IgA in mucosal host defense

IgA is quantitatively the most important of the immunoglobulins, having a synthetic rate exceeding that of all other immunoglobulins combined when secretory as well as circulating IgA is taken into account. In humans it is encoded by two genes within the immunoglobulin gene locus on chromosome 14. The 5' IgA gene encodes IgAl, the predominant circulating IgA and a major component of the IgA in mucosal secretions. The more 3' IgA gene encodes IgA2, the IgA that is particularly abundant in mucosal secretions. IgAl differs from IgA2 in being susceptible to cleavage in its hinge region by proteases secreted by a number of different bacteria. Cleavage can lead to markedly reduced function.

Figure 2 IgA in serum and secretions are different. IgA in serum is predominantly the product of bone marrow cells, there is more lgA1 than lgA2, it is produced at a rate of about 1.2 g day 1 and is monomeric. In contrast, secretory IgA is produced primarily by intestinal plasma cells and contains J chain, also produced by plasma cells. There is more lgA2 than lgA1 and it is produced a! a rate of about 3.2 g day \ Finally, IgA in secretions contains a portion of the receptor used for translocation across the epithelial cell, the polymeric immunoglobulin receptor (secretory component).

Another difference between IgAl and lgA2 is that the latter occurs in two allotypic forms, lgA2(ml) and IgA2(m2), which are distinguished from one another by the fact that IgA2(ml) lacks interchain (H-L) disulfide bonds. The IgA heavy chain, in common with the IgM heavy chain, has an extra cysteine residue in the C-terminal segment. This permits IgA to interact J (joining) chain to form IgA dimers and trimers. IgA polymerization is important to IgA function because polymerized IgA (plgA) has an increased capacity to bind to and agglutinate antigens.

Polymeric immunoglobulin receptor (secretory component)

Only dimerized IgA and IgM can react with the polymeric immunoglobulin receptor (plgR, secretory component, SC) produced by epithelial cells. plgR acts as a transport receptor for IgA and becomes parr of the secreted IgA molecule. It renders the IgA molecule less susceptible to proteolytic digestion and more mucophilic, thus enhancing the ability of the IgA molecule to interact with potential pathogens and to prevent their attachment to the epithelial surface. The sequence of events occurring during IgA transport involves first the binding of polymeric IgA to plgR on the basolateral surface of the epithelial cell, followed by endocytosis of IgA into vesicles, movement of IgA-containing vesicles to the apical surface of the cell, and finally, release of IgA plgR complexes into the mucosal lumen (Figure 2). This final step requires cleavage of the plgR receptor molecule so that the receptor for IgA becomes part of the secreted IgA molecule. Cellular synthesis and translocation of plgR is independent of the presence of IgA and usually exceeds the amount necessary for transport, leading to the secretion of free plgR.

IgA transport mediated by plgR occurs in the epithelium of the digestive tract, the salivary glands, the bronchial mucosa and the lactating mammary

Intestinal mucosa 3.2 g day-' secretory IgA

Intestinal mucosa 3.2 g day-' secretory IgA

Mucosal plasma cell

J chain

lgA2>lgA1

Mucosal plasma cell

J chain lgA2>lgA1

glands. It also occurs in the uterine epithelium, where it is regulated by the effects of estrogen on plgR synthesis by uterine epithelial cells. IgA transport mediated by plgR also takes place in the liver, in which case it results in secretion of IgA into the bile. This involves the biliary epithelial cells, and in rodents, hepatocytes. Hepatic uptake of IgA may be one mechanism by which IgA secreted into the circulation is redirected back to the mucosa in species with well-developed plgR-mediated hepatic transport capabilities, possibly to clear the circulation of potentially damaging antigenic material that has penetrated the mucosal barrier and become bound to circulating IgA.

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