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The Fischer rat shows an age-related loss of both hepatic blood to bile transport and secretory component-specific binding sites for polymeric immunoglobulin (Ig) A. This age-related loss of hepatic IgA receptor function is also shown by cultured hepatocytes. It is reported here that compared with young cells, binding and uptake of 125I-polymeric IgA by cultured hepatocytes was markedly reduced in cells from senescent animals. In addition, cells from old animals showed markedly diminished secretion of secretory component determined by enzyme-linked immunosorbent assay and expression of polymeric immunoglobulin receptor determined by incorporation of 35S-labeled amino acid and fluorography. It is suggested that the age-related decrease in IgA receptor-mediated transport from serum to bile results, at least in part, from decreased expression and secretion of total hepatic secretory component.

Most research on the effects of ageing on gut mucosal immunity has been performed using rodents. However, there are inherent difficulties in the extrapolation of rodent data to humans. This study was initiated to define age-related changes in the gastrointestinal (GI) mucosal immune response in non-human primates. Antibody responses were measured in young and old rhesus monkeys (Macaca mulatta) immunized intraduodenally with cholera toxin (Ctx)/cholera toxoid (Ctd). Antigen-specific immunoglobulin A (IgA) antibody levels were markedly lower while anti-Ctx IgG and IgM titres were higher in the intestinal lavage samples of old as compared to young animals. Total IgA concentrations in gut lavage were independent of age or immune status. Measurable titres of anti-Ctx IgA in the saliva of both age groups support the common mucosal immune hypothesis. Flow cytometric analysis was used to identify age-related shifts in the expression of cell surface antigens on peripheral blood lymphocytes. The relative number of both IgA+ and Ctx+ cells was dramatically reduced in the blood of old monkeys. Collectively, these data suggest that the GI mucosal immune response to Ctx is compromised in old rhesus macaques. The deficit in immune responsiveness, namely reduced anti-Ctx IgA antibody secretion into the intestinal lumen, may be a consequence of alterations in the process of maturation and homing of specific antibody-secreting B lymphocytes.

In the rat, asialoorosomucoid and rat dimeric immunoglobulin A are both taken up by hepatocytes via receptor-mediated endocytosis. The fate of these two proteins, however, differs significantly. Rat dimeric IgA is taken up into smooth vesicles, transported to the bile canaliculus and secreted intact into the bile, whereas asialoglycoproteins are internalized via coated vesicles and transported to lysosomes for degradation. Recently, several studies both in the rat and in cultured human hepatoma cells have suggested that the receptor for asialoglycoproteins may play a role in the hepatic uptake and processing of human polymeric IgA. Using receptor-binding techniques, we have provided quantitative data for the competition of human monomeric, polymeric and secretory IgA with asialoorosomucoid for its receptor on liver plasma membrane preparations from rat, monkey and man. Some IgA molecules required desialylation with neuraminidase to enhance markedly their efficacy for asialoorosomucoid inhibition. Quantitatively, human IgA molecules showed an affinity for the ASOR receptor similar to that for asialoceruloplasmin. Rat dimeric IgA does not compete for this binding site. We conclude that human IgA can compete with ligands for the asialoglycoprotein receptor of rat, monkey and human liver. This receptor may provide an alternative pathway for the hepatic processing of IgA and IgA immune complexes when secretory component-mediated uptake is not available as in the monkey and man, particularly under pathological conditions where serum IgA concentrations accumulate to abnormally high levels.

The receptor for polymeric immunoglobulins is responsible for the transport of immunoglobulin A (IgA) through epithelial cells and its subsequent delivery to mucosal surfaces. We have extended our previous studies of the IgA receptor in the liver of the aging Fischer rat to include the small intestine. Basolateral membrane-enriched fractions prepared from rat small intestinal enterocytes exhibit a single binding site for dimeric IgA. This receptor is specific for molecules that interact with rat secretory component, e.g., rat dimeric IgA and IgM and human polymeric IgA but not human monomeric IgA or rat secretory IgA. Inhibition of binding by rabbit-antirat secretory component also indicated that binding is specific for secretory component. Both liver and intestinal membranes showed virtually identical binding specificity. Membranes from crypt cells show increased IgA binding (320 fmol bound per milligram protein) compared with villous cells (105 fmol bound per milligram protein); however, other than increased binding, crypt cells show the same binding characteristics as villous cells. In contrast to our previous findings, in which liver plasma membranes from old rats showed a four-fold decrease in IgA binding compared with young adult rats, membrane fractions from rat enterocytes showed no alterations in dimeric IgA binding with increased age.

Characterization of the receptor for dimeric immunoglobulin A (dIgA) on an isolated rat liver plasma membrane-enriched fraction showed a single class of binding sites specific for dIgA. Both the rat and human immunoglobulins competed for the binding site, but human IgA bound much less strongly to the receptor. Other proteins did not compete for the dIgA receptor, including asialoorosomucoid. Scatchard analysis of binding data from young adult, mature, and senescent animals indicated an age-dependent decrease in the number of receptors present on liver plasma membranes. This loss of receptors with increasing animal age may be responsible for the concomitant reduction in hepatobiliary secretion of dIgA.