IgA Nephropathy and Henoch-Schoenlein Purpura Nephritis: Aberrant Glycosylation of IgA1, Formation of IgA1-Containing Immune Complexes, and Activation of Mesangial Cells

Abstract

Large numbers of studies have demonstrated that abnormal humoral and cellular immunity may contribute to the pathogenesis of IgA nephropathy. On the other hand, clinical evidence indicates that bone marrow cells and mucosal immunity may also play a key role. Based on these findings, impaired immune regulation in the 'mucosa-bone-marrow axis' has been postulated in IgA nephropathy patients. However, the underlying mechanisms still remain unclear. This is mainly due to difficulties in the clinical approach to the complicated immune system. Therefore, appropriate animal models are required. We recently established several useful animal models. Using these models, our group is approaching underlying mechanisms in which bone marrow and mucosal cells interrelate and finally induce this disease. Up to now, results from these models and its clinical feedback have suggested that mucosal IgA responses to antigens may be altered by Th2-biased background or dysregulation of innate immunity in this disease. This abnormal mucosal IgA immune system may result in failure of mucosal antigen elimination and thus increases in memory cells in the bone marrow.

Clustered O-Glycans of IgA1

“…In this work, we demonstrate the complete analysis of O-glycoform microheterogeneity and site localization of the glycoforms in a naturally Gal-deficient IgA1 (Ale) myeloma protein that mimics the nephritogenic IgA1 in patients with IgAN (8,9). Reversed phase (RP) LC FT-ICR MS successfully identified 10 distinct IgA1 HR fragments representing Ͼ99% of total IgA1.…”

“…1). Aberrant O-glycosylation of IgA1 is involved in the pathogenesis of IgA nephropathy (IgAN) and the closely related Henoch-Schö nlein purpura nephritis (1,8). Interestingly, the aberrantly glycosylated molecules, IgA1 in IgAN and MUC1 in cancer, are recognized by the immune system as neoepitopes as evidenced by formation of specific antibodies (9 -11).…”

“…We have successfully demonstrated this in the analysis of IgA1 O-glycans from patients with IgAN versus healthy controls and disease controls (13)(14)(15). This included proximal assessment of sites with galactose (Gal)-deficient O-glycans after digests with IgAspecific proteases (8). Several studies have demonstrated the value of mass spectrometry (MS) in identifying Gal-deficient IgA1 in patients with IgAN (16 -21), including our work that demonstrated the first direct localization of native sites of O-glycan chains in the hinge region (HR) of IgA1 by use of electron capture dissociation (ECD) (20,22).…”

“…Aberrantly glycosylated IgA1, deficient in Gal in some of the O-glycans in the HR, in serum is rare in healthy individuals but is present at elevated levels in IgAN patients (13,15). This distinctive IgA1 is in circulating immune complexes (8,10,15) and in the glomerular deposits of IgAN patients (16,29). The absence of Gal apparently leads to the exposure of neoepitopes, including terminal and sialylated N-acetylgalactosamine (GalNAc) residues (9,10).…”

“…Lectin Western Blot-Samples of IgA1 (Ale) myeloma protein were digested with a single protease at a time (8) and then separated under reducing conditions by SDS-PAGE. The blots were developed with a GalNAc-specific lectin from Helix aspersa (HAA; Sigma-Aldrich) (14).…”