The N-glycans determine the differential blood clearance and hepatic uptake of human immunoglobulin (Ig)A1 and IgA2 isotypes.
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.
Rifai
A
A
Department of Pathology, Rhode Island Hospital, Brown University, Providence, Rhode Island 02903, USA.
Fadden
K
K
Morrison
S L
SL
Chintalacharuvu
K R
KR
D000818:Animals; D000906:Antibodies / Q000737:chemistry; D037263:Asialoglycoprotein Receptor; D006023:Glycoproteins / Q000235:genetics / Q000493:pharmacokinetics*; D006031:Glycosylation; D006801:Humans; D007070:Immunoglobulin A / Q000235:genetics / Q000378:metabolism*; D007126:Immunoglobulin Allotypes / Q000235:genetics / Q000378:metabolism; D007132:Immunoglobulin Isotypes / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D008817:Mice, Mutant Strains; D008970:Molecular Weight; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000493:pharmacokinetics
D000906:Antibodies; D037263:Asialoglycoprotein Receptor; D006023:Glycoproteins; D007070:Immunoglobulin A; D007126:Immunoglobulin Allotypes; D007132:Immunoglobulin Isotypes; D011956:Receptors, Cell Surface; D011994:Recombinant Proteins; C034639:polymeric IgA