IgA Glycosylation and IgA Immune Complexes in the Pathogenesis of IgA Nephropathy
Section snippets
IGA1: Structure and Glycosylation
IgA1 represents 1 of 2 structurally and functionally distinct subclasses of IgA, the other being IgA2.26, 27, 28 Unlike IgA2, the heavy chains of IgA1 molecules contain a unique insertion in its hinge-region segment between the first and second constant region domains (Fig. 1A). This hinge region, which has a high content of proline, serine, and threonine, is the site of attachment of as many as 5 O-linked glycan chains consisting of N-acetylgalactosamine with a β1,3-linked galactose that may
IGAN: A Disease of Aberrant Glycosylation
Analysis of the glycosylation of IgA1 in patients with IgAN has provided new insights into the mechanisms underlying formation of immune complexes and their deposition in the mesangium.18, 23, 40, 41, 42, 43, 44 Specifically, aberrant glycosylation of the O-linked glycans (galactose deficiency) in IgA1 hinge region appears to be a key pathogenetic factor contributing to the development of IgAN.18, 23, 39, 40, 41, 45 Notably, galactose-deficient IgA1 is the predominant glycosylation variant of
Biosynthesis and Catabolism of IgA1
When the daily synthesis of all isotypes of immunoglobulins is taken into account, the production of IgA far exceeds the synthesis of IgG, IgM, IgD, and IgE combined. However, more than two thirds of all IgA finishes its short lifespan in the external secretions (half-life of IgA in the circulation is ∼4-5 days).28 Quantitative studies of IgA production and the distribution of IgA-producing cells in tissues clearly indicate that 90% to 95% of circulatory IgA is produced in the bone marrow,
Biosynthesis of O-Linked Glycans on IgA1
O-linked glycans of IgA1 are synthesized in a step-wise manner, beginning with attachment of N-acetylgalactosamine to serine or threonine, catalyzed by uridine-5′-diphospho-N-acetylgalactosaminyl-transferase 2 (GalNAcT2) (Fig. 2).59, 60 The O-glycan chain then is extended by sequential attachment of galactose and/or sialic acid residues to the N-acetylgalactosamine. The addition of galactose is mediated by core 1 β1,3-galactosyltransferase (C1β3GalT1) that transfers galactose from UDP-galactose
Anti-IgA1 Antibodies as a Component of Circulating Immune Complexes
Although IgA1-IgG immune complexes have been detected by many investigators, the true nature of IgA1-IgG interaction was shown only recently.23 Dissociability of circulating immune complexes at acidic pH and inhibition of reformation by N-acetylgalactosamine–bearing glycoproteins implied an antigen-antibody nature of the IgA1-IgG interaction in these complexes.23 The presence of IgG antibodies, and to a lesser degree IgA1 or IgM antibodies, to IgA1 in sera of healthy individuals and patients
Biological Activities of IgA1-Containing Immune Complexes
Cultured human mesangial cells present a convenient model to evaluate biologic activities of IgA complexes.40, 41, 85, 86 Immune complexes from sera of patients with IgAN containing galactose-deficient IgA1 bind to the mesangial cells more efficiently than do uncomplexed IgA1 or immune complexes from healthy controls. Assessment of the biological activity of IgA1 complexes showed that large-molecular-weight IgA1 complexes stimulated cellular proliferation and production of some cytokines (eg,
Hypothetical Model of the Pathogenesis of IgAN
Based on published data, a hypothetical model of the pathogenesis of IgAN is emerging. Some IgA1 molecules produced by immunoglobulin-secreting cells in patients with IgAN are galactose deficient and consequently recognized by anti–glycan IgG (or IgA1) antibodies. The resultant immune complexes are too bulky to enter the space of Disse in the liver. IgA1-containing immune complexes that escape normal clearance mechanisms reach the renal circulation and pass through the larger fenestrae in the
References (100)
The immunohistology of IgA nephropathy
Am J Kidney Dis
(1988)Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors
Am J Kidney Dis
(2000)- et al.
IgA nephropathy and related diseases
Recurrence of IgA nephropathy in renal allografts
Am J Kidney Dis
(1988)- et al.
Galactose-deficient IgA1 in sera of IgA nephropathy patients is present in complexes with IgG
Kidney Int
(1997) - et al.
Shared idiotypes in mesangial deposits in IgA nephropathy are not disease-specific
Kidney Int
(1993) - et al.
Aberrant glycosylation in IgAN
Kidney Int
(2004) Immunobiology of IgA
Am J Kidney Dis
(1988)- et al.
Comparative studies of the biological properties of human IgA subclasses
Protides Biol Fluids
(1989) - et al.
Mucosal immunoglobulins
Structure of the carbohydrate units of IgA1 immunoglobulin IIStructure of the O-glycosidically linked oligosaccharide units
J Biol Chem
The glycosylation and structure of human serum IgA1, Fab, and Fc regions and the role of N-glycosylation on Fcα receptor interactions
J Biol Chem
Human serum IgA1 is substituted with up to six O-glycans as shown by matrix assisted laser desorption ionisation time-of-flight mass spectrometry
Carbohydr Res
Determination of aberrant O-glycosylation in the IgA1 hinge region by electron capture dissociation Fourier transform-ion cyclotron resonance mass spectrometry
J Biol Chem
Heterogeneity of O-glycosylation in the hinge region of human IgA1
Mol Immunol
Mesangial IgA1 in IgA nephropathy exhibits aberrant O-glycosylation: observations in three patients
Kidney Int
Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy
Kidney Int
Interactions of human mesangial cells with IgA and IgA-containing circulating immune complexes
Kidney Int
IgA1-containing immune complexes in IgA nephropathy differentially affect proliferation of mesangial cells
Kidney Int
Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels
Kidney Int
Reactivities of N-acetylgalactosamine-specific lectins with human IgA1 proteins
Mol Immunol
IgA immune complexes in Henoch-Schönlein purpura
Lancet
Increased immunoglobulin A and immunoglobulin A1 cells in bone marrow trephine biopsy specimens in immunoglobulin A nephropathy
Am J Kidney Dis
Biosynthesis of truncated O-glycans in the T cell line JurkatLocalization of O-glycan initiation
J Biol Chem
Initiation of O-glycan synthesis in IgA1 hinge region is determined by a single enzyme, UDP-N-acetyl-α-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 2
J Biol Chem
Cloning and expression of human core 1 β1,3-galactosyltransferase
J Biol Chem
Molecular cloning and characterization of a novel UDP-Gal:GalNAcα peptide β1,3-galactosyltransferase (C1Gal-T2), an enzyme synthesizing a core 1 structure of O-glycan
J Biol Chem
Identification and characterization of CMP-NeuAc:GalNAc-IgA1 α2,6-sialyltransferase in IgA1-producing cells
J Mol Biol
Sialic acidsXIII. A uridine diphosphate D-galactose: mucin galactosyltransferase from porcine submaxillary gland
J Biol Chem
Aberrant synthesis of antibodies directed at the Fab of IgA in patients with IgA nephropathies
Clin Immunol Immunopathol
Immunoglobulin-antiimmunoglobulin interactions and immune complexes in IgA nephropathy
Am J Kidney Dis
Galactose and N-acetylgalactosamine-specific endocytosis of glycopeptides by isolated rat hepatocytes
Cell
Human hepatic lectinPhysicochemical properties and specificity
J Biol Chem
Selective hepatobiliary transport of human polymeric IgA in mice
Mol Immunol
Analysis of the hepatobiliary transport of IgA with monoclonal anti-idiotype and anti-allotype antibodies
Mol Immunol
Role of hepatocytes in the uptake of IgA and IgA-containing immune complexes in mice
Mol Immunol
Glomerulonephritis
Lancet
Identification of a novel Fcα receptor expressed by mesangial cells
Kidney Int
Expression of Fc α/μ receptor by human mesangial cells: a candidate receptor for immune complex deposition in IgA nephropathy
Biochem Biophys Res Commun
Secretory IgA N- and O-glycans provide a link between the innate and adaptive immune systems
J Biol Chem
Glycoform composition profiling of O-glycopeptides derived from human serum IgA1 by matrix-assisted laser desorption ionization-time of flight-mass spectrometry
Anal Biochem
Structural analyses of O-glycan sugar chains on IgA1 hinge region using SELDI-TOFMS with various lectins
Biochem Biophys Res Commun
Les depots intercapillaires d’IgA-IgG (intercapillary deposits of IgA-IgG)
J Urol Nephrol
Selective deposition of immunoglobulin A1 in immunoglobulin A nephropathy, anaphylactoid purpura nephritis, and systemic lupus erythematosus
J Clin Invest
IgA nephropathy and Henoch-Schönlein syndrome
Prognostic indicators in childhood IgA nephropathy
Nephron
IgA nephropathy and thin basement membrane disease in association with Crohn disease
Pediatr Nephrol
Confirmation of tonsillar anomalies in IgA nephropathy: a multicenter study
Nephron
Characteristics of IgA and macromolecular IgA in sera from IgA nephropathy transplanted patients with and without IgA nephropathy recurrence
Contrib Nephrol
IgA serology in recurrent and non-recurrent IgA nephropathy after renal transplantation
Nephrol Dial Transplant
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Supported in part by grants from the National Institutes of Health DK78244, DK61525, DK71802, and DK64400, and by a grant from Czech Republic VZ MSM0021620812.