SIgA is a fundamental immunoglobulin in mucosal immunity. Its core structure is shared with other antibodies, consisting of two identical heavy chains and two identical light chains. Each heavy/light chain pair forms a Fab region responsible for antigen binding, while a flexible hinge region connects these to an Fc region that mediates effector functions (33). At mucosal surfaces like the oral cavity, salivary sIgA predominantly exists in a polymeric form, which corresponds to mucosal site-specific dimeric IgA (dIgA) that is composed of two monomeric units covalently linked by a joining (J) chain (34).

The synthesis and secretion of salivary sIgA are highly localized. It is primarily produced by mucosal plasma cells and antibody-secreting cells (ASCs) derived from B cells residing within the salivary glands and the lamina propria of the oral mucosa, operating independently of the gut-associated lymphoid tissue (GALT) (5, 7, 11, 13, 35). Following synthesis, dIgA is transported across the epithelium via transcytosis. This critical process is mediated by the polymeric immunoglobulin receptor (pIgR), synthesized by the epithelial cells themselves (11, 36). Upon release, the extracellular portion of the pIgR, known as the secretory component (SC), remains bound to the IgA complex, forming the complete and stable sIgA molecule (4, 6, 37). The bound SC is essential for sIgA's remarkable resilience. It masks vulnerable sites on the IgA molecule, providing robust protection against proteolytic degradation in the enzymatically hostile environment of the oral cavity, thereby preserving its functionality (4, 6, 27, 38). Functionally, sIgA is the major immunoglobulin and primary specific defense factor in saliva. It primarily targets oral pathogens (e.g., Streptococcus, Candida), dietary antigens, and toxins, playing a pivotal role in maintaining oral microbial homeostasis through immune exclusion and neutralization (4, 39).

Salivary sIgA is the principal antibody defending oral mucosal surfaces through multiple coordinated mechanisms. Its functional integrity relies on its unique structure, particularly the J chain and SC. The J chain is essential for forming dIgA and binding to the pIgR for transcytosis. SC, derived from cleaved pIgR, covalently binds to IgA, protecting it from proteolysis and enhancing its interaction with mucosal components like mucins, thereby optimizing immune exclusion (4, 11, 27, 36, 38).

A primary defensive function is immune exclusion. SIgA cross-links environmental microorganisms, preventing their adhesion and invasion. Specifically, it can directly bind to mannans on the cell wall of C. albicans. By occupying adhesins binding sites on the fungal surface, it prevents adhesins from interacting with epithelial cells, thereby inhibiting the mucosal adhesion of C. albicans (8, 36, 40, 41). The direct binding of sIgA to C. albicans inhibits its adhesion and invasion, reduces the stimulation of epithelial cells, and then down-regulates the secretion of pro-inflammatory mediators such as CXCL8/IL-8, IL-1α and IL-1β by epithelial cells, maintains mucosal homeostasis, and avoids tissue damage caused by excessive inflammation (24, 42). SIgA has been verified in vitro experiments to neutralize virulence factors like viruses (such as HIV) and bacterial toxins (such as lipopolysaccharide) (8, 9). During pIgR-mediated transport, it can even inactivate viruses intracellularly to prevent the damage in cells (27). Within the oral cavity, salivary sIgA interferes with biofilm formation by inhibiting microbial colonization and disrupting the initial steps of biofilm maturation on surfaces like dental plaque, helping maintain microbial balance (8, 10, 11).

Salivary sIgA does not act in isolation but synergizes with other salivary components. It binds to mucins to form a stable mucus barrier that traps pathogens and facilitates clearance via saliva flow. This interaction prolongs salivary sIgA's residence time, enhancing its functions (4, 11). Collaboration with antimicrobial peptides could further inhibits pathogen growth. Furthermore, sIgA actively interacts with immune cells to modulate immunity. It can influence dendritic cell maturation and guide T-cell differentiation towards regulatory subtypes, supporting mucosal tolerance (43). SIgA-antigen complexes can be presented by dendritic cells to activate CD8⁺ T cells, linking humoral and cellular immunity (44). Engagement of FcαRI (Fcα receptor I) on neutrophils and macrophages by sIgA triggers antimicrobial responses: it promotes antibody-dependent cellular phagocytosis (ADCP) of pathogens like C. albicans and can induce antibody-dependent cellular cytotoxicity (ADCC) (9, 12). Human NK cells express a novel IgA receptor, which could binds to sIgA and specifically regulates the killing activity of NK cells against target cells (45). These interactions are crucial for clearing pathogens from mucosal surfaces.

Clinical studies demonstrate a clear inverse relationship between salivary sIgA levels and oral candidiasis severity. Patients exhibit significantly lower salivary sIgA concentrations and excretion rates compared to healthy individuals, a deficit linked to impaired production by B cells and plasma cells (40). C. albicans itself can directly suppress human oral mucosal epithelial cells’ secretion of IgA (2). Consequently, IgA-deficient individuals face a markedly higher frequency of candidal infections (36, 46).

Multiple systemic diseases and conditions profoundly influence salivary sIgA levels and function, thereby impacting candidiasis risk. In HIV/AIDS, salivary concentrations of total IgA and subclasses (especially IgA2) are significantly reduced, with declines worsening as the disease progresses; diminished salivary flow further compromises mucosal defense (47). Sjögren's syndrome impairs salivary gland function, leading to hyposalivation, decreased salivary sIgA, and increased Candida carriage (11, 46). Similarly, diabetes mellitus promotes Candida colonization through elevated salivary glucose, while patients have the phenomenon of decreased saliva secretion (5). Other conditions like autoimmune diseases and malignancies also indirectly weaken sIgA-related immunity (18).

Medical interventions are major modifying factors. Immunosuppressants (e.g., corticosteroids, chemotherapy) and broad-spectrum antibiotics alter salivary proteins including sIgA and disrupt microbiome balance, predisposing to infection (13, 18). Head and neck radiotherapy (HNRT) damages salivary glands, causing hyposalivation, xerostomia, reduced salivary sIgA levels, and significantly increased Candida colonization and candidiasis incidence (3, 15, 48). Cancer patients undergoing such therapies exhibit markedly lower salivary sIgA levels and salivary flow, which enhances the salivary microbial load (49, 50). C. albicans is the predominant pathogen in these settings.

Age can affect salivary sIgA mediated mucosal defense: salivary gland dysfunction and decreased salivary flow in the elderly weaken the protective effect of salivary sIgA, which is also associated with diseases such as denture stomatitis (a common subtype of oral candidiasis in the elderly population). Infants are also susceptible to oral candidiasis (11, 18, 51). Salivary sIgA concentrations also follow circadian rhythms. Critically, lifestyle like tobacco smoking independently reduces salivary sIgA levels, induces epithelial keratinization, and impairs neutrophil function, all favoring Candida colonization and establishing smoking as a key risk factor for clinical candidiasis (46, 52). These predisposing factors contributing to oral candidiasis by affecting salivary sIgA levels or function are all shown in Figure 1.

As a commensal, C. albicans colonizes 30%–70% of healthy individuals (24). C. albicans initiates a pathogenic switch through hyphal formation and secretion of virulence factors, leading to Candida overgrowth and potential systemic spread in immunocompromised hosts (23, 53). While clinical studies frequently correlate reduced salivary secretory sIgA levels with the severity of oral candidiasis, conflicting findings have also been documented. For instance, elevated salivary sIgA levels are observed in certain populations (e.g., HIV-positive children, patients with uncontrolled diabetes, and individuals with denture stomatitis), who concurrently display an increased risk of oral candidiasis. This paradox may arise from sIgA functional impairment, such as decreased antibody avidity or an insufficient compensatory rise during active infection, rather than mere concentration decreased (46, 54–57). These controversies underscore that both the “quality” (functional attributes) and “quantity” (concentration) of sIgA are critical for mucosal defense, with functional parameters like avidity and specificity being as important as absolute levels (4, 11). Differences in salivary sIgA indicators and disease incidence between healthy individuals and susceptible to oral candidiasis are shown in Table 1.

SIgA targets a variety of C. albicans antigens. It preferentially binds to the hyphal morphotype, targeting hypha-enriched cell-surface adhesins such as Als1, Als3, and Hwp1, which are key mediators of host tissue adherence (53). SIgA also targets fungal lectin-like protein. Specific epitopes recognized include mannan and specific mannoproteins like phosphoglycerate kinase and fructose bisphosphate aldolase (58, 59).

A key protective mechanism of sIgA is the inhibition of the yeast-to-hyphal transition, a critical virulence step. SIgA effectively suppresses hyphal growth and adhesion. Molecularly, sIgA reduces the ergosterol content of C. albicans and feedback-upregulates the expression of the ergosterol biosynthesis pathway (including ERG3, ERG11, etc.), thereby inhibiting hyphal development. In vitro experiments, exogenous supplementation of ergosterol can reverse this phenomenon, while in vivo experiments have confirmed that sIgA significantly inhibits the adhesion and virulence of C. albicans (60). C. albicans can control the appropriate level of hyphal exposure through the expression of NRG1, thereby inducing a specifically targeted and non-destructive IgA immune response in the mucosal system. This response is able to suppress uncontrolled C. albicans hyperproliferation without triggering either excessive inflammation to damage the host or strong immune clearance, thus maintaining a state of “host-fungal commensal homeostasis” (23). Compared to serum IgG, sIgA exerts a more significant inhibitory effect on hyphal growth and epithelial damage (60).

SIgA also exerts regulatory effects on fungal metabolic activity and colonization: it disrupts metabolic homeostasis by interfering with ergosterol biosynthesis (60), and exerts a dose-dependent inhibitory effect on the adhesion of C. albicans to oral epithelial cells, thereby preventing the subsequent invasion of host cells (24, 60). Furthermore, the interaction between sIgA and C. albicans dampens the epithelial secretion of pro-inflammatory mediators (e.g., CXCL8/IL-8, IL-1α, IL-1β), indirectly creating an unfavorable microenvironment for colonization (24).

Conversely, C. albicans employs multiple strategies to evade sIgA-mediated immunity. It secretes secreted aspartyl proteinases (SAPs) that degrade sIgA by cleaving peptide bonds in it, inactivating its protective function and facilitating fungal adherence and invasion (61). Antigenic variation also serves as an escape mechanism. During germ tube formation, the release of cell wall mannoproteins alters surface antigens, further lowering sIgA reactivity and aiding immune evasion (62). C. albicans growth in acidic saliva significantly reduces sIgA reactivity, potentially explaining the link between low salivary pH and candidiasis (63). C. albicans forms biofilms, whose dense extracellular matrix could physically impede sIgA penetration, preventing it from reaching and neutralizing underlying fungal cells (13). The mechanism of sIgA interaction with C. albicans is illustrated in Figure 2.

Salivary sIgA can bind to secretory mucins in saliva and transmembrane mucins (e.g., MUC1) on the surface of oral mucosal epithelial cells, participating in the formation of a mucus layer that covers the oral mucosa, selectively recruit specific bacteria (e.g., certain Streptococcus species) to anchor within it, forming a stable beneficial microbial community, occupying the ecological niche of pathogenic bacteria, and inhibiting the formation of harmful biofilms (11). Furthermore, probiotics (such as Lactobacillus and Bifidobacterium) and prebiotics can indirectly promote sIgA secretion and enhance its function by regulating the oral microbiota, holding potential roles in sIgA-based immunological interventions—probiotics can induce cytokine secretion, promote the production of immunoglobulins (including IgA, IgG, IgM) and antimicrobial substances, and induce sIgA synthesis to correct microbiota imbalance, thereby improving the defense function of epithelial cells (20, 64, 65). As a core effector molecule of oral mucosal immunity, salivary sIgA further regulates the balance of the oral microbiota through multiple mechanisms to indirectly alleviate Candida overgrowth: first, it exerts weak interference on the adhesion of beneficial bacteria such as Lactobacillus and Bifidobacterium, protecting these beneficial bacteria from immune clearance and promoting their mucosal colonization to enhance their competitive advantage—metabolites including lactic acid (lowering the local oral pH to 4.0–4.5), lactocidin, and hydrogen peroxide produced during the proliferation of these beneficial bacteria can further inhibit the nutrient uptake and virulence expression of Candida (20, 66–68); second, sIgA can regulate the structure of the oral microbiota, break the co-aggregation interaction between Candida and auxiliary pathogenic bacteria such as Streptococcus mutans, reduce the formation of synergistic pathogenic biofilms, and indirectly weaken the excessive proliferation ability and pathogenicity of Candida (20, 68).