Immunoglobulin A (IgA, also referred to assIgA in its secretory form) is anantibody that plays a role in theimmune function ofmucous membranes. The amount of IgA produced in association with mucosal membranes is greater than all other types of antibody combined.[3] In absolute terms, between three and five grams are secreted into the intestinallumen each day.[4] This represents up to 15% of total immunoglobulins produced throughout the body.[5]
IgA has two subclasses (IgA1 andIgA2) and can be produced as a monomeric as well as a dimeric form. The IgA dimeric form is the most prevalent and, when it has bound the Secretory component, is also calledsecretory IgA (sIgA). sIgA is the mainimmunoglobulin found inmucous secretions, includingtears,saliva,sweat,colostrum and secretions from thegenitourinary tract,gastrointestinal tract,prostate andrespiratory epithelium. It is also found in small amounts in blood. The secretory component of sIgA protects the immunoglobulin from being degraded by proteolytic enzymes; thus, sIgA can survive in the harshgastrointestinal tract environment and provide protection againstmicrobes that multiply in body secretions.[6] sIgA can also inhibit inflammatory effects of other immunoglobulins.[7] IgA is a poor activator of thecomplement system, andopsonizes only weakly.[8]
IgA exists in twoisotypes, IgA1 and IgA2. They are both heavilyglycosylated proteins.[9] While IgA1 predominates in serum (~80%), IgA2 percentages are higher in secretions than in serum (~35% in secretions);[10] the ratio of IgA1 and IgA2 secreting cells varies in the different lymphoid tissues of the human body:[11]
Both IgA1 and IgA2 have been found in external secretions likecolostrum, maternal milk,tears andsaliva, where IgA2 is more prominent than in the blood.[10]Polysaccharide antigens tend to induce more IgA2 than protein antigens.[11]
Both IgA1 and IgA2 can be in membrane-bound form.[13] (seeB-cell receptor)
The heavy chain of IgA1, in contrast to IgA2, features an extended hinge region. This is thought to allow IgA1 to adapt more effectively to varying epitope spacings on multivalent antigens, while also presenting less resistance to bacterial proteases.[14]
It is also possible to distinguish forms of IgA based upon their location – serum IgA vs. secretory IgA. In serum IgA is predominantly monomeric with a minor population of IgA polymers (dimers in healthy individuals).[citation needed]
IgA has the unique ability to be secreted by B cells either as a monomer or as a covalently-linked polymer of multiple IgA subunits.Polymers of 2–4 IgAmonomers, but most commonly 2, are covalently linked to one molecule of theJ chain (joining chain) inside the B cell prior to secretion as a J chain-coupled polymeric IgA molecule. TheJ chain is apolypeptide with a backbone molecular mass of 15 kDa but typically ~18 kDa when glycosylated, rich withcysteine and structurally completely different from other immunoglobulin chains. As such, themolecular weight of a J chain-coupled dimer of IgA is ~340 kDa.
The oligomeric forms of IgA in the external (mucosal) secretions also contain a polypeptide of a much larger molecular mass (70 kDa) called thesecretory component that is produced byepithelial cells. This molecule originates from the poly-Ig receptor (130 kDa) that is responsible for the uptake and transcellular transport of J chain-containing polymeric (but not monomeric, which is devoid of J chain) IgA across the epithelial cells and into secretions such as tears, saliva, sweat and gut fluid.[citation needed]
In the blood, IgA interacts with anFc receptor called FcαRI (orCD89), which is expressed on immune effector cells, to initiate inflammatory reactions.[15] Ligation of FcαRI by IgA containing immune complexes causesantibody-dependent cell-mediated cytotoxicity (ADCC), degranulation ofeosinophils andbasophils,phagocytosis bymonocytes,macrophages, andneutrophils, and triggering of respiratory burst activity bypolymorphonuclear leukocytes.[15] UnlikeIgM andIgG, which activate complement through the classical pathway, IgA can activate complement via thealternative andlectin pathways.[16]
The high prevalence of IgA in mucosal areas is a result of a cooperation betweenplasma cells that produce polymeric IgA (pIgA), and mucosal epithelial cells that expresspolymeric immunoglobulin receptor (pIgR).[15] Polymeric IgA (mainly the secretory dimer) is produced byplasma cells in thelamina propria adjacent to mucosal surfaces. It binds to the pIgR on thebasolateral surface of epithelial cells, and is taken up into the cell viaendocytosis. The receptor-IgA complex passes through the cellular compartments before being secreted on theluminal surface of the epithelial cells, still attached to the receptor.Proteolysis of the receptor occurs, and the dimeric IgA molecule, along with a portion of the receptor known as thesecretory component (SC), is free to diffuse throughout thelumen, with dimeric IgA and SC together forming the so-called secretory IgA (sIgA)[17] In the gut, IgA can bind to the mucus layer covering the epithelial cells. In this way, a barrier capable of neutralizing threats before they reach the epithelial cells is formed.[citation needed]
Secretory IgA levels fluctuate diurnally, with the highest levels found in the small intestine and feces around ZT6, the middle of the light period.[18] The regulation of IgA secretion is related to the microbiota, and IgA is known to control specific members of oscillating microbes through direct interactions.[18] However, the underlying cause of the rhythmic secretion of IgA is not completely understood and may differ from one region of the body to another.
Production of sIgA against specific antigens depends on sampling ofM cells and underlyingdendritic cells, T cell activation, and B cellclass switching in GALT,mesenteric lymph nodes, and isolated lymphoid follicles in the small intestine.[19]
sIgA primarily acts by blockadingepithelial receptors (e.g. by binding their ligands on pathogens), by sterically hindering attachment to epithelial cells, and by immune exclusion.[19] Immune exclusion is a process of agglutinatingpolyvalent antigens or pathogens by crosslinking them with antibody, trapping them in the mucus layer, and/or clearing themperistaltically. The oligosaccharide chains of the component of IgA can associate with the mucus layer that sits atop epithelial cells.[19] Since sIgA is a poor opsonin and activator of complement, simply binding a pathogen isn't necessarily enough to contain it—specific epitopes may have to be bound tosterically hinder access to the epithelium.[19]
Clearance of IgA is mediated at least in part byasialoglycoprotein receptors, which recognizesgalactose-terminating IgA N-glycans.[9]
Decreased or absent IgA due to an inherited inability to produce IgA is termedselective IgA deficiency and can produce a clinically significantimmunodeficiency.[20]
Anti-IgA antibodies, sometimes present in individuals with low or absent IgA, can result in serious anaphylactic reactions when transfused with blood products that incidentally contain IgA. However, most persons with suspected IgA anaphylactic reactions had experienced acute generalized reactions that were from causes other than anti-IgA transfusion.[21]
Neisseria species includingNeisseria gonorrhoeae (which causesgonorrhea),[22]Streptococcus pneumoniae,[23] andHaemophilus influenzae type B[24] all release aprotease that destroys IgA. Additionally,Blastocystis species have been shown to have several subtypes that generatecysteine andaspartic protease enzymes which degrade human IgA.[25]
IgA nephropathy is caused by IgA deposits in the kidneys. The pathogenesis involves the production of hypoglycosylated IgA1, which accumulates and subsequently leads to the formation of immune complexes and the production of IgA-specific IgG, further leading to tissue inflammation.[26]
Celiac disease involves IgA pathology due to the presence of IgA antiendomysial antibodies.[27][28] Additional testing has been conducted using IgA trans-glutaminase autoantibodies which has been identified as a specific and sensitive for the detection of celiac disease.[29][30]
Henoch–Schönlein purpura (HSP) is a systemic vasculitis caused by deposits of IgA andcomplement component 3 (C3) in small blood vessels. HSP occurs usually in small children and involves the skin and connective tissues, scrotum, joints, gastrointestinal tract and kidneys. It usually follows an upper respiratory infection and resolves within a couple weeks as the liver clears out the IgA aggregates.[31]
Linear IgA bullous dermatosis and IgA pemphigus are two examples of IgA-mediated immunobullous diseases. IgA-mediated immunobullous diseases can often be difficult to treat even with usually effective medications such as rituximab.[32]
Vancomycin can induce a linear IgA bullous dermatosis in some patients.[33]
