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Most antibodies in the body belong to the IgA class (3, 4, 5, 6, 7). IgA is the primary secreted antibody (1). IgA accumulates mutations throughout an individual's lifetime (1). Mutations in IgA are often linked to microbial induction (1). Early-life diet can independently influence IgA induction, its repertoire, and mutation diversity (1)
In both germ-free and colonized mice, different diets were tested (1). Dietary lipopolysaccharide contamination activated Toll-like receptor (TLR) 4 signaling (1). TLR 4 signaling enhanced germinal center activity in the intestinal immune system (1). Lipopolysaccharide's impact on mucosal immune induction was observed only when delivered in colloidal liposomes (1). Delivery method of lipopolysaccharide is crucial for its effectiveness (1)
Plasmablasts and plasma cells are the primary producers of IgA as a dimer in the presence of (2, 3, 4, 5, 6, 7):
* Treg-derived Transforming Growth Factor Beta (TGF-beta)
* Epithelial cell-derived B cell Activating Factor of the Tumor Necrosis Factor (TNF) family (BAFF)
* A Proliferation-Inducing Ligand (APRIL)
B cells / B Lymphocytes in the intestine are transformed into secreted immunoglobulin A (sIgA) / IgA-synthesizing Plasmablast / Plasma cells (17).
The IgA+ plasma cells are generated in the mucosa. They then migrate to their “classic” effector site, the lamina propria of the intestine (29).
Located in the lamina propria of both the large and small intestines (3, 4, 5, 6, 7), the production of immunoglobulin A (IgA) in intestinal Plasmablast / Plasma cells is positively influenced by epithelial-associated bacteria such as mucispirillum and segmented filamentous bacteria (SFB) (13).
Production is induced by bacteria and their SCFAs. Lactobacillus rhamnosus GG promotes early B lineage development and secreted immunoglobulin A (sIgA) / IgA production in the Lamina Propria in piglets (14). It promotes local antigen-specific immune responses (particularly in the IgA class) (19).
Bacteroides ovatus as the species that best induced gut secreted immunoglobulin A (sIgA) / IgA production (20).
Bifidobacterium bifidum H3-R2 enhanced the production of secretory immunoglobulin A (SIgA), and promoted splenic lymphocyte proliferation, natural killer (NK) cell activity and phagocytosis of macrophages in immunosuppressed mice (21).
Enhancement of serum secreted Immunoglobulin A (sIgA) / IgA response to attenuated Salmonella typhi Ty21a has also been found (22).
Antibiotic exposure is associated with increased secreted Immunoglobulin A (sIgA) / IgA coating of Enterococcus sp and Lactobacillales (23) and it is therefore expected that each individual harbors a distinct IgA-coated bacterial repertoire (24). Interestingly, environmental factors have also been shown to influence IgA responses to bacteria (24).
Short-chain fatty acids (SCFAs) increase secretion of secretory IgA (sIgA) by B cells / B Lymphocytes (27). Acetate - one of the major gut microbial metabolites - increases the production of secreted immunoglobulin A (sIgA) / IgA in the colon and alters the IgA pool's capacity to bind to specific microorganisms, including Enterobacterales. Acetate controls the selective IgA binding to certain microorganisms. It orchestrates the interactions between epithelial and immune cells, induces microbially stimulated CD4 T cells to support T cell-dependent IgA production, and consequently changes the localization of these bacteria in the colon (28).
Dimeric IgA complexes are bound by the polymeric immunoglobulin receptor (pIgR) on the basolateral membrane of IECs and actively transcytosed into the intestinal lumen (17).
IgA binds to the polymeric Ig receptor on the basolateral surface of intestinal epithelia (6). SIgA binds to commensals and soluble antigens. Thus, a large part of the commensal microbiota in the intestine is covered with IgA antibodies (24). Early studies of gut microbiota revealed that secretory IgA coat only a fraction of human and murine microbiota (31, 32).The binding of IgA to the commensal microbiota is mostly glycan-mediated.
This blocks the adhesion of the bacteria to epithelial cells and the penetration through the epithelial barrier (15). By that, bacterial virulence is affected (16). During infection, secreted Immunoglobulin A (sIgA) / IgA-coated pathogens are cleared via a process called immune exclusion (25, 26).
Induction of sIgA against commensal antigens is T cell independent in mice (30).
Sutterella species are associated with low secretory IgA levels, as they degrade the secretory component (SC) of SIgA as well as IgA itself (18).
While the IgA is lacking, anaerobic bacteria expand, including segmented filamentous bacteria (SFB) (17)
IgA recognition of beneficial bacteria is decreased in acutely malnourished children. Child undernutrition is a global health challenge exacerbated by poor sanitation and intestinal inflammation. In contrast to healthy control mice, undernourished mice fail to develop Secreted Immunoglobulin A (sIgA) / IgA recognition of intestinal Lactobacillus. Due to rapid bacterial adaptation, glycan-mediated interactions between Lactobacillus and host antibodies are lost in malnourished mice (33).
Together these data indicate that diet-driven bacterial adaptations shape Secreted Immunoglobulin A (sIgA) / IgA recognition in the gut (33).
The defects in Secreted Immunoglobulin A (sIgA) / IgA production could elicit dysbiosis of commensal microbiota (34).
Maternal secretory immunoglobulin A (SIgA) in breast milk plays a central role during the early postnatal period (8, 9). Regulated by genetics and maternal microbial exposure, maternal secretory immunoglobulin A (SIgA) in breast milk shapes the microbiota and the infant immune system (9).
Secreted Immunoglobulin A (sIgA) is crucial for mucosal immune defense. sIgA neutralizes harmful toxins and regulates the composition and function of the commensal microbiota. This process maintains homeostasis at mucosal surfaces (3, 4, 5, 6, 7). Secreted Dimeric IgA in response to defined surface and non-surface membrane antigens of nonpathogenic microbiota accounts for most Antibody production in mammals (10). IgA+ plasma cells produce large quantities of IgA on mucosal surfaces. IgA protects the host from pathogens and restricts commensals' access to the subepithelium (29). Most microbes, irrespective of their microbial phylogeny, can induce specific IgA in monocolonized gnotobiotic mice (11, 12).
The production of secretory immunoglobulin A (SIgA) by Peyer's patches (PPs) and by plasma cells in the lamina propria favors the selection of commensal species, protects against the translocation of pathogenic bacteria into the bloodstream, and can neutralize bacterial toxins (35, 36).
Secreted Immunoglobulin A (sIgA) / IgA has been shown to play a role in maintaining a healthy balance between the host and bacteria. However, IgA antibodies also play an important role in neutralizing pathogens in the gastrointestinal tract. The distinction between the two roles of IgA - protection and balance maintenance - has implications for function and how production is regulated (37).
IgA blocks the adhesion of the bacteria to epithelial cells, and affects bacterial virulence (16).
Secretory immunoglobulin A (sIgA) that binds to commensal and invading microbes contributes to the homeostasis of intestinal mucosal immunity and barrier function (38).
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(5) Lycke et al. 2017 Mucosal Immunol. 10, 1361-1374
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(22) Collins et al. 1998 Int. Dairy Journal 8: 487-490
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(30) Macpherson et al. 2000 Science 288: 2222
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see also:
Bacteria & Secreted Immunoglobulin A (sIgA) / IgA
Gut microbiota & Secreted Immunoglobulin A (sIgA) / IgA