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Abstract

Secretory immunoglobulin A is the characteristic and predominant immunoglobulin of the mucosal immune system; it participates in immunological protection at the level of mucous membrane surfaces. During the past 10 to 15 years, a great deal of experimental and clinical evidence has shown that the liver is very much involved in the sIgA system.

In certain animals (rats, mice, rabbits), polymeric forms of IgA are efficiently cleared by the liver and transported into bile by a receptor-mediated vesicular pathway across hepatocytes. Taking advantage of this easily accessible pathway, investigators have defined many of the events in the external secretion of pIgA, including details about the synthesis and secretion of its receptor, secretory component. In the rat hepatocyte, secretory component is synthesized as a transmembrane glycoprotein and is expressed preferentially on the sinusoidal plasma membrane; circulating pIgA that binds to secretory component is internalized into endocytic vesicles and transported across the hepatocyte to the bile canalicular membrane, where the pIgA is released into bile as a soluble complex with a portion of the secretory component, the complex being secretory IgA. In some other animals (dog, guinea pig, sheep) as well as man, biliary epithelial cells, not hepatocytes, express secretory component and perform the transcytosis and secretion of pIgA into bile. In those species, much of the pIgA that reaches bile is synthesized locally in plasma cells that populate the biliary tree; this design is analogous to the release of sIgA into various mucosae in the body.

The major biological functions ascribed to the secretion of IgA into bile are enhancement of immunological defense of the biliary and upper intestinal tracts and the clearance of harmful antigens from the circulation as IgA-antigen complexes. However, the importance of biliary IgA antibodies is largely unclarified, and man lacks the capacity for effective clearance of IgA-antigen complexes via the secretory component-mediated transhepatocellular pathway; whether this deficit contributes to the propensity for man to develop IgA immune complex diseases should be clarified.

Among liver diseases, alcoholic disease is most closely linked to alterations in IgA metabolism. This association is manifested principally by the deposition of IgA along the sinusoids in the livers of the majority of alcoholics and in the renal mesangium of many. The IgA1 subclass of IgA predominates in the IgA deposits in both tissues; the possibility that this predominance is related to abnormalities in the removal of circulating IgA1 by asialoglycoprotein receptors on hepatocytes is an intriguing consideration.

Thus, the liver plays a unique role in mucosal immunity and in the physiology of IgA in normal and disease states. Further study of the associations between the liver and IgA, particularly in man, is clearly needed.