably not possible due to steric hindrance (Figure 1D) (24). It remains to be elucidated how dIgA exactly interacts with the FcαRI. Binding of SIgA to FcαRI is hampered because of steric hindrance by SC. In order for SIgA to activate cells, co-stimulation of FcαRI, and the lectin Mac-1 (CD11b/CD18) was necessary (54).

Little is known about the difference between IgA1 and IgA2 binding to FcαRI (if any) or the influence of glycosylation on binding capacity. It was however shown that a specific mutation (Asn58 to Glu58) resulted in an altered glycosylation pattern of FcαRI, which increased the binding capacity of IgA nearly 2-fold (55). Removal of sialic acids led to a nearly 4-fold increase of IgA binding. This demonstrates the importance of glycosylation at position 58 of FcαRI in binding affinity for IgA (55). N-glycans located at the external surface of the IgA heavy chain were important for interaction with FcαRI as well (56). Furthermore, it was demonstrated that alterations in IgA1 glycosylation and impaired sialylation of FcαRI were linked to increased binding of IgA1 to FcαRI on neutrophils of patients with IgA nephropathy, which may influence pro-inflammatory functions (47). In transfectants, eosinophils, and monocytes FcαRI binding capacity for IgA immune complexes was enhanced by incubation with several cytokines like GM-CSF, IL-4, and IL-5, without affecting the expression level of the FcαRI on the cell surface (43, 57).

Competitive binding for FcαRI has been described for pentraxins, including the acute phase C reactive protein and serum amyloid P component, resulting in cell activation (58). These proteins are characterized by a pentameric ring-like structure containing five subunits, which recognize a similar site on FcαRI as IgA. However, mutations in FcαRI outside the IgA binding site did not affect IgA binding, but enhanced pentraxin binding 2-fold, suggesting that pentraxins bind to a broader region on FcαRI than IgA (58).

Importantly, Staphylococcus aureus and group A and B streptococci developed evasion strategies for IgA-mediated elimination by FcαRI-expressing immune cells by producing several decoy proteins that obstruct binding of IgA to FcαRI (22, 23). Anti-IgA proteins from group B streptococci include Sir22, Arp4 and an unrelated β protein, whereas Staphylococcus aureus produces staphylococcal superantigen-like protein seven. These proteins bind to specific Fc residues (amino acids Pro440-Phe443; i.e. PLAF) in the Cα2 and Cα3 domains of IgA (22, 23, 59). The fact that pathogens evolved and developed mechanisms to evade IgA-mediated elimination by FcαRI-expressing immune cells (60), challenges the dogma of IgA as a non-inflammatory and possibly redundant antibody.

Cross-linking of FcαRI by IgA immune complexes (or IgA-opsonized pathogens) induces a variety of processes, including phagocytosis, antibody-dependent cellular cytotoxicity, superoxide generation, release of inflammatory mediators, and cytokines as well as antigen presentation (61–65). Due to hampered binding of SIgA to FcαRI, SIgA does not induce efficient uptake of pathogens by neutrophils or Kupffer cells. However, respiratory burst in neutrophils can be triggered by SIgA, although less efficiently compared to serum IgA (54). Phagocytosis of IgA-coated bacteria or yeast particles by neutrophils was enhanced after priming with GM-CSF or IL-8 (43, 66). Uptake of IgA-coated particles induces increased reactive oxygen species production, subsequently resulting in the release of neutrophil extracellular traps (NETs), which are web-like structures consisting of DNA and proteins (e.g., elastase and myeloperoxidase) able to catch pathogens (61). FcαRI cross-linking furthermore induces release of the neutrophil chemoattractant leukotriene B4 (LTB4) by neutrophils, thereby generating a positive migration feedback loop (64). LTB4 was also shown to mediate migration of monocyte derived DCs (67). As such, in case of mucosal infection neutrophils can function as potent phagocytes, which eliminate invading IgA-coated pathogens, and attract DCs that present antigens to T cells. It was recently shown that in vitro generated human mucosal CD103⁺ DCs (cultured with retinoic acid) express FcαRI. After stimulation with IgA-coated Staphylococcus aureus in the presence of Pam3CSK4 CD103⁺ DCs produced pro-inflammatory cytokines including TNF-α, IL-1β, IL-6, and IL-23, which was dependent on FcαRI (68). Furthermore, IgA-stimulated CD103⁺ DCs enhanced IL-17 production by allogeneic T cells and IL-22 production by intestinal type three innate lymphoid cells, respectively. This suggests that FcαRI crosslinking by IgA induces a pro-inflammatory T helper 17 response accompanied with IL-22 induced activation of epithelial cells, which might contribute to tissue repair (68).

In order to initiate optimal effector functions after FcαRI cross-linking, FcαRI needs association with the FcR γ-chain, which contains an immunoreceptor tyrosine-based activation motif (ITAM) in its intracellular domain (69–72). After cross-linking of FcαRI, the src family kinase Fyn aggregates with the receptor complex and phosphorylates the tyrosines in the ITAM in order to act as docking sites for signaling molecules (69, 73, 74). Recruited Syk associates with the phosphorylated ITAM and plays an essential role in the signaling cascade. It directly activates phosphoinositide 3-kinase and phospholipase Cγ, which are involved in two separate signaling routes. These pathways are interconnected and can therefore modulate each other (69, 72, 75). Eventually the signaling pathways will activate the cell, resulting in pro-inflammatory functions (18, 66). Alternatively, it was demonstrated that inhibitory signals can also be transduced via the FcαRI-FcR γ-chain complex. Monomeric targeting of FcαRI (not leading to cross-linking) results in an inhibitory signal and is dependent on Lyn instead of Fyn kinase (74). Phosphorylation of Syk, LAT, and ERK is hampered by “inhibisomes” that contain signaling molecules and both inhibitory and activating receptors (20, 76). Inhibisomes impair activating Fc receptor functioning via a process referred to as inhibitory ITAM (ITAMi) receptor signaling that initiates anti-inflammatory responses to dampen pro-inflammatory responses induced by other Fc receptors (77). Thus, Lyn and Fyn are essential molecules controlling ITAM inhibition and activation, respectively (74). Signaling via FcαRI was recently described in more detail in Aleyd et al. (18).

The functions of SIgA in the intestinal lumen have been well-characterized (Figure 2A). SIgA and commensal microbes have important roles in maintaining balance between tolerance toward non-harmful commensals and food compounds vs. immunity against pathogens (78, 79). When SIgA is released from the epithelial layer into the lumen, it remains attached to the outer mucus layer (80). This close localization to bacteria enables SIgA to disturb bacterial motility and to surround pathogens that have a hydrophilic shell. SIgA coating blocks entrance of pathogens into the intestinal epithelium (a process called immune exclusion). This coating leads to agglutination, because antibody-mediated crosslinking of surface antigens will lead to formation of bacterial clumps. Peristaltic bowel movements ensure removal of bacterial aggregates. Bacterial products like enzymes and toxins can be neutralized by SIgA and adherence to host cells, including epithelial cells, is prevented (78). Thus, together with the mucus layer, SIgA forms a barrier against pathogens, and commensals by preventing colonization and penetration of the mucosal epithelium, thereby avoiding infection and antigen leakage into the systemic circulation (81).

Recently the interplay between luminal microbiota and SIgA was investigated in more detail (4, 82) (Figure 2A). It is still unclear how SIgA and the microbiota exactly relate to each other, but it was described that SIgA shapes and diversifies the gut microflora on the one hand, while the microbiota on the other hand has an important role in regulating IgA levels (82–84). During weaning up to 70% of intestinal commensals are coated with SIgA in mice and the majority of human fecal bacteria in healthy donors are opsonized with IgA, emphasizing the importance of this association in maintaining homeostasis (31, 85). A wide variety of commensals can be opsonized with polyreactive IgA, although it remains unclear how these IgA antibodies are generated, what the relevant targets are and how binding affects the fitness and physiology of commensals (86). In contrast to commensals, pathogens elicit highly specific T-cell dependent IgA responses (86, 87). Genetic background was shown to influence the repertoire diversity and abundance of innate IgA as germ free (GF) naïve BALB/c mice already had substantial innate IgA levels, independent of microbiota colonization, while this was not the case for C57BL/6 mice (83).

Furthermore, highly glycosylated IgA was able to bind to several gram negative bacteria, which modulated their gene expression, leading to enhanced processing of fibers and production of butyrate as well as a diversified microbiota composition (82). Moreover, it was shown that the disbalanced microbiota of colitogenic mice became more balanced and diversified after oral administration of the monoclonal IgA W27, which is a high-affinity polyreactive antibody (84). Importantly, mice lacking IgA, J-chain or pIgR were unable to efficiently protect themselves against mucosal infections. These mice have an altered gut microbiota as well as increased mucosal permeability, which renders them more susceptible to develop colitis (80, 88–94). Of note, lack of J-chain or pIgR also led to absence of SIgM which may have contributed to altered microbiota and compromised immunity (88, 91, 94). A diversified microbiota can regulate the amount of SIgA present in luminal secretions by enhancing the level of pIgR on epithelial cells (1, 31, 95), illustrating the complex interrelationship between IgA (and IgM) and the microbiota in maintaining homeostatic conditions.

It was described that SIgA can be translocated back into the lamina propria (retrograde transport). SIgA and SIgA immune complexes can be transported across specialized epithelial cells, referred to as M cells, which are located in the Peyer's patches of the intestine. Dectin-1 that is expressed by M cells may facilitate transepithelial transport (11, 96). Additionally, a role for TfR1 on epithelial cells in retrotransport of SIgA-coated gliadin was reported in studies investigating celiac disease (12). Retrotransported SIgA immune complexes can be taken up by DCs that are present in the subepithelial dome. In vitro models support an essential role for DC-SIGN in recognizing SIgA immune complexes (13). The retrograde transport mechanism and recognition of SIgA by DCs is thought to be essential in monitoring the antigenic status of the intestinal lumen.

On route through epithelial cells, dIgA has the ability to intercept and disarm viruses and redirect them into the lumen, after which they are removed with the feces (Figure 2B). Neutralization of several viruses by IgA including sendai, influenza, rota, measles, and human immunodeficiency virus (HIV), as well as bacterial LPS was demonstrated in vitro (97–104). IgA has enhanced neutralizing capacity compared to other Ig isotypes due to the N-linked glycosylation of position N459D in the heavy chain Cα3 (105). This effect is independent of the antigen binding site as glycosylated non-specific IgA neutralized the virus as well.

IgA deficient mice, J-chain deficient mice (lacking dIgA, SIgA, and SIgM) and pIgR deficient mice (lacking SIgA and SIgM) have defects in clearing viruses, are more susceptible to reinfection and lack protective immunity (106–108), which emphasizes the important role of IgA in anti-viral immune responses. By contrast, in a recent study pIgR knock-out mice showed a reduced acute norovirus infection rate, suggesting that pIgR and natural polymeric immunoglobulins may promote viral infections. It was suggested that the less diversified intestinal microbiota present in pIgR deficient mice was responsible for reduced infection. pIgR deficient mice had enhanced levels of the anti-viral cytokine IFN-γ, which might explain the reduced infection rates (109).

Food particles and commensal microbiota are abundantly present in the lumen and can continuously reach the lamina propria through diffusion (via epithelial tight junctions) or transcytosis (Figure 2C). These non-harmful components need to be tolerated and they need to be cleared from the mucosa to avoid the formation of immune complexes, which may trigger undesired immune responses. In the lamina propria dIgA can eliminate both non-harmful and harmful components from the tissue by transporting immune complexes back into the lumen through association with the pIgR (97, 101). Additionally, FcαRI⁺ residing immune cells may help to clear IgA-opsonized pathogens. Under homeostatic conditions, only few FcαRI⁺ cells are found in mucosal areas (own unpublished data). However, as dIgA-opsonized complexes have the ability to cross-link FcαRI, leading to release of LTB4, neutrophils can be rapidly recruited (64) (Figure 2C). Furthermore, in vitro generated FcαRI⁺ CD103⁺ DCs were shown to produce pro-inflammatory cytokines after stimulation with IgA-coated Staphylococcus aureus in the presence of Pam3CSK4, suggesting that a protective adaptive immune response is initiated during mucosal infections (68).

It was demonstrated that a variety of commensal microbes in the gut influenced serum IgA levels, which protected mice against lethal sepsis when the intestinal barrier was damaged (110). Serum IgA was shown to target the same epitopes and used the same V-gene segments as plasma cells in the gut (111), suggesting that systemic and mucosal plasma cells originated from the same B cell clone. Diminished serum IgA titers were found in GF mice compared to specific pathogen free mice, supporting the essential role for microbiota diversity in IgA production (110, 112). Mice lacking pIgR and SIgA have epithelial barrier disruption, enhanced numbers of IgA-secreting plasma cells and systemic immune activation indicated by increased levels of serum IgG and IgA (113, 114). Higher levels of albumin were found in the feces, suggesting leakage of serum proteins across the epithelium (113). At the same time intestinal proteins and microorganisms can leak into the tissue and enter the bloodstream. After entering the portal circulation they will encounter Kupffer cells in the liver, which are specialized FcαRI⁺ macrophages that can eliminate IgA-coated bacteria from the bloodstream (Figure 2D) (34). Kupffer cells, macrophages, and monocytes produced increased levels of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6) after cross-linking of FcαRI in the presence of pathogen recognition receptor ligands (such as Pam3CSK4, LPS, flagellin) (reflecting IgA-opsonized pathogens) (115).

In contrast to the activating properties of complexed serum IgA, monomeric serum IgA was capable of downregulating cell responses and promoted powerful anti-inflammatory effects (Figure 2D). This is referred to as ITAMi signaling (see above) (19). Monomeric targeting of the FcαRI with serum IgA may protect against enhanced receptor activation, which is beneficial in inflammatory diseases characterized by the presence of IgG immune complexes or enhanced FcεRI signaling.

Selective IgA deficiency is the most common human immunodeficiency and is characterized by a serum IgA concentration of <7 mg/dL. Both serum IgA and mucosal IgA are very low or absent in selective IgA deficient patients (6, 117). Defects in B cell isotype switching, terminal differentiation of IgA⁺ plasma cells into secretory cells or long-term survival of IgA-secreting plasma cells can result in IgA deficiency (118, 119). Unbalanced cytokine production (including IL-4, IL-6, IL-7, IL-10, and IL-21) has been reported with a key role for TGF-β, as it induces isotype switching and differentiation of antigen-stimulated B cells into IgA-secreting plasma cells (120, 121). The initial defect may lie in the stem cell compartment as IgA deficiency can be transferred by bone marrow transplantation (122).

A significant heterogeneity exists among IgA deficient patients. Many patients are asymptomatic and only few show minor clinical symptoms. This may in part be due to better hygiene, vaccination, and antibiotic use in modern Western society. Furthermore, it was shown that increased production of IgM and/or IgG can partially compensate for the lack of IgA (Figure 3A) (123, 124). IgA deficient patients can develop severe pathology when IgG and/or IgM does not compensate for IgA loss (117, 125). Conflicting reports on the influence of IgA deficiency on fecal microbiota in patients have been reported. One study showed a significantly less diverse fecal microbiota of IgA deficient patients compared to healthy controls, and specific taxa were lost in IgA deficient patients (124). Another study reported a mild loss in microbial diversity in IgA deficient patients (117). SIgM could partially rescue the microbiota composition in IgA deficient patients (117). However, SIgM targeted a broader range of microbes and showed less specificity for microbes compared to SIgA (124). Patients can have increased C reactive protein levels, which is indicative for enhanced inflammation, along with an increased risk of death 10–15 years after initial diagnosis (126, 127). In a recent study no risk association was found between IgA deficiency and hospital infections (127). IgA deficiency was also not more common among hospitalized individuals compared to healthy blood donors (123). However, patients have moderate enhanced susceptibility to gastrointestinal, urinary, and recurrent respiratory infections, allergies, celiac disease, and autoimmune diseases (6, 128, 129). Forty-five percent of IgA deficient patients have the 8.1 haplotype (HLA-A1, B8, DR3, DQ2 haplotype) compared to 16% in the general population (123, 130). The 8.1 haplotype is also commonly found in patients with autoimmune diseases (including rheumatoid arthritis and systemic lupus erythematosus), which are strongly associated with IgA deficiency (123). These findings suggest that patients share predisposing genes, which may explain the increased prevalence of selective IgA deficiency in certain autoimmune disorders.

Eighty-four percent of IgA deficient patients were positive for a wide variety of allergens in skin prick tests (131). The link between IgA deficiency and allergies may be explained by higher levels of circulating antigens due to increased permeability at mucosal surfaces. Alternatively FcαRI may not be able to induce ITAMi signaling in the absence of monomeric serum IgA, possibly resulting in overactivation of immune cells that can lead to development of allergies and autoimmune diseases (132).

Anti-IgA antibodies, usually of the IgG subclass, are commonly found in IgA deficient patients (40%), although their etiology remains unknown. Transfusing IgA-containing blood products to treat IgA deficiency is therefore complicated, as IgA-anti-IgA immune complexes can induce severe reactions, especially when anti-IgA antibodies of the IgE subclass are present (133, 134).

Allergic diseases are inflammatory conditions of which the majority are characterized by high specific IgE levels and activated mast cells (135). Alterations in microbiota diversity reduced immunological tolerance, potentially resulting in food allergies, allergic rhinitis, and asthma (136). It was suggested that the current hygienic life style in the western world altered normal microbiota colonization in infants thereby contributing to the enhanced prevalence of allergies (“hygiene hypothesis”) (137). A less diverse composition of the microbiota was associated with lower IgA levels, suggesting that IgA can be involved in the development of allergic diseases as well. Studies investigating the link between IgA levels and allergy and asthma have however been conflicting. In children, serum IgA levels correlated negatively with asthma severity (138). Moreover, it was shown that lower levels of intestinal bacteria were coated with IgA in infants with asthma (139). In adults, both house dust mite sensitization and airway hyper-responsiveness correlated negatively with serum IgA (140). Furthermore, asthma symptoms like shortness of breath and sputum production inversely correlated with, respectively mucosal SIgA and serum IgA levels (141). These results suggest a potential link between low IgA levels and the risk and severity of allergic asthma, which supports a protective role for IgA in allergy. However, data has also been reported showing enhanced specific IgA levels in patients with allergic rhinitis and atopic asthma (142, 143). Moreover, allergen specific IgA in combination with eosinophilia were common characteristics of asthma and allergic rhinitis (142), possibly because IgA can induce eosinophil survival, thereby contributing to disease severity (144). These results demonstrate a dual role of IgA in allergies, which is currently ill-understood.

Rheumatoid arthritis (RA) is a systemic and chronic autoimmune disorder characterized by infiltration of inflammatory immune cells in the joints, resulting in swelling and pain. Presence of autoantibodies including rheumatoid factor (RF) and anti-citrullinated protein antibodies are commonly present, which can be of the IgM, IgG or IgA isotype. High IgA anti-citrullinated protein antibodies and IgA RF titers correlate with worse disease prognosis and severity, and have been used as predictive value for disease progression (145–147). This suggests that IgA contributes to disease pathology. It was demonstrated that blocking the interaction between IgA RF and macrophage FcαRI resulted in reduced levels of TNF-α (148). Additionally, neutrophils stimulated with plasma of RA patients, containing IgA RF, induced NET release, which was inhibited by blocking FcαRI (149). Thus, IgA-immune complexes in patients can induce pro-inflammatory functions of neutrophils and macrophages, which are prominently present in inflamed joints (150), and as such contribute to inflammation in RA.

IgA nephropathy (IgAN) is the most common form of glomerulonephritis and progresses to end-stage kidney failure in 50% of patients. IgA levels are increased in both serum and urine of IgAN patients. A link with RA was suggested, as patients can also have enhanced IgA RF in their serum. This condition is referred to as rheumatoid nephropathy (151). It was hypothesized that galactose-deficient O-glycans in IgA1, produced by plasma cells in the gut, can trigger the production of anti-glycan IgG/IgA antibodies, after which formed immune complexes deposit in the glomeruli where renal injury is initiated (152, 153). The enzymes responsible for production of O-linked glycans are glycosyltransferases, which expression are amongst others regulated by bacterial products, suggesting that the microbiome regulates the specific glycosylation pattern of IgA1 during the initial phase of IgAN (154, 155). In mice, galactose-deficient IgA1 was not cleared from the murine circulation and deposited in the kidney (15). FcαRI⁺ Kupffer cells were unable to clear circulating IgA of IgAN patients in vivo (156). In transgenic mice expressing the human FcαRI on monocytes and macrophages, soluble FcαRI-IgA complexes that were deposited in the mesangium, induced glomerular and interstitial macrophage infiltration, hematuria, mesangial matrix expansion, and mild proteinuria (157, 158). Moreover, in FcαRI transgenic and human IgA knock-in mice soluble FcαRI-IgA complexes induced kidney inflammation by interacting with TfR1 on mesangial cells, which induced the release of pro-inflammatory mediators. Additionally, the expression of transglutaminase 2 was induced, which subsequently enhanced the expression of TfR1, thereby inducing a pathogenic amplification loop (157). Of note, shedding of FcαRI from macrophages of transgenic mice may have aggravated disease, which will likely not occur in patients as human macrophages express lower FcαRI levels. Nonetheless, IgA-soluble FcαRI complexes have been found in patients with IgAN, and serum IgA immune complexes bound more avidly to TfR1 in vitro compared to those from healthy controls (158, 159). It was demonstrated that IgAN and Henoch-Schönlein purpura nephritis patients had reduced levels of soluble FcαRI and transglutaminase 2 in their urine (160), which makes it plausible that soluble FcαRI immune complexes deposit in the human kidney.

IgA vasculitis, also known as Henoch-Schönlein purpura, is the most common form of vasculitis. The condition is characterized by IgA1 immune deposits and neutrophil infiltrates affecting the small vessels. As a result, red blood cells can leak into the skin leading to typical cutaneous hemorrhages, which leads to diagnosing the disease (161, 162). The pathology of IgA vasculitis remains unclear. However, it is suggested to represent a systemic equivalent of IgAN, as IgA vasculitis can be accompanied with nephropathy, resembling IgAN (163). Unlike IgAN, which is characterized by deposits of galactose-deficient IgA1, it is unknown which type of IgA accumulates in IgA vasculitis (152, 164).

Increased levels of soluble FcαRI-IgA complexes were found in sera of adult and pediatric vasculitis patients with or without co-existing nephritis, which was associated with decreased FcαRI expression on monocytes (165, 166). Furthermore, it was proposed that IgA1 anti-endothelial cell antibodies might play a role. Serum IgA from IgA vasculitis patients was shown to bind in vitro to human but not bovine glomerular endothelial cells (167). IgA anti-endothelial cell antibodies induced the production of IL-8 by endothelial cells, thereby contributing to an inflammatory environment and neutrophil recruitment (168, 169). In addition to enhanced levels of serum TNF-α, which promoted anti-endothelial cell antibody binding to endothelial cells, IL-8 production increased inflammation in IgA vasculitis patients (167, 169, 170). It was hypothesized that neutrophils become activated by IgA-FcαRI mediated cross-linking, resulting in inflammatory processes like reactive oxygen species production and NET formation. Moreover, IgA-activated neutrophils release LTB4, inducing neutrophil migration, thereby enhancing a positive feedback loop, which may result in pathogenesis observed in IgA vasculitis (162).

Inflammatory bowel disease is characterized by chronic inflammation in the intestinal tract and is subdivided into ulcerative colitis and Crohn's disease (171). The barrier function in these patients is disrupted allowing bacteria to invade the subepithelial lamina propria (171). Downregulation of pIgR on intestinal epithelial cells and a disturbed microbiota were observed in IBD patients (172). It was proposed that intracellular signaling pathways and protein trafficking was altered due to damage caused by the inflammatory environment resulting in pIgR regulation defects (10). Mice lacking pIgR have enhanced numbers of IgA-secreting plasma cells, possibly as compensation. Increased production, combined with diminished transcytosis of dIgA into the lumen may potentially result in accumulation of dIgA in the lamina propria. Invading bacteria can become opsonized with dIgA, potentially resulting in activation of neutrophils by cross-linking of FcαRI, leading to tissue damage. Neutrophils that had taken up IgA were observed in the mucosa of ulcerative colitis patients (64). Cross-talk between Fc receptors and TLRs was induced by antibody-coated bacteria, resulting in release of pro-inflammatory mediators (e.g., LTB4) by DCs, which may also contribute to inflammation in IBD. LTB4 induces recruitment of neutrophils and monocytes. Additionally, simultaneous triggering of FcαRI and TLR4 on neutrophils resulted in enhanced release of pro-inflammatory TNF-α (173). Furthermore, due to diminished SIgA levels in the lumen, neutralization, and immune exclusion of microbes is decreased, which may worsen disease in patients (10). Patients have increased levels of specific IgA against microbiota in their serum (174). Highly IgA-coated bacteria obtained from IBD patients induced colitis in GF mice (175). The extent to which IgA responses against microbiota differ in homeostatic conditions vs. IBD, remain unclear (86).

Surprisingly, an increased amount of fecal bacteria of IBD patients was opsonized with IgA compared to those obtained from healthy control feces (85, 175, 176). It was suggested that leakage of serum IgA or dIgA due to a disrupted epithelial layer contributed to enhanced fecal bacteria coating (176, 177). The exact role of IgA and FcαRI in inflammatory bowel disease however remains to be elucidated.

Celiac disease is a multifactorial autoimmune disease characterized by a damaged small intestinal mucosa and nutrient malabsorption following gluten ingestion. Individuals carrying the DQ2 and DQ8 HLA haplotypes have an increased risk to develop celiac disease (178). Gliadin, a glycoprotein of gluten, can complex with specific IgA, after which it can be retrotransported across the epithelium via the TfR (Figure 3B). Celiac disease patients have increased expression of TfR on their epithelial cells, allowing increased retrotransport (12). Intracellular degradation of these peptides is disturbed in patients and after entrance in the lamina propria gliadin peptides are deamidated by tissue transglutaminase after which they are presented to HLA-DQ2 or HLA-DQ8 expressing CD4⁺ T cells. This results in the release of pro-inflammatory mediators, concomitant tissue damage and production of autoantibodies (179). IgA anti-tissue transglutaminase antibodies play a key role in disease pathogenesis (180). Presence of these antibodies serve to diagnose the disease and are furthermore linked to other IgA-related diseases like dermatitis herpetiformis and IgA nephropathy (Figure 3B). In dermatitis herpetiformis aberrant IgA antibodies are directed against structural proteins maintaining cell-cell adhesion in the epidermis leading to skin tissue damage (181). It is hypothesized that celiac disease patients can develop dermatitis herpetiformis as high avidity IgA anti-tissue transglutaminase antibodies form immune complexes and deposit in the dermis of these patients, although it is ill understood why some patients develop dermatitis herpetiformis, and others do not. Furthermore, small bowel inflammation in celiac disease is mostly the result of mononuclear cell infiltration, whereas neutrophils accumulate in the skin of dermatitis herpetiformis patients (181). Patient neutrophils have increased ability to bind IgA without FcαRI expression alteration, supporting that FcαRI is primed (e.g., by cytokines or differential glycosylation) (182).

Gluten exposure can also lead to glomerular IgA deposition and IgAN (183). Transgenic human IgA and FcαRI knock-in mice developed severe pathology when gluten were present in their diet, including intestinal injury, increased IgA1–soluble FcαRI complexes, mesangial IgA1 deposition, and elevated serum IgA1 anti-gliadin antibodies. IgAN patients also have increased IgA1 anti-gliadin antibodies in their serum, suggesting that entrance of gluten can potentially result in loss of oral tolerance thereby contributing to IgAN (184). Consumption of a gluten-free diet can resolve manifestations of celiac disease, dermatitis herpetiformis, and IgAN.

Linear IgA Bullous Disease (LABD) patients suffer from extensive skin damage and blister formation caused by the presence of IgA autoantibodies against collagen XVII, and concomitant neutrophil accumulation (Figure 3C). Collagen XVII plays a critical role in maintaining adhesion between dermis and epidermis in the skin (185). Neutrophil activation is likely the direct result of FcαRI triggering by IgA autoantibodies (186). Tissue damage was induced in the presence of neutrophils and serum of LABD patients (containing IgA anti-collagen XVII autoantibodies) in an ex vivo skin model, as presence of activated neutrophils led to separation of the dermis from the epidermis (reflecting blister formation) (186). Eosinophil influx has been observed in the skin of LABD patients as well, suggesting that these cells might also contribute to disease pathology through FcαRI mediated respiratory burst activity (185).

Administration of specific IgA (passive immunization) or enhancing IgA production through active immunization might be effective strategies to combat viral and bacterial infections (104). Intranasal passive administration of either specific monomeric or polymeric IgA against a mycobacterium tuberculosis antigen led to short, but effective protection against infection in mice (187). The short protection duration was probably due to degradation of IgA by bacterial proteases present in the respiratory tract fluid. Furthermore, mice expressing human FcαRI on blood neutrophils and monocytes had a lower mycobacterium tuberculosis infection rate compared to control mice after inoculation of human IgA mAb, supporting an additive beneficial role for FcαRI in clearing the infection (188). Wild type (WT) mice which orally received Salmonella typhimurium that had been complexed with human plasma-derived IgA and IgM had reduced intestinal infection rates compared to mice exposed to Salmonella typhimurium only. Enhanced bacterial clearance was observed when SC was coupled to plasma-derived IgA and IgM (189). Polymeric IgA against influenza virus reached the nasal mucosa after intravenous administration and protected WT mice against infection, and was 10 times more effective than IgG in reducing viral shedding (190, 191). Passive immunization with recombinant dIgA showed better prevention against intra-rectal simian HIV transmission in rhesus macaques. Dimeric IgA could either directly neutralize simian HIV or the virus was trapped by large immune complexes preventing entrance in the epithelial barrier (103). It was demonstrated that IgA isolated from serum of HIV survivors and vaccinated HIV patients neutralized HIV through occupying the CD4 binding site of the virus (192, 193). By contrast, in another study, HIV specific IgA levels in plasma interfered with IgG effector functions in vitro, thereby increasing HIV infection risk (194). Recently, it was reported that oral and nasal administrated HIV antigens bound to SIgA were retro transported through M cells and reached sub-epithelial DCs, thereby inducing both mucosal and systemic humoral and cellular immune responses in CX3CR1/GFP transgenic mice (195). Vaccination with SIgA-HIV antigen protected these mice from infection after challenge with a recombinant vaccinia virus expressing the HIV antigen (195, 196). This demonstrates the potential of SIgA to serve as a vaccine carrier for HIV via mucosal administration.

Vaccination with live attenuated polio induced intestinal IgA production and induced long-lived memory immune responses in elderly who still had detectable serum and salivary IgA levels (197–199), which suggested that priming with live virus is needed to obtain IgA responses after booster vaccination with inactivated polio virus. Furthermore, WT mice that were immunized and re-challenged with reovirus had enhanced serum and intestinal IgA levels and were protected from infection (108, 200). IgA^−/− mice were unable to clear reovirus infection (108). Mice immunized with hemagglutinin (surface protein on influenza virus) produced anti-influenza specific SIgA, which protected mice from infection after intranasal administration (201). Mice deficient of IgA, J-chain or pIgR showed compromised immune protection (106–108), supporting that IgA enhances protective immunity against viral and bacterial infections.

Antibodies targeting specific tumor-associated antigens like epidermal growth factor receptor (EGFR) and human epidermal growth factor two (HER2) are increasingly used to treat solid tumors (respectively colorectal cancer and breast cancer) (202). These therapeutic antibodies are often of the IgG isotype and have long half-life, can activate complement, and recruit natural killer cells as well as macrophages as cytotoxic effector cells (202, 203). Alternatively, IgA or FcαRI bispecific antibodies (BsAb) may represent promising novel drugs to treat cancer by enhancing activation of FcαRI-expressing immune cells (204). For instance, BsAb targeting both tumor antigens and FcαRI efficiently recruited neutrophils in vitro, which was not observed after targeting Fcγ receptors (205–207). Moreover, (immature) neutrophils were able to kill tumor cells more efficiently due to FcαRI-induced antibody dependent cellular cytotoxicity (62, 203, 208). Similarly, IgA anti-tumor mAbs mediated tumor killing more efficient compared to IgG mAbs. In vitro studies demonstrated the superior ability of FcαRI to induce neutrophil-mediated tumor cell killing for multiple tumor antigens, including EGFR, HER2, EpCAM, HLA-II, CD20, CD30, and carcinoembryonic antigen (203, 205, 209).

Unfortunately, in vivo tumor targeting using IgA anti-tumor mAbs has been difficult as mice do not express a homolog of the human FcαRI, and human IgA has a short half-life in mice (158). The generation and utilization of FcαRI transgenic mice (71, 158) can contribute to study IgA as therapeutic antibody in vivo. Treatment with IgA anti-HER2 or IgA anti-EGFR anti-tumor mAbs resulted in significantly enhanced anti-tumor cytotoxicity in FcαRI transgenic mice compared to WT littermates, which was mediated by FcαRI-expressing macrophages (210, 211). Furthermore, IgA anti-CD20 mAbs inhibited B cell lymphoma cell proliferation in vitro and recruited FcαRI-expressing immune cells in vivo in FcαRI transgenic mice (212, 213).

Thus, IgA antibodies have been shown to recruit neutrophils and macrophages as effector cells, but the short half-life of IgA in serum is a major drawback for use of IgA as therapeutic antibody. Compared to IgG, the glycosylation sites of therapeutic IgA mAbs that are produced in non-human systems (like rodent cells) have higher immunogenic potential (high glycosylation) and therapeutic IgA will be likely cleared efficiently from the human (or murine) circulation. Increasing the sialylation of glycans on IgA mAbs enhanced their serum half-life due to decreased clearance by the ASGPR in the liver (210). Inducing sialylation of IgA mAbs was done by using fully human systems thereby augmenting their in vivo therapeutic potential (211, 214–216). Increased sialylation of the N-glycans in IgA anti-HER2 mAbs resulted in significantly reduced tumor growth in FcαRI-transgenic SCID mice bearing BT-474 tumors (214). Addition of an albumin-binding domain to IgA1 (IgA1-albumin) enhanced interaction of the antibody with the FcRn, which extended the half-life of IgA1 in vivo. Although ex vivo studies showed that IgA1-albumin induced lower maximal tumor cell lysis, enhanced tumor cell killing was observed in vivo (211). Another modified IgA molecule against EGFR lacking glycosylation and free cysteine's, and with a stabilized heavy and light chain linkage, showed increased efficacy by interacting with FcαRI-expressing myeloid cells in vivo. Some therapeutic activity was observed in non-FcαRI transgenic mice demonstrating contribution of Fab-mediated effector functions as well (216). Although IgA antibodies are not used in clinical studies yet, engineering IgA with increased half-life represents a promising strategy for targeting tumors in patients.

Enhancing ITAMi signaling by monomeric targeting of the FcαRI may be a promising strategy to inhibit IgG-induced phagocytosis and IgE-mediated allergic diseases (20). Monovalent targeting of FcαRI with the anti-FcαRI mAb A77 inhibited degranulation of RBL-2H3 transfected cells and reduced airway inflammation in FcαRI transgenic mice after crosslinking FcεRI with IgE immune complexes in an allergic asthma model (20, 217). Furthermore, naturally occurring serum IgA dampened immune responses by inducing ITAMi signaling via FcαRI (19). FcαRI transgenic mice (expression on monocytes/macrophages), which developed RA after injection with IgG anti-collagen had reduced manifestations or even complete resolution of arthritis after treatment with monomeric IgA. IgG-induced ITAM signaling was blocked efficiently, implicating a potential role of monomeric IgA in treatment of autoimmune diseases with IgG autoantibodies (218). Moreover, prior targeting of FcαRI by Fab A77 suppressed inflammation in transgenic mice with FcαRI-expressing monocytes and macrophages that suffered from IgG immune complex glomerulonephritis and obstructive nephropathy (219). Renal inflammation induced by pristane was characterized by enhanced serum IgG levels, pro-inflammatory cytokines and immune infiltration in FcαRI transgenic mice with receptor expression on monocytes and macrophages. Blocking FcαRI with Fab MIP8a inhibited cytokine production, leukocyte recruitment and inflammation (77). Furthermore, renal inflammation induced by CpG (TLR9 agonist) in these FcαRI transgenic mice was downregulated by monomeric occupancy of FcαRI (220). Thus, monomeric targeting of FcαRI is suggested to induce anti-inflammatory properties, which could be useful in treatment of inflammatory diseases with involvement of myeloid cells.

Blocking FcαRI might be effective in IgA-mediated inflammation. In vitro it was shown that neutrophils stimulated with IgA immune complexes obtained from RA patients released neutrophil extracellular traps. FcαRI blocking on neutrophils with the anti-FcαRI mAb MIP8a reduced NET formation and might alleviate neutrophil induced tissue damage in RA patients (149). IgA autoantibodies in serum of LABD patients induced neutrophil-mediated tissue damage in an ex vivo human skin model. FcαRI blocking with MIP8a prevented IgA induced tissue damage (186). Similarly, peptides targeting the interaction sites of IgA and FcαRI showed effective blocking of IgA binding to FcαRI, and reduced IgA-induced neutrophil migration in vitro. These peptides were able to penetrate into human skin, supporting that they might function as novel therapy in skin autoimmune diseases (221). As such, blocking FcαRI might serve as therapeutic strategy for IgA-associated inflammatory diseases.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.