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The N-glycans determine the differential blood clearance and hepatic uptake of human immunoglobulin (Ig)A1 and IgA2 isotypes.

Rifai A, Fadden K, Morrison SL, Chintalacharuvu KR - J. Exp. Med. (2000)

Bottom Line: The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1.The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2.In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Rhode Island Hospital, Brown University, Providence, Rhode Island 02903, USA.

ABSTRACT
Human immunoglobulin (Ig)A exists in blood as two isotypes, IgA1 and IgA2, with IgA2 present as three allotypes: IgA2m(1), IgA2m(2), and IgA2m(n). We now demonstrate that recombinant, chimeric IgA1 and IgA2 differ in their pharmacokinetic properties. The major pathway for the clearance of all IgA2 allotypes is the liver. Liver-mediated uptake is through the asialoglycoprotein receptor (ASGR), since clearance can be blocked by injection of excess galactose-Ficoll ligand and suppressed in ASGR-deficient mice. In contrast, only a small percentage of IgA1 is cleared through this pathway. The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1. IgA1 and IgA2 that are not rapidly eliminated by the ASGR are both removed through an undefined ASGR-independent pathway with half-lives of 14 and 10 h, respectively. The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2. In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy.

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Hepatic uptake of IgA2 in the presence of a saturating dose of galactose-Ficoll in wild-type mice (WT) and in ASGR−/− mice. The hepatic content of radioactivity 10 min after injection is shown as the percentage of injected dose in blood-free liver. Each bar represents the mean ± SD of three mice.
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Figure 6: Hepatic uptake of IgA2 in the presence of a saturating dose of galactose-Ficoll in wild-type mice (WT) and in ASGR−/− mice. The hepatic content of radioactivity 10 min after injection is shown as the percentage of injected dose in blood-free liver. Each bar represents the mean ± SD of three mice.

Mentions: The hepatic uptake data at 10 min (Fig. 6) confirmed a role for the ASGR in the clearance of IgA. Galactose-Ficoll significantly (P = 0.0028) reduced the hepatic uptake of IgA1 (from 10 to 7.8% of administered dose) in C57BL/6 mice. Galactose-Ficoll had an even more dramatic effect on hepatic uptake of all three IgA2 allotypes. Similar decreased hepatic uptake of all three IgA2 allotypes was also observed in ASGR−/− mice. Thus, both blocking and inactivating the receptor demonstrate that the hepatic ASGR plays a major role in the rapid elimination of human IgA2 from the circulation.


The N-glycans determine the differential blood clearance and hepatic uptake of human immunoglobulin (Ig)A1 and IgA2 isotypes.

Rifai A, Fadden K, Morrison SL, Chintalacharuvu KR - J. Exp. Med. (2000)

Hepatic uptake of IgA2 in the presence of a saturating dose of galactose-Ficoll in wild-type mice (WT) and in ASGR−/− mice. The hepatic content of radioactivity 10 min after injection is shown as the percentage of injected dose in blood-free liver. Each bar represents the mean ± SD of three mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193211&req=5

Figure 6: Hepatic uptake of IgA2 in the presence of a saturating dose of galactose-Ficoll in wild-type mice (WT) and in ASGR−/− mice. The hepatic content of radioactivity 10 min after injection is shown as the percentage of injected dose in blood-free liver. Each bar represents the mean ± SD of three mice.
Mentions: The hepatic uptake data at 10 min (Fig. 6) confirmed a role for the ASGR in the clearance of IgA. Galactose-Ficoll significantly (P = 0.0028) reduced the hepatic uptake of IgA1 (from 10 to 7.8% of administered dose) in C57BL/6 mice. Galactose-Ficoll had an even more dramatic effect on hepatic uptake of all three IgA2 allotypes. Similar decreased hepatic uptake of all three IgA2 allotypes was also observed in ASGR−/− mice. Thus, both blocking and inactivating the receptor demonstrate that the hepatic ASGR plays a major role in the rapid elimination of human IgA2 from the circulation.

Bottom Line: The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1.The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2.In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Rhode Island Hospital, Brown University, Providence, Rhode Island 02903, USA.

ABSTRACT
Human immunoglobulin (Ig)A exists in blood as two isotypes, IgA1 and IgA2, with IgA2 present as three allotypes: IgA2m(1), IgA2m(2), and IgA2m(n). We now demonstrate that recombinant, chimeric IgA1 and IgA2 differ in their pharmacokinetic properties. The major pathway for the clearance of all IgA2 allotypes is the liver. Liver-mediated uptake is through the asialoglycoprotein receptor (ASGR), since clearance can be blocked by injection of excess galactose-Ficoll ligand and suppressed in ASGR-deficient mice. In contrast, only a small percentage of IgA1 is cleared through this pathway. The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1. IgA1 and IgA2 that are not rapidly eliminated by the ASGR are both removed through an undefined ASGR-independent pathway with half-lives of 14 and 10 h, respectively. The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2. In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy.

Show MeSH
Related in: MedlinePlus