Abstract
IgA nephropathy (IgAN), the most common primary glomerular disease worldwide, is characterized by glomerular deposition of IgA1-containing immune complexes. The IgA1 hinge region (HR) has up to six clustered O-glycans consisting of Ser/Thr-linked N-acetylgalactosamine usually with β1,3-linked galactose and variable sialylation. Circulating levels of IgA1 with abnormally O-glycosylated HR, termed galactose-deficient IgA1 (Gd-IgA1), are increased in patients with IgAN. Current evidence suggests that IgAN is induced by multiple sequential pathogenic steps, and production of aberrantly glycosylated IgA1 is considered the initial step. Thus, the mechanisms of biosynthesis of aberrantly glycosylated IgA1 and the involvement of aberrant glycoforms of IgA1 in disease development have been studied. Furthermore, Gd-IgA1 represents an attractive biomarker for IgAN, and its clinical significance is still being evaluated. To elucidate the pathogenesis of IgAN, it is important to deconvolute the biosynthetic origins of Gd-IgA1 and characterize the pathogenic IgA1 HR O-glycoform(s), including the glycan structures and their sites of attachment. These efforts will likely lead to development of new biomarkers. Here, we review the IgA1 HR O-glycosylation in general and the role of aberrantly glycosylated IgA1 in the pathogenesis of IgAN in particular.
Highlights
IgA nephropathy (IgAN) is a mesangioproliferative glomerulonephritis associated with depositions of IgA-containing immune complexes [1]
IgAN can develop after bonemarrow transplantation due to a non-graft-versus-host-disease-related multi-hit process associated with glomerular deposition of aberrantly glycosylated IgA1 [11]
The levels of galactose-deficient IgA1 (Gd-IgA1) produced by cultured IgA1producing cells from peripheral blood correlate with the donors’ serum levels of Gd-IgA1 measured by lectin enenzyme-linked immunosorbent assay (ELISA)
Summary
IgA nephropathy (IgAN) is a mesangioproliferative glomerulonephritis associated with depositions of IgA-containing immune complexes [1]. These deposits are exclusively of IgA1 subclass [2]. IgAN can develop after bonemarrow transplantation due to a non-graft-versus-host-disease-related multi-hit process associated with glomerular deposition of aberrantly glycosylated IgA1 (see for details below) [11]. Based on these observations, it is thought that the glomerular IgA deposits are derived from circulating IgA1-containing complexes. We review pathological and clinical significance of aberrant glycosylation of IgA1 in IgAN
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