Production and secretion of immunoglobulins in the gastrointestinal tract.

ABSTRACT

Two decades ago it was shown that the major immunoglobulin (Ig) present in human secretions is a dimeric IgA covalently bound to an epithelial glycoprotein of about 80 kD, now called the secretory component (SC). Pentameric IgM is likewise actively enriched in most exocrine fluids and is associated with SC, although not in a covalently stabilized complex. Three findings explain the selective translocation of polymeric Ig (pIg) into exocrine fluids (1) preferential local production; (2) J-chain-expressing capacity of pIg-producing immunocytes; and (3) SC-mediated epithelial transport. Human hepatocytes lack SC and the human liver, therefore, cannot act as an efficient "IgA pump". This is in contrast to the rat liver which shows a remarkable capacity for transport of dimeric IgA from blood into the bile. The J chain of pIg and the epithelial SC represent the "lock and key" in the glandular transport of secretory IgA (SIgA) and SIgM. It has recently been shown that SC is synthesized as a transmembrane protein of about 95 kD and constitutes the actual pIg surface receptor. Complexing between ligand and receptor in the plasma membrane is followed by endocytosis. The completed SIgA and SIgM molecules are then translocated in cytoplasmic vesicles through the epithelial cell to the gland lumen along with an excess of free SC. The main function of SIgA is to exert immune exclusion; that is, by intimate cooperation with innate nonspecific defense factors it decreases penetration of soluble antigens and inhibits epithelial colonization of bacteria and viruses. Especially in selective IgA deficiency, SIgM may exert a similar protective function since its synthesis is markedly increased in the intestinal mucosa. Leakage of IgG into exocrine fluids is enhanced by mucosal irritation. Although IgG should not be considered as a SIg, it may contribute to immune exclusion. This is seen especially in the respiratory tract where IgG is less easily subjected to proteolytic degradation than in the intestinal juice. In contrast, by activating complement, IgG antibodies may at the same time be phlogistic and accelerate mucosal penetration of antigens. IgG may thus contribute to persistent immunopathology in mucosal disease. The same is true for IgE antibodies which may be carried into mucous membranes and secretions by mast cells and cause their degranulation with local histamine release. Traces of IgD may likewise be found in the secretions but without obvious biologic significance. Regulation of secretory immunity takes place both in organized lymphoepithelial structures, such as the Peyer's patches, and adjacent to the glands in the lamina propria.(ABSTRACT TRUNCATED AT 400 WORDS)