Elsevier

Seminars in Nephrology

Volume 28, Issue 1, January 2008, Pages 78-87
Seminars in Nephrology

IgA Glycosylation and IgA Immune Complexes in the Pathogenesis of IgA Nephropathy

https://doi.org/10.1016/j.semnephrol.2007.10.009Get rights and content

Summary

Circulating immune complexes containing aberrantly glycosylated IgA1 play a pivotal role in the pathogenesis of IgA nephropathy (IgAN). A portion of IgA1 secreted by IgA1-producing cells in patients with IgAN is galactose-deficient and consequently recognized by anti-glycan IgG or IgA1 antibodies. Some of the resultant immune complexes in the circulation escape normal clearance mechanisms, deposit in the renal mesangium, and induce glomerular injury. Recent studies of the origin of these aberrant molecules, their glycosylation profiles, and mechanisms of biosynthesis have provided new insight into the autoimmune nature of the pathogenesis of this common renal disease. An imbalance in the activities of the pertinent glycosyltransferases in the IgA1-producing cells favors production of molecules with galactose-deficient O-linked glycans at specific sites in the hinge region of the α heavy chains. By using sophisticated analytic methods, it may be possible to define biomarkers for diagnostic purposes and identify new therapeutic targets for a future disease-specific therapy.

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

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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.

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