Besides its role of a neutralizing antibody that excludes antigens, S-IgA has also a function in antigen sampling, allowing a selective transcytosis of antigens from the lumen to the MALT (40). Not all encountered antigens form a threat for the host and it is essential that not all antigens lead to an activation of the immune system in order to avoid the development of aberrant inflammatory responses. Ideally, this means that upon inhalation of a harmless antigen, a suppression or down-regulation of the immune effector cell responses is induced and this immune suppressive effect is addressed as mucosal tolerance.

S-IgA is a key player in maintaining this mucosal tolerance, mainly because of is its inability to trigger an inflammatory response after binding its specific receptor FcαRI individually. FcαRI, which is expressed by the myeloid cell compartment, needs to collaborate with other receptors as mentioned above in order to amplify or inhibit the production of certain cytokines. The binding of IgA to its antigen leads to the formation of immune complexes (ICs) and their capacity to induce either tolerance or inflammation via the FcαRI depends on the absence or presence of a second signal. In the absence of additional signals, the recognition of ICs by FcαRI facilitates the uptake of antigens which leads to only a partial activation of DCs and does not trigger any proinflammatory responses (41). This function is key in the induction of the development of mucosal tolerance to, e.g., certain inhaled allergens where S-IgA seems to play a role (see below), although still very little is known about its mechanisms.

In addition to maintaining the mucosal tolerance, S-IgA plays an important role in the first-line immune defense against harmful inhaled agents such as pathogenic microbiota. It is able to provide this defense function through different mechanisms at different locations within the mucosa.

IgA can bind microbes in both a canonical and non-canonical way (42). Canonical binding includes Fab region-dependent binding of the antibody to the microbial antigen, while non-canonical binding describes all other binding modalities that are not determined by the complementarity determining regions (CDR) at the end of the Fab arms.

One of the oldest functions attributed to S-IgA is immune exclusion. Immune exclusion comprises of a series of events being agglutination, mucus entrapment and clearance of the airways (43). S-IgA first blocks the adherence of toxins and bacterial surface antigens, such as adhesins or pili that promote epithelial invasion by direct recognition of receptor binding domains (44). Then, agglutination occurs via crosslinking of IgA with microbial antigens, leading to the formation of macroscopic clumps of pathogens. It has been shown in both the gut as well as in the airways that those agglutinated clumps are then entrapped in the epithelial mucus layer which leads to their clearance out of the airways (45, 46). This entrapment is mostly mediated thanks to the oligosaccharide side chains of SC (47, 48) which emphasizes the advantages of S-IgA over monomeric IgA in secretions. At the level of the nasal mucosa, it has been shown that Fab-dependent recognition of S-IgA of a specific Streptococcus pneumoniae pilus protein, was required for binding to nasal fluid, leading to bacterial agglutination and immune exclusion. Also in mice, S-IgA treatment resulted in rapid immune exclusion of pilus-expressing pneumococci from the airways (49). This S-IgA function is addressed as passive immunity because it is able to eliminate pathogens from the lumen without the initiation of an adaptive immune response. In addition to eliciting this passive immune function in the lumen, specific IgA antibodies have also been shown to neutralize intracellular viruses (50) or proinflammatory antigens such as LPS (51) while in transit through the epithelium.

Nevertheless, although the rather poor complement activation functions of IgA in comparison to IgG and IgM, subepithelial dimeric (d) IgA is also able to activate an adaptive immune response. Pathogens that penetrate the epithelial layer will be opsonized by local d-IgA present in the subepithelial space. Under homeostatic conditions, IgA-opsonized pathogens are scarce in the lamina propria, but become very high on invasion by microorganisms during infection. These antibody-opsonized pathogens will not only activate FcαRI but also pathogen-sensing receptors, such as Toll-like receptors (TLRs), providing a second signal to the same immune cell. The combination of these two signals can then co-activate otherwise tolerogenic DCs into pro-inflammatory cells which induce an active adaptive immune response by activating T helper (Th)17 cells and type 3 innate lymphoid cell (ILC) responses (52).

The importance of IgA in the protective anti-bacterial immune response seems clear, since bacteria evolved into developing anti-IgA or anti-FcαRI bacterial proteins that prevent IgA-FcαRI interactions in order to avoid phagocytosis by FcαRI-expressing cells (53).

It is known that the nose and paranasal sinuses house a diverse microbiome with both commensal and pathogenic bacteria (54, 55). In healthy individuals, commensal microbes form a symbiosis with the host and they can even contribute to the mucosal barrier against incoming external pathogens. One of the most important functions of the mucosal immune system is to distinguish between pathogenic agents and innocuous commensals.

Because both commensals and invading pathogens often express similar antigens, the recognition of microbial structures by pathogen recognition receptors (PRR) such as TLRs is insufficient to explain how the mucosal immune system can discriminate commensals from invading bacteria (52). In view of the immunomodulatory capacities of IgA, it is believed that this antibody plays a crucial role in this distinction which has been investigated largely in the gut. Here, it has been reported that IgA might be responsible for the maintenance rather than elimination of indigenous bacteria to keep the diversity in gut (56). At the level of the intestinal mucosa, it is known that IgA binds to the surface of certain members of the intestinal microbiota (it has been estimated that up to 74% of bacteria in the gut lumen are coated with S-IgA) and for the majority of these microbes, this does not lead to their clearance from the intestinal system (57). Recent publications have revealed new properties of this IgA coating, including the control of the host's tolerance toward certain commensals (58). Why certain microbes are IgA-coated and others not, still remains a question mark. It has been suggested that IgA can directly or indirectly modulate the gene expression of microbes (59, 60) leading to different responses from epithelial or other cells toward the bacteria depending on their IgA-coating (60). Another explanation might be that bacterial IgA-coating depends on and might even control the pathogenicity of the microbe; Palm and colleagues combined both human and murine samples of chronic inflammatory bowel disease and found that IgA-coating of microbiota determined the “colitogenic” capacity of the concerned bacteria (61). More prove to support this theory is coming from patients suffering from SIgAD that seem to present with a dysbiosis of the gut microbiota, characterized by overrepresentation of certain pathogenic species, as well as a simultaneous underrepresentation of certain beneficial commensals (62–64). It has also been shown that S-IgA coating of micro-organisms can facilitate the formation of a biofilm that favors the growth of slow-growing commensals while attenuating that of pathogens (65).

There is some minor evidence that similar pathways may be playing in the airways. For example, pIgR^−/− mice that completely lack S-IgA, show a persistent activation of innate immune responses to resident lung microbiota, driving progressive small airway remodeling and emphysema (66). Interestingly, it has recently also been shown that disrupted SIgA-microbiota interactions in the gut are linked to an increased risk of developing allergies and asthma in children (67). This does not only emphasize the importance of IgA-microbial interactions in the development of allergies, but also the potential systemic signaling and interchangeability of the different microbial compartments in the human body.

Viral rhinitis or common cold is one of the most common conditions in the world. In case of bacterial superinfection, rhinitis will virtually always evolve to a bacterial rhinosinusitis.

Due to the important role of IgA in first line defense against inhaled pathogens, leading to their neutralization and elimination out of the respiratory tract, people presenting with SIgAD are expected to suffer from recurrent airway infections. Indeed, epidemiological studies haves shown that recurrent infections of the respiratory system are the most common finding in patients with SIgAD (72); upper airway infections, including recurrent rhinitis and rhinosinusitis are found in 48–78% of these patients (71–73). However, as mentioned above, not all patients experience this problem and this might be due to a compensatory function of IgM, which has functional similarities to IgA and is often increased in these individuals.

IgA has shown to be very effective at tackling viruses in virus-infected epithelial cells and in redirecting antigens to the lumen when they enter the lamina propria (74). Upper airway infection with certain viruses such as rhinovirus (75), influenza (76), and SARS-CoV2 (77) has shown to induce an increase of S-IgA in the nasal lavage and for influenza, it has been proven that this nasal S-IgA plays an important role in the protection against viral infection in humans (76). This is supported by murine studies where transfer of nasal IgA from immunized to naïve mice leads to protection against influenza infection (78) and mice lacking S-IgA have increased viral load after intranasal challenges (79). No articles are currently discussing the role of IgA in the development of acute bacterial rhinosinusitis, however, patients with cystic fibrosis and CRS who were chronically infected with Pseudomonas aeruginosa, showed increased S-IgA concentrations in their nasal secretions (69, 80). At the level of the lower airways it has been shown that reduced respiratory S-IgA production can lead to an increased susceptibility toward P. aeruginosa (81). More proof of the importance of S-IgA in the prevention of recurrent upper airway infections is coming from endurance athletes. Strenuous exercise has shown to decrease S-IgA production as measured in the saliva and there is evidence that this decrease is linked to the occurrence of increased upper respiratory tract infections witnessed in elite athletes (82–84).

Allergic rhinitis (AR) is the most common cause of chronic rhinitis and its prevalence is situated between 23 and 30% in Europe (85). In genetically predisposed atopic individuals, DCs that are exposed to respiratory allergens induce an immunological shift of T-cells toward the Th2 subtype with a production of allergen-specific IgEs by activated B-lymphocytes. After this sensitization phase, re-exposure leads to a crosslinking of the allergen with the mast cell-bound specific IgEs which causes mast cell degranulation and acute allergic symptoms (3). Th2 related cytokines such as IL-4, IL-5, IL-13 attract eosinophils to the nose that release cytotoxic granule proteins and other products (such as lipids and extracellular traps) in the nasal mucosa, giving rise to airway oedema, damage, and remodeling.

Several studies have shown that S-IgA is a potent stimulus for eosinophils and among all immunoglobulins S-IgA even represents the main trigger of eosinophil degranulation, possibly due to eosinophils expressing a specific receptor for SC (86, 87). Blood eosinophils incubated with S-IgA in vitro release large amounts of eosinophil cationic protein, eosinophil peroxidase, eosinophil-derived neurotoxin, as well as IL-4 and IL-5 (88, 89). In addition to eosinophils, basophils also degranulate on activation by S-IgA and S-IgA may thus favor a Th2 profile through the modulation of the cytokine response of these cells (90). In AR patients, nasal allergen challenge induces a biphasic increase of IgA in the nasal mucosa (91), similar to IgE, and specific nasal IgA responses have been reported in patients with AR sensitized to house dust mite (92), grass (93), ragweed (94), birch pollen (95), and red cedar (96). In the latter study, IgA levels in nasal lavages were shown to correlate with nasal symptoms (96). Nevertheless, this view of the IgA response as a pathogenic mechanism in AR acting along with IgE, is contested by several observations: first, SIgAD or delayed serum IgA production in childhood is a well-known risk factor for atopy (97, 98) and patients with sIgAD suffer more frequently from AR compared to the general population (71, 72). Second, in contrast to the specific IgE response, there is evidence that the production of allergen-specific IgA seems to play a rather protective role leading to the induction of tolerance toward the respiratory allergens. Healthy individuals show for example allergen-specific IgA antibodies but no IgE, and allergic patients show lower total IgA levels and a relative deficiency in allergen-specific IgA antibodies in their serum compared to healthy controls (13, 14). In neonatal studies, S-IgA in breast milk has been linked to reduced risk for developing atopic diseases (99–102). At a later age, high salivary S-IgA levels were associated with less development of allergic symptoms in a group of sensitized Swedish children (103). Also, a biopsy study performed in adult AR patients showed reduced levels of tissue IgA compared to healthy controls, which was linked to a decreased pIgR expression at the level of the epithelium (15). In addition to these human data, several animal studies support this theory of a protective role of IgA in AR. One study showed that intranasal administration of ragweed-specific IgA protected against allergic inflammation in sensitized mice (104). Another murine study showed that the production of specific IgA in neonatal mice prevented the development of cockroach allergy (105).

More evidence for this tolerance-inducing role of IgA is coming from allergen immunotherapy (AIT) research as will be discussed below. However, the mechanisms by which IgA can prevent or modulate AR still need to be elucidated.

In about 20–30% of chronic rhinitis patients, no infection nor IgE-mediated allergy can be demonstrated and this pathology is addressed as non-allergic, non-infectious rhinitis or short “NAR” (106). NAR comprises a heterogeneous group of chronic rhinitis subtypes, such as drug-induced rhinitis, hormonal-induced rhinitis and occupational rhinitis. However, in about 50% of the NAR patients, no specific causal factor can be found and this is addressed as idiopathic rhinitis (IR) (107). The disease mechanisms of NAR patients are much less studied than their allergic peers and to our knowledge, no studies have investigated the course nor the role of IgA in NAR.

Regarding IgA in CRS, it has been reported that 16.7% of patients with CRS have low levels of IgA with 6.2% of them matching the definition of SIgAD (108). Conversely, SIgAD present more frequently with CRS (up to 78%) compared to individuals with normal antibody levels (72).

Several studies have studied the IgA production in CRS patients (Table 1). At the serum level, all studies seem to agree that no significant differences are detected between CRS patients and controls (111, 116). However, at the level of local IgA production, differences are detected between CRS patients and healthy controls. Four studies found higher levels of IgA (total and/or IgA1) in sinus tissue from patients with CRSwNP (15, 109, 113, 115) and three of them showed increased numbers of IgA+ plasma cells (109, 113, 115). Two studies reported also on an overexpression of BAFF, an important inducer of local IgA class switching, in CRSwNP patients (112, 115). These findings indicate an increase in the local IgA production by type 2 inflamed polyp tissue (as is the case for IgE) and most of the plasma cells detected in NP tissue are actually of the IgA producing type (118). One recent article suggests the possibility of local conversion of bacterial antigen-specific IgA to IgE that might occur in a Th2 environment (110), but more insight is needed to confirm its relevance.

With regards to S-IgA levels in nasal secretions, results are a bit less straightforward; while a large study performed by Tsybikov et al. (114) found increased S-IgA levels in 54 patients with CRSwNP compared to 40 healthy controls, this increase was not in keeping with the—smaller—study by Hupin et al. (15). Although, they confirmed the previously described increase in tissue IgA in CRSwNP patients, this was not translated into higher S-IgA levels in the nasal secretions, but rather due to an accumulation of IgA in the subepithelial tissue. This could be explained by the fact that CRSwNP patients showed significantly lower expression levels of pIgR on their epithelium, leading to a reduced transepithelial transport of the immunoglobulin. Although, no significant differences in S-IgA were detected, they did demonstrate reduced antigen-specific IgA levels directed toward S. aureus Enterotoxin B (SEB) (15), a powerful superantigen linked to the severity of Th2 inflammation. Most of the other studies looking at IgA levels in CRS did not characterize the specificity of IgA in patients. However, other study found elevated mucosal levels of autoreactive IgA to nuclear antigens, including double stranded DNA and basement membrane components that might contribute to the disease mechanism (117).

Very little additional information can be retrieved from animal models, mostly due to the lack of well-established CRS models. Only one article reported on increased S-IgA levels in nasal secretions of mice with experimentally induced CRS (119).

Patients presenting with agammaglobulinemia are successfully treated with IgG replacement therapy, which reduces the frequency of invasive bacterial infections. Due to the incapacity of IgA to activate complement by itself, agammaglobulinemia patients do generally not receive IgA replacement therapy, nor do patients with SIgAD. However, agammaglobulinemia patients on IgG treatment often still present with chronic respiratory disease (137–139) and IgA-enriched immunoglobulin preparations could offer a solution. A limited number of these preparations, also containing IgM (Pentaglobin and Trimodulin) have been tested in humans (140). These preparations showed better opsonizing capacities toward certain pathogenic bacteria compared to IgG replacement alone (141, 142) with better clinical outcomes regarding respiratory infections. IgA-only enriched IgG preparations have previously shown successful results in treating intestinal infections in children (143, 144) but have not been tested for the prevention or treatment of respiratory infections. Endonasal administration of serum-derived IgA in children at risk for recurrent airway infections, reduced the number of infectious episodes and increased their endogenous IgA production compared to placebo (145). Although, these results seem promising, the downside of these preparations is that the enrichment is based on serum-derived IgA, which is less resistant to bacterial proteases compared to S-IgA because of the abundance of the IgA1 isoform and the absence of SC.

Allergen immunotherapy (AIT) is unlike anti-allergic drugs the only disease-modifying treatment option for AR, which has been shown to have long-term benefits (146). AIT is based on the administration of the causal allergens in high dosages in order to modulate the immune response of the allergic patient via an immune deviation of Th2-cell response toward a Th1-cell response with the consequent suppression of Th2 cells, induction of regulatory T and B cells and induction of IgG-blocking antibodies (104). Although, we know that both the subcutaneous (SCIT) and sublingual (SLIT) administration routes are very effective in treating AR, several unanswered questions remain regarding its mechanisms. Successful AIT is associated with an increase in IgA responses (100); in a 2-year double blind trial, grass pollen AIT induced a shift in allergen-specific antibody response toward IgA2, which correlated with increased local TGF-β expression and induced monocyte IL-10 expression (147). A recent study comparing subcutaneous and sublingual grass pollen AIT reported mainly increases in allergen specific IgA after sublingual AIT compared to the subcutaneous form, suggesting a more important role of this immunoglobulin in the mechanism of SLIT compared to SCIT (101). It is believed that IgA acts as a scavenger that binds the allergens in the mucosal lumen before they can trigger pro-inflammatory signals by binding their specific mast-cell bound IgE. Data to support this is coming from murine experiments; it has been shown that intranasal treatment of mice with antigen-specific monoclonal IgA antibody prevented increases in airway hyperreactivity, tissue eosinophilia, and IL-4 and IL-5 production after allergen challenge (104), suggesting that neutralization of aeroallergens by IgA is a protective mechanism achieving a form of molecular allergen avoidance.

It has been postulated that exposure to bacterial products early in life, reduces the risk of developing allergies and airway infections by increasing the immune response efficacy. Based on this concept, oral bacterial lysates have been tried and proven successfully in the prevention of recurrent viral respiratory tract infections (148–150). The effect is believed to be elicited by the modulation of DC activity, monocyte-macrophages, B-cells, regulatory T cells, and airway epithelial cells (151). One of the studies that showed a beneficial effect of oral bacterial lysate on recurrent airway infections in patients at risk, demonstrated an increase in serum and S-IgA levels, which coincided with the administration of the bacterial lysate (151). More studies are needed to investigate the clinical relevance of this S-IgA increase and its potential consequence on the nasal microbiome.

Antibiotics are widely used in the treatment of acute and chronic rhinosinusitis, even in more chronic protocols, in spite of the restricted indications mentioned in the European guidelines (5). The use of antibiotics is known to affect the intestinal and respiratory microbiota, possibly leading to an imbalance of their microbiome by over- or under-growth of certain species. One study combining both murine and human data showed that antibiotic use led to a microbial shift that reduced the TLR- and APRIL-dependent respiratory S-IgA production, leading to an increased susceptibility toward certain pathogens such as P. aeruginosa. In mice, the nasal application of polyclonal intestinal IgA attenuated the severity of P. aeruginosa infection and its mortality, after an antibiotic-induced decrease in IgA (81).

Several studies mentioned above have indicated that a rich microbial environment can contribute to mucosal tolerance and protective IgA responses, leading to an improved protection against respiratory infections and inflammation. This has brought forward the idea of using a microbial-derived molecule as a potential candidate to stimulate protective IgA responses and preventing the development of infections and allergy. Cholera toxin is the most widely experimentally used mucosal adjuvant, which is capable of inducing an IgA response through TLR-primed DCs. Studies in mice have shown that the co-administration of an experimental allergen and cholera-toxin prevents sensitization to the allergen (152, 153). Others found that intratracheal administration of cholera toxin can suppress allergic inflammation through the induction of airway luminal IgA secretions, an effect that was not seen in mice lacking S-IgA (154). This has led to the hypothesis that the administration of cholera toxin to patients with impaired IgA synthesis could contribute to a broader antibody repertoire with increased mucosal IgA levels leading to an improved mucosal immunity and local homeostasis (155). Nonetheless, this remains to be further explored in human disease.

In comparison to serum IgA, S-IgA is much less sensitive to proteolytic activity of bacteria and the SC contributes to the efficiency of its immune exclusion capacity (47). Therefore, local replacement therapy of S-IgA might be more effective in patients suffering from agammaglobulinemia, SIgAD and other immune deficiencies, at preventing recurrent infections compared to replacement therapy using serum IgA. Anecdotal studies in mice have suggested that local application of S-IgA can be protective against certain infections (81, 156) and this is a potential track to be explored for treating refractory or recurrent infections.

Although AIT has shown to provide long-lasting beneficial effects for a substantial number of AR patients, SCIT still carries a risk of important adverse reactions and SLIT is susceptible to failure due to therapeutic compliance issues. Also, it shows variable efficacy between patients, and generally takes 3–5 years to induce tolerance. For these reasons, researchers have been looking for alternative ways to induce allergen tolerance. One of the possibilities is the administration of a so-called passive AIT under the form of antigen-specific immunosuppressive antibodies that have the ability of competing with IgE for allergen binding and functionally preventing the immediate hypersensitivity response. This hypothesis has been tested in both cat- and birch-allergic patients, receiving subcutaneous injections with a pre-selected allergen-blocking IgG against the respective major allergens showing beneficial results for over 2 months after only one injection (157, 158). Because of the mucosal advantage of IgA over IgG, a similar therapeutic potential may lie in the local administration of isolated allergen-specific IgA, which has been shown to be effective in an in vivo mouse model of airway allergy (104). Nonethesless, the efficacy and applicability of this approach in allergic patients needs however to be studied.