The Journal of Experimental Medicine
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Published online 19 June 2000.
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© The Rockefeller University Press, 0022-1007/2000/6/2171/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 12, June 19, 2000 2171-2182

Original Article

The N-Glycans Determine the Differential Blood Clearance and Hepatic Uptake of Human Immunoglobulin (Ig)A1 and IgA2 Isotypes

Abdalla Rifaia, Kim Faddena, Sherie L. Morrisonb, and Koteswara R. Chintalacharuvub
a Department of Pathology, Rhode Island Hospital, Brown University, Providence, Rhode Island 02903
b Department of Microbiology, Immunology and Molecular Genetics, and the Molecular Biology Institute, University of California, Los Angeles, California 90095

Correspondence to: Koteswara R. Chintalacharuvu, Department of Microbiology, Immunology and Molecular Genetics, Molecular Biology Institute, 611 Charles Young Drive South, MBI 519, University of California, Los Angeles, CA 90095-1489. Tel:310-206-5127 Fax:310-206-7286 E-mail:kotec{at}lifesci.ucla.edu.

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.

Key Words: asialoglycoprotein, glycosylation, IgA, liver, blood clearance


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