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.

[1]  B. Julian,et al.  Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies. , 1999, The Journal of clinical investigation.

[2]  J. C. Collins,et al.  IgA interaction with the asialoglycoprotein receptor. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[3]  J. van Hattum,et al.  Immunoglobulin A in the diagnosis of alcoholic liver disease. , 1988, Gastroenterology.

[4]  P. V. Balaji,et al.  Molecular dynamics simulations of asialoglycoprotein receptor ligands. , 1993, Biochemistry.

[5]  R. Coppo,et al.  Removal systems of immunoglobulin A and immunoglobulin A containing complexes in IgA nephropathy and cirrhosis patients. The role of asialoglycoprotein receptors. , 1993, Laboratory investigation; a journal of technical methods and pathology.

[6]  L. Nitti,et al.  Clearance kinetics and fate of macromolecular IgA in patients with IgA nephropathy. , 1989, Laboratory investigation; a journal of technical methods and pathology.

[7]  S. Morrison,et al.  Divergence of human alpha-chain constant region gene sequences. A novel recombinant alpha 2 gene. , 1994, Journal of immunology.

[8]  T. Willnow,et al.  The Major Subunit of the Asialoglycoprotein Receptor Is Expressed on the Hepatocellular Surface in Mice Lacking the Minor Receptor Subunit* , 1996, The Journal of Biological Chemistry.

[9]  B. Julian,et al.  Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG. , 1997, Kidney international.

[10]  S. Morrison,et al.  Elimination of N-linked glycosylation sites from the human IgA1 constant region: effects on structure and function. , 1997, Journal of immunology.

[11]  W. Brown,et al.  The liver and IgA: Immunological, cell biological and clinical implications , 1989, Hepatology.

[12]  J. Davin.  Pathogenesis of IgA nephropathy. , 1995, Acta clinica Belgica.

[13]  M. Mannik,et al.  Clearance of circulating IgA immune complexes is mediated by a specific receptor on Kupffer cells in mice , 1984, The Journal of experimental medicine.

[14]  R. Dwek,et al.  The Glycosylation and Structure of Human Serum IgA1, Fab, and Fc Regions and the Role of N-Glycosylation on Fcα Receptor Interactions* , 1998, The Journal of Biological Chemistry.

[15]  A. Hernvann,et al.  Increased Serum Concentration of IgA2 Subclass and IgA2/IgA1 Ratio: Specific Markers of Chronic Alcoholic Abuse? , 1997, European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies.

[16]  P. Plotz,et al.  Modulation of the circulation and hepatic uptake of immune complexes by carbohydrate recognition systems. , 1982, Journal of immunology.

[17]  S. Harper,et al.  Galactosylation of N‐ and O‐linked carbohydrate moieties of IgA1 and IgG in IgA nephropathy , 1995, Clinical and experimental immunology.

[18]  J. Ravetch,et al.  Divergent roles for Fc receptors and complement in vivo. , 1998, Annual review of immunology.

[19]  A. Jones,et al.  Human IgA as a heterovalent ligand: switching from the asialoglycoprotein receptor to secretory component during transport across the rat hepatocyte , 1986, The Journal of cell biology.

[20]  P. Plotz,et al.  Influence of antigen on immune complex behavior in mice. , 1981, The Journal of clinical investigation.

[21]  J. Vaerman,et al.  Hepatobiliary transport of plasma IgA in the mouse: contribution to clearance of intravascular IgA , 1985, European journal of immunology.

[22]  W. Brown,et al.  Abnormal surface distribution of the human asialoglycoprotein receptor in cirrhosis , 1992, Hepatology.

[23]  J. Mcghee,et al.  Comparative Studies of the Biological Properties of Human IgA Subclasses , 1989 .

[24]  J. Mcghee,et al.  Immunoglobulin A (IgA): molecular and cellular interactions involved in IgA biosynthesis and immune response. , 1987, Advances in immunology.

[25]  J. Mestecky,et al.  Receptor-mediated binding and uptake of immunoglobulin A by human liver. , 1988, Gastroenterology.

[26]  H. Hodgson,et al.  IgA in alcoholic cirrhosis. , 1983, Clinical and experimental immunology.

[27]  G. Noseda,et al.  Metabolic properties of human IgA subclasses. , 1973, Clinical and experimental immunology.

[28]  P. Weigel,et al.  Ethanol feeding causes inactivation of both state 1 and state 2 rat hepatic asialoglycoprotein receptors. , 1997, Alcoholism, clinical and experimental research.

[29]  R. Kumashiro,et al.  Usefulness of technetium-99m-galactosyl human serum albumin liver scintigraphy for assessment of severity of alcoholic hepatitis. , 1996, Alcoholism, clinical and experimental research.

[30]  R. Hammer,et al.  Asialoglycoprotein receptor deficiency in mice lacking the minor receptor subunit. , 1994, The Journal of biological chemistry.

[31]  A. van de Wiel,et al.  Characteristics of serum IgA and liver IgA deposits in alcoholic liver disease , 1987, Hepatology.

[32]  M. Kerr,et al.  The structure and function of human IgA. , 1990, The Biochemical journal.

[33]  A. Geubel,et al.  Changes in size, subclass, and metabolic properties of serum immunoglobulin A in liver diseases and in other diseases with high serum immunoglobulin A. , 1983, The Journal of clinical investigation.

[34]  Mark C. Field,et al.  Structural analysis of the N-glycans from human immunoglobulin A1: comparison of normal human serum immunoglobulin A1 with that isolated from patients with rheumatoid arthritis. , 1994, The Biochemical journal.

[35]  M. Mannik,et al.  Clearance kinetics and fate of mouse IgA immune complexes prepared with monomeric or dimeric IgA. , 1983, Journal of immunology.

[36]  P. Plotz,et al.  Stable, soluble, model immune complexes made with a versatile multivalent affinity-labeling antigen. , 1982, Biochemistry.

[37]  M. Kerr,et al.  The Fab and Fc fragments of IgA1 exhibit a different arrangement from that in IgG: a study by X-ray and neutron solution scattering and homology modelling. , 1999, Journal of molecular biology.

[38]  R. Stockert,et al.  The asialoglycoprotein receptor: relationships between structure, function, and expression. , 1995, Physiological reviews.