Version July 2025
INTRODUCTION —
Immunoglobulin A (IgA) accounts for most of the immunoglobulin in secretions and a significant amount of circulating immunoglobulin. In secretions, it serves to protect the mucosal tissues from microbial invasion and maintain immune homeostasis with the microbiota. The distribution, structure, production, biologic functions, and regulation of IgA will be discussed in this review.
Selective IgA deficiency is reviewed separately. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and "Selective IgA deficiency: Management and prognosis".)
DISTRIBUTION —
IgA is the most abundant antibody isotype in the body, comprising almost 75 percent of the body's total immunoglobulin. The majority of IgA is found in the various mucous secretions, including saliva, milk, colostrum, tears, and secretions from the intestinal and respiratory tract, genitourinary tract, and prostate [1-3].
Normal serum levels — IgA is the second most abundant isotype in the circulation, following immunoglobulin G (IgG) [4-8]. IgA levels, generally absent at birth, gradually increase throughout the first year of life to approximately 30 percent of adult levels at one year. Adult levels of IgA are reached in adolescence [9]. Normal serum levels range from 61 to 356 mg/dL [10].
Abnormal levels — Increased serum levels of IgA are seen in several inflammatory disorders, including IgA nephropathy, immunoglobulin A vasculitis (Henoch-Schönlein purpura), acquired immune deficiency syndrome (AIDS), alcohol-associated cirrhosis, advanced hepatitis, IgA myeloma, and several autoimmune diseases (eg, rheumatoid arthritis, systemic lupus erythematosus).
Decreased levels of serum IgA are primarily found in some inborn errors of immunity (IEI), particularly in selective IgA deficiency, common variable immunodeficiency (CVID), and ataxia-telangiectasia, and may be secondary to acute and chronic lymphocytic leukemia, chronic myelogenous leukemia, macroglobulinemia, and heavy chain disease. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Differential diagnosis'.)
STRUCTURE —
The IgA molecule was first described in 1953 [4]. Since then, major technical advancements have led to better understanding of its structure. High-resolution analyses of IgA and secretory IgA using the cryo-electron microscopy (cryo-EM) technology can reveal their various forms and receptor interactions [11,12]. Each IgA molecule is composed of two heavy chains and two light chains. Each heavy chain consists of one variable and three constant regions, whereas each light chain has one variable and one constant region. One monomeric IgA molecule has two Fab portions, which bind antigens (figure 1).
There are two subclasses of IgA monomer: IgA1 and IgA2. Each IgA subclass has slightly different constant heavy chains, which are encoded by two separate alpha-1 and alpha-2 genes on chromosome 14 [5-8]. The main structural difference between them is that IgA1 has a longer hinge region compared with IgA2.
Forms — IgA is found in the body in two forms: monomeric and polymeric. Circulating IgA in the peripheral blood is generally monomeric, whereas the polymeric forms are found in mucosal secretions of the respiratory, intestinal, and genitourinary systems, hence the name "secretory IgA" [5-8,13].
●Monomeric serum IgA is mostly composed of IgA1 molecules. These have two Fab portions that bind antigens (figure 1). Once the Fab portions have bound antigens, the Fc portion binds to Fc-alpha receptors (Fc-alpha RI/CD89) located on the cell surface of neutrophils, eosinophils, monocytes, macrophages, dendritic cells, and Kupffer cells [8,14]. IgA binding to this receptor initiates ingestion and destruction of the microorganism by the phagocyte. (See "The adaptive humoral immune response", section on 'Opsonization'.)
●IgA in its polymeric form is primarily dimeric IgA consisting of two monomeric IgA molecules linked to each other with a J (joining) chain and stabilized with a small molecule called the secretory piece (figure 1). This complex is referred to as "secretory IgA." The J-chain serves as a template for incorporation of monomers to form a stable IgA polymer, which has an amyloid-like assembly of the oligomerized structure. The J-chain also confers asymmetry for polymeric immunoglobulin receptor (pIgR) binding on the basolateral surface and transcytosis through the epithelium to the mucosa, and it has a significant role in pIgR/secretory piece binding to dimeric IgA [11,15]. The antigen-binding capacity of the dimeric IgA is twice that of the monomer. Larger secretory IgA polymers (tetrameric or pentameric structures) have higher neutralizing potency, particularly for low-affinity repetitive antigenic epitopes, such as those found on the surface of many bacteria and viruses. Trimeric, tetrameric, and larger forms, which have six to eight antigen-binding sites or more, have been shown in nasal secretions of healthy individuals [13]. Secretory IgA in the intestine, particularly in the lower intestine, is mostly composed of IgA2 molecules, whereas the IgA1 isotype dominates in the parotid gland [16]. The shorter hinge region of IgA2 enables secretory IgA to resist bacterial proteases in the lumen of the gastrointestinal system [16,17]. The secretory piece of the secretory IgA dimer is actually the secreted component of the polymeric immunoglobulin receptor, which is located on the basolateral surface of the mucosal epithelial cell [18,19]. The secretory piece protects the IgA dimer from being degraded by the proteolytic enzymes of the lumens. (See 'Production' below.)
Secretory IgA not only binds to bacterial antigens via specific recognition by means of Fab portions but also coats some bacterial species through N- and O-glycan-mediated nonspecific innate interactions [20]. (See 'Production' below.)
Glycosylation — Glycosylation of IgA can have both beneficial and detrimental effects.
The N- and O-glycans of secretory IgA are similar to the glycans on microbial surfaces and appear to act as decoys, binding to receptors for these molecules on the luminal surfaces of intestinal epithelial cells and preventing bacterial attachment. In addition, N- and O-glycans are probably functional in coating of the numerous and diverse bacteria indigenous to the oral cavity and intestinal tract.
Glycosylation of immunoglobulins can impact susceptibility to certain diseases. Both IgA1 and IgA2 carry a number of N-linked oligosaccharides (ie, glycans). In addition, the hinge region of IgA1 harbors nine potential O-glycosylation sites, of which three to five are usually occupied by O-glycans [20-22]. Both IgA molecules are more heavily glycosylated compared with IgG. Glycome investigation of the circulating IgA O- and N-glycans shows that glycosylation is largely genetically determined and conserved across ancestries. Glycosylation features, such as bisection, fucosylation, galactosylation, and sialylation, vary by age and sex. Aging and female sex are associated with increased N-glycan bisection, which is the most heritable trait, and galactosylation and sialylation of N- and O-glycans decrease by age, suggesting a possible connection with inflammatory and autoimmune conditions [23].
Certain glycosylation patterns of IgA1 molecules are also implicated in the pathogenesis of inflammatory and autoimmune diseases [24]. In IgA nephropathy, serum IgA1 with reduced galactose in O-linked glycans in the hinge region (galactose-deficient IgA1 [Gd-IgA1]) is increased. Other glycosylation patterns, such as reduced sialylation of O-glycans and modified N-glycosylation of IgA1, have also been reported [25]. However, aberrant glycosylation is not sufficient for disease onset; specific IgA1 antibodies targeting beta-2-spectrin and chromobox 3 (CBX3) antigens selectively expressed on the kidney mesangial cell surface appear to play a trigger role in nephritogenic immune complex formation and deposition in IgA nephropathy.
PRODUCTION —
Daily IgA production (serum plus secretory IgA combined) greatly exceeds production of all other immunoglobulins [26-30]. Approximately 75 percent of all produced immunoglobulin is IgA, primarily in the gut, milk, and bronchial secretions. Serum IgA is produced by plasma cells in the bone marrow. It is not clear where these plasma cells are originally generated or whether there is a contribution of mucosal plasma cells to the bone marrow compartment [30]. Secretory IgA is produced locally in the mucosal tissues and is not derived from serum IgA. In fact, serum IgA and secretory IgA are molecules with different biochemical and immunochemical properties produced by cells with different organ distributions [8]. In the gastrointestinal system, IgA originates from the follicular B cells of the gut-associated lymphoid tissue (GALT), which is composed of organized Peyer's patches, mesenteric lymph nodes, isolated lymphoid follicles, and nonorganized lamina propria. Further discussions of the mucosal immune system in the context of the development of food allergy and inflammatory bowel disease are found separately. (See "Pathogenesis of food allergy", section on 'The gut immune system' and "Immune and microbial mechanisms in the pathogenesis of inflammatory bowel disease", section on 'The mucosal immune system'.)
IgA production occurs by T cell-dependent mechanisms in Peyer's patches or mesenteric lymph nodes, as well as by T cell-independent mechanisms in the lamina propria [1-3,31]. Intestinal epithelial cells, dendritic cells, and local stromal cells may contribute to T cell-independent production of IgA locally by secreting thymic stromal lymphopoietin (TSLP), interleukin (IL) 6, IL-10, tumor necrosis factor (TNF) alpha, transforming growth factor (TGF) beta, B cell-activating factor (BAFF), and a proliferation-inducing ligand (APRIL) [2,3]. A general discussion of antibody production is found elsewhere. (See "The adaptive humoral immune response".)
During development, intestinal B cells undergo VJ (for light chains) and VDJ (for heavy chains) gene somatic hypermutation (SHM) and class-switch recombination (CSR) from immunoglobulin M (IgM) to IgA, mainly in the germinal center of Peyer's patches and mesenteric lymph nodes. In the distal human gut, IgA2-producing plasma cells appear to develop in the lamina propria by direct CSR from IgM to IgA2 in a T cell-independent manner [32]. A T cell-independent pathway is also sufficient to coat most small intestinal microbes, resulting in increased uptake of microbes into Peyer's patches and thereby inducing the IgA production with a positive feedback [33]. (See "Immunoglobulin genetics".)
The IgA-secreting plasma cell, which has developed through T cell-dependent or T cell-independent pathways, migrates in the lamina propria to reach the proximity of the epithelial surface and releases IgA molecules. These IgA molecules bind to the polymeric immunoglobulin receptor on the basolateral surface of the mucosal epithelium. This same receptor is involved in the transport of pentameric IgM across epithelial surfaces to form secretory IgM. Bound IgA and immunoglobulin receptor complex is internalized into the cell and transported to the apical surface of the epithelium, the process of transcytosis. On the surface, the IgA molecule dissociates from the immunoglobulin receptor and is secreted into the lumen carrying a part of the immunoglobulin receptor, which is called the secretory piece. Dimeric IgA molecules bind antigens in the gut and are expelled [15].
FUNCTIONS —
IgA appears to be important in immune functions, although it has intrigued investigators for years that many patients with IgA deficiency do not experience more frequent or severe infections [7,16]. This disconnect between the immunologic role of IgA and clinical observations in individuals with IgA deficiency is presumed to be attributable to redundant immunologic mechanisms that protect the host from microbial invasion. Specifically, secretory IgM may perform many of the same functions as IgA and may somewhat compensate for lack of IgA in normal neonates and in patients with IgA deficiency [34]. Selective IgA deficiency and possible compensation by IgM are discussed in detail separately. (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis" and "Selective IgA deficiency: Management and prognosis".)
Serum IgA — The function(s) of serum IgA is not fully understood. One important role appears to be activation of the phagocytic system through the binding of the Fc portion to the cell surface receptors [2,8,21]. Serum IgA binds to Fc-alpha-RI (CD89), the only Fc receptor monospecific for IgA on granulocytes, monocytes, some dendritic cells, macrophages, and B cells. Binding leading to clearance of immune complexes (formed by foreign antigens and IgA) from the circulation by the phagocytic system [35,36]. The longer hinge region of IgA1 may be facilitating cross linking that results in proinflammatory signal transduction. Binding of IgA to Fc-alpha-RI can also lead to cellular inhibition, such that Fc-alpha-RI acts as a regulator of cellular responses and may play a role in various disorders including IgA nephropathy, IgA vasculitis, and blistering skin diseases such as dermatitis herpetiformis [37,38].
Serum IgA does not fix complement or activate the classic complement pathway and therefore does not have a considerable role in complement-mediated effector immune functions. The lack of complement activation means that this mechanism can clear antigens from the circulation without generating significant inflammation [35,39]. However, interaction of IgA with Fc-alpha-RI can lead to anti-, non-, or proinflammatory responses, depending on the environment. Binding of monomeric serum IgA to Fc-alpha-RI, without cross-linking of the receptor, causes phosphorylation of an immunoreceptor tyrosine-based activation motif (ITAM), which in turn induces the recruitment of the tyrosine phosphatase SHP-1 (ie, Src homology region 2 domain-containing phosphatase 1) to Fc-alpha-RI, leading to deactivation of several activating pathways of the immune system [40]. On the other hand, cross-linking of Fc-alpha-RI by IgA that has opsonized a bacterium results in induction of proinflammatory cellular functions, such as phagocytosis, antibody-dependent cellular cytotoxicity (ADCC), respiratory burst, degranulation, antigen presentation, and release of cytokines and inflammatory mediators [37,41]. The relative roles of IgA subclasses in inducing inflammation is still an area of investigation. Both subclasses, IgA1 and IgA2, induce proinflammatory cytokines from monocytes and macrophages when stimulated in vitro. However, IgA2, which is most prevalent in the lower intestine, appears to selectively promote inflammation by CD103+ dendritic cells, which may be important during intestinal infections [42].
With the balanced IgA effects, inflammatory reactions and autoimmune processes are prevented in normal individuals. On the contrary, in IgA-deficient patients, Fc-alpha-RI inhibitory signaling would be eliminated because of the absence of IgA binding with Fc-alpha-RI, resulting in a predisposition to autoimmune processes [35].
Secretory IgA — Secretory IgA is the most abundant immunoglobulin in mucous secretions. Mucosal membranes in the body cover an approximate area of 200 to 400 m2, harboring an estimated 15,000 to 36,000 species and 1800 genera of microbiota [21,43-46]. Secretory IgA coats endogenous bacteria in the oral cavity, intestinal tract, respiratory, and genital tracts. This limits the epithelial adherence and penetration of these bacteria and confines the bacteria to the mucosal surfaces [45].
Features of innate and adaptive immunity — Secretory IgA functions as part of both the adaptive and innate immune systems [16,20,44,45,47]. Certain features, like the ability of the Fab sites to bind specific antigens and undergo somatic hypermutation (SHM) to increase their affinity for those particular antigens, are characteristic of the adaptive immune response. Through the Fab sites, IgA antibodies bind bacterial antigens and interfere with bacterial adherence to epithelial cells, thereby protecting mucosal epithelial cells from specific bacterial pathogens [18]. Secretory IgA can also bind and neutralize viruses or toxins, such as Escherichia coli or Shigella enterotoxin, and inflammatory microbial molecules, such as lipopolysaccharide (LPS) [2,3,31,35,39,43-45,48].
Secretory IgA appears to have a crucial role in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Nasal mucosa is the primary site for entry of SARS-CoV-2 viruses before entry into the lower respiratory tract, and dimeric secretory IgA is reported to be 15 times more powerful at SARS-CoV-2 viral neutralization compared with the monomeric form in the sera [49,50]. It is suggested that there is an impaired secretory IgA response in patients with severe SARS-CoV-2 infection [51]. In addition, in patients with selective IgA deficiency, the risk of severe coronavirus disease 2019 (COVID-19) infection is higher, infection duration and viral shedding periods are prolonged, and the response to SARS-CoV-2 vaccination is lower [49,52].
Intestinal homeostasis — Secretory IgA appears to be central to intestinal homeostasis between the host and commensal bacteria. Most of the commensal bacteria within the body are located in the gastrointestinal tract [1-3,31]. IgA is probably critical in regulating bacterial communities, favoring commensal organisms in biofilms and preventing pathogen overgrowth.
This has been demonstrated in activation-induced cytidine deaminase (AID) knockout mice that lack secretory IgA, in which excessive expansion of anaerobic bacteria in the entire proximal intestinal system can develop [53,54]. Dysbiosis of the intestine has also been observed in another AID gene-targeted mouse model, in which SHM is disrupted while class-switch recombination (CSR) is preserved [55]. Aberrant anaerobic expansion is found in other murine models with IgA deficiency (eg, recombination-activating gene 2 [RAG2] knockouts, severe combined immunodeficiency [SCID] models) [56]. Similarly, some patients with selective IgA deficiency or common variable immunodeficiency (CVID) develop small bowel bacteria overgrowth syndrome, resulting in various clinical manifestations of the intestine [2]. This type of change in the intestinal microbial ecology may cause activation of mucosal immune cells, including intraepithelial lymphocytes, cells of the isolated lymphoid follicles, Peyer's patches, and mesenteric lymph nodes. In addition, this inflammatory state may become systemic and involve lymphocytes of all germinal centers and lymphoid tissues. In a cohort of 28 patients with CVID, low IgA and IgM levels in the stool correlated with an altered gut microbiome composition compared with healthy donors. These data further highlight the significance of secretory IgA in intestinal homeostasis [57].
The inability of secretory IgA to fix complement and stimulate the release of inflammatory mediators may also play a role in creating a noninflammatory host microbial relationship [40,58]. Consistent with this concept, patients with selective IgA deficiency, as well as those with other primary antibody deficiencies, such as CVID and hyperimmunoglobulin M syndromes, tend to develop inflammatory bowel disease in addition to gastrointestinal infections [2]. Patients with selective IgA deficiency or CVID may also develop intestinal nodular lymphoid hyperplasia, which may be due to polyclonal activation of intestinal B cells by bacterial overgrowth (picture 1). (See "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Gastrointestinal disorders (noninfectious)' and "Selective IgA deficiency: Clinical manifestations, pathophysiology, and diagnosis", section on 'Gastrointestinal' and "Clinical manifestations, epidemiology, and diagnosis of common variable immunodeficiency in adults", section on 'Gastrointestinal disease'.)
Secretory IgA in milk — Secretory IgA is the most important immunoglobulin in human breast milk [59]. It is produced by maternal plasma cells in the mammary gland and is directed against microbial structures encountered on the mucosal surfaces of the mother [60]. The IgA concentration peaks in the colostrum and remains high until seven to eight months of age, with a gradual decrease in mature milk [61]. IgA concentration is particularly high in the breast milk of mothers who have preterm newborns to meet the demands of the infant [62]. Secretory IgA antibodies in milk are of broad spectrum with the ability to recognize different types of both indigenous and pathogenic microorganisms and dietary allergens. Antibody reactivity profiling by peptide arrays of breast milk IgA to full proteome sequences of three types of rhinoviruses has shown numerous epitopes localizing to the virion capsid surface, which may provide protection against rhinoviruses in early infancy [63]. In addition, secretory IgA may reduce the allergenicity of dietary antigens by binding to them [59]. The IgA fraction also contains natural autoantibodies that enhance the immune response and probably modulate development of the entire immune system of the infant [64]. (See "Infant benefits of breastfeeding".)
REGULATION —
IgA production is regulated by the molecules that influence somatic hypermutation (SHM) and class-switch recombination (CSR). These molecules include receptors that mediate T and B cell interaction (CD40, CD40L), molecules important in receptor editing (eg, activation-induced cytidine deaminase [AID]), and cytokines, such as transforming growth factor (TGF) beta, interleukin (IL) 6, and IL-10. SHM and CSR are critical to the various functions of IgA [2,3]. Diversification of IgA through SHM is critical to maintaining a balanced commensal bacterial population in the gut. CSR from IgM (the most efficient complement fixing immunoglobulin isotype) to IgA (which does not fix complement) contributes to a hypoinflammatory state within the intestine, as discussed previously. (See 'Intestinal homeostasis' above.)
The inhibitory coreceptor programmed cell death 1 (PD-1) in mice has been shown to affect the B cell germinal center dynamics by controlling the number and nature of T helper cells in the Peyer's patches with an impact on selection of IgA plasma cells and, ultimately, the bacterial composition of the gut [65,66]. Another regulator of secretory IgA production appears to be T helper type 17 (Th17) cells in mice [67,68]. It has been demonstrated that Th17 cells increase polymeric immunoglobulin receptor expression in the bronchial epithelium in response to inhaled antigen [67] and also upregulate intestinal polymeric immunoglobulin receptor and IgA, thereby contributing to gut homeostasis [68]. In addition, Th17 cells have been shown to acquire a follicular helper T cell phenotype and induce the development of IgA-producing germinal center B cells in Peyer's patches, resulting in high-affinity T cell-dependent IgA production [69].
IgA-BASED THERAPY —
There are no IgA preparations available for passive immunization in clinical practice, although mucosal administration of polyclonal secretory IgA would be expected to enhance the immune response against a broad spectrum of mucosal pathogens. Purification and production of large amounts of polyclonal secretory IgA is a significant challenge, and research on IgA antibodies administered via nasal, oral, or intramuscular routes to provide passive infection protection is ongoing. However, one report showed that polymeric IgA and IgM antibodies obtained from plasma were able to associate with recombinant secretory component molecules ex vivo, resulting in functional secretory-like antibodies and suggesting a potential for development of secretory IgA- and IgM-based mucosal therapies [70].
Neutralizing IgA monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been engineered, with monomeric and secretory variants showing high antigen-binding affinities and increased stability in mucosal secretions [71].
Monomeric IgA as a therapeutic antibody isotype is receiving increased attention because of its ability to recruit effector cells different from those recruited by IgG molecules, such as polymorphonuclear cells, and also to activate monocytes and macrophages [55,72]. There is a growing interest in designing IgGA cross-isotype or chimeric antibodies with an Fc domain that contains two tandemly expressed Fc, one from IgG (Fcg) and one from IgA (Fca). This would allow binding of a greater number of FcR molecules and lead to both IgA-like and IgG-like effector functions [72-74]. IgA isotype and IgGA cross-isotype chimeric antibodies need to be developed further to be employed in the treatment of infectious, autoimmune, and malignant diseases.
Another therapeutic approach is targeting Fc-alpha RI (CD89) to counteract IgA-mediated biological activities. Anti-CD89 monoclonal antibodies have been developed that inhibit IgA-induced neutrophil activation and reduce anti-autoantigen IgA-induced neutrophil influx, which could be useful in linear IgA bullous disease [75].
SUMMARY
●Abundance and location of IgA – Immunoglobulin A (IgA) is the most abundant antibody isotype, comprising almost 75 percent of the body's total immunoglobulin. The majority of IgA is found in the various mucous secretions of the respiratory, intestinal, and genitourinary systems. Normal serum levels range from 61 to 356 mg/dL. (See 'Distribution' above.)
●Serum versus secretory IgA – IgA has two forms: monomeric and polymeric (mostly dimeric) (figure 1). IgA circulates in the blood in monomeric form (ie, serum IgA). It is mostly in dimeric form (ie, secretory IgA) in mucosal secretions. (See 'Structure' above.)
●Functions of IgA – Immunologic functions of IgA include protection from microbial invasion, intestinal homeostasis with commensal organisms and immune modulation, and dampening of inflammatory pathways that could lead to autoimmune processes:
•Serum IgA binds to monocytes and granulocytes and clears immune complexes from the circulation. It can do so without activating complement or generating significant inflammatory signals, which is believed important in dampening inflammatory processes that lead to the formation of autoantibodies. (See 'Serum IgA' above.)
•Secretory IgA helps protect mucosal surfaces from microbial invasion by coating microbes to prevent adherence to epithelial cells and by neutralizing microbial toxins and inflammatory molecules, such as lipopolysaccharide (LPS). However, there are apparently other overlapping mechanisms for this purpose because many IgA-deficient individuals do not suffer from excessive infections. (See 'Features of innate and adaptive immunity' above.)
•Secretory IgA promotes intestinal homeostasis between the host and commensal bacteria by regulating bacterial communities, favoring commensal organisms in biofilms, and preventing pathogen overgrowth. Because IgA can function without activating complement or stimulating the release of inflammatory mediators, it is likely critical for the creation of noninflammatory host microbial interactions. (See 'Intestinal homeostasis' above.)
•Secretory IgA in breast milk protects the infant from infection and contains natural autoantibodies that enhance the immune response and probably modulate development of the immune system. (See 'Secretory IgA in milk' above.)
