IgA in glomerular deposits is exclusively of the IgA1 subclass, and levels of the polymeric form of IgA1 are elevated in the serum of patients with IgAN [
14‐
16]. Galactose deficiency of
O-linked glycans in the hinge region of IgA1 is the beginning of a sequence of events that may lead to renal injuries. This galactose-deficient IgA1 (Gd-IgA1) consists of terminal
N-acetylgalactosamine (GalNAc) or sialylated GalNAc [
17‐
19]. Normal serum IgA1 is thought to contain little or no galactose-deficient
O-glycans [
20] (Fig.
1), but some
O-glycans of circulatory IgA1 in healthy individuals are galactose-deficient [
21]. In recent years, an increase in serum Gd-IgA1 levels in patients with IgAN was quantitatively confirmed for the first time by Moldoveanu et al. using
Helix aspersa agglutinin lectin, which recognizes GalNAc residues [
22]. Analysis of immortalized IgA1-secreting cells derived from the circulation of patients with IgAN and healthy controls has shown that Gd-IgA1 is related to decreased activity of core 1 β1,3-galactosyltransferase (C1GalT1) and elevated activity of α-2,6-sialyltransferase 2 (ST6GalNAc-II) [
23]. Recent studies have shown that these enzymatic activities may be regulated by genetic mechanisms and dysregulation of mucosal immunity [
24‐
26]. Mucosal infections, such as tonsillitis and upper respiratory infections, are associated with exacerbation of urinary abnormalities in patients with IgAN. In fact, Gd-IgA1-dependent modulation of C1GalT1 and ST6GalNAc-II is induced by interleukin (IL)-6 and IL-4 [
26]. Importantly, Toll-like receptor (TLR) 9 plays a key role in the progression of IgAN [
27,
28], and overexpression of tonsillar TLR9 is correlated with the production of Gd-IgA1 [
29]. Furthermore, repeated TLR9 activation induces tonsillar expression of a proliferation-inducing ligand (April), which participates in the generation and survival of antibody-producing plasma cells, resulted in production of Gd-IgA1 [
30].
Previous reports have indicated that glomerular IgA1 in IgAN is aberrantly glycosylated [
31,
32]. A fraction of Gd-IgA1 from the glomerular deposits is excreted into the urine and thus represents a disease-specific marker of IgAN. Urinary excretion of Gd-IgA1 discriminates patients with IgAN from patients with other proteinuric renal diseases [
33]. Furthermore, the level of urinary Gd-IgA1 is correlated with proteinuria in patients with IgAN. Urinary Gd-IgA1 thus may represent a disease-specific marker of IgAN. We recently established a novel lectin-independent method exploiting monoclonal antibody (KM55 mAb) for measuring serum levels of Gd-IgA1 [
34]; this method could be used worldwide for standardized measurement of serum Gd-IgA1 (Immuno-Biological Laboratories Co., Ltd.). In addition, we verified glomerular Gd-IgA1 was specifically detected in IgAN [
35]. Further studies are ongoing to establish a measurement system for urinary Gd-IgA1 using KM55 mAb.