O-Glycosylated IgA Rheumatoid Factor Induces IgA Deposits and Glomerulonephritis

Abstract

Structural aberrations of O-linked glycans present in the IgA1 hinge region are associated with IgA nephropathy, but their contribution to its pathogenesis remains incompletely understood. In this study, mice implanted with hybridoma secreting 6-19 IgA anti-IgG2a rheumatoid factor, but not 46-42 IgA rheumatoid factor bearing the same IgA allotype, developed mesangial deposits consisting of IgA, IgG2a, and C3. Studies in immunoglobulin-and C3-deficient mice revealed that the development of these glomerular lesions required the formation of IgA-IgG2a immune complexes and subsequent activation of complement. The proportion of polymeric and monomeric forms, the IgG2a-binding affinity, and the serum levels of IgA-IgG2a immune complexes were similar between 6-19 IgA-and 46-42 IgA-injected mice. In contrast, the analysis of oligosaccharide structures revealed highly galactosylated O-linked glycans in the hinge region of 6-19 IgA and poorly O-glycosylated in the hinge region of 46-42 IgA. Furthermore, the structure of N-linked glycans in the CH1 domain was the complex type in 6-19 IgA and the hybrid type in 46-42 IgA. In summary, this study demonstrates the presence of O-linked glycans in the hinge region of mouse IgA and suggests that 6-19 IgA rheumatoid factor-induced GN could serve as an experimental model for IgA nephropathy.

Henoch–Schönlein purpura nephritis

“…In a mouse model for IgA nephritis, mice lacking either C3 or IgG did not develop the IgAN phenotype [39]. Also, glomerular MBL deposition has been found to be associated with a severe clinical presentation, and initial C4d deposition has been shown to be a risk factor for a worse clinical outcome [24,40].…”

O-Linked Glycosylation Determines the Nephritogenic Potential of IgA Rheumatoid Factor

“…10 Indeed, we recently demonstrated the presence of O-glycans in the hinge region of murine IgA monoclonal rheumatoid factors (RFs) bearing the Igh-2 a allotype. 11 More significantly, comparative analysis of two murine IgA anti-IgG2a RFs bearing the Igh-2 a allotype (6-19 and 46-42) revealed that highly O-glycosylated 6-19 IgA RF mAbs induced severe glomerular lesions characterized by abundant mesangial IgA deposits, together with IgG2a and C3, whereas poorly O-glycosylated 46-42 IgA failed to provoke glomerular lesions. However, we also noted a marked difference in the structure of N-linked glycans (N-glycans) present in the CH1 domain between nephritogenic 6-19 IgA RF and non-nephritogenic 46-42 IgA RF (i.e., biantennary and triantennary complex types in [6][7][8][9][10][11][12][13][14][15][16][17][18][19] IgA versus hybrid type with features of both high mannose-type and complex-type oligosaccharides in 46-42 IgA).…”

“…However, we also noted a marked difference in the structure of N-linked glycans (N-glycans) present in the CH1 domain between nephritogenic 6-19 IgA RF and non-nephritogenic 46-42 IgA RF (i.e., biantennary and triantennary complex types in [6][7][8][9][10][11][12][13][14][15][16][17][18][19] IgA versus hybrid type with features of both high mannose-type and complex-type oligosaccharides in 46-42 IgA). Thus, we could not exclude the implication of structural differences in N-glycans in IgAN-like glomerular lesions induced by [6][7][8][9][10][11][12][13][14][15][16][17][18][19] IgA RF.…”

“…In addition, three independent 6-19 IgA antiIgG2a RF mAbs were established from C57BL/6 (B6) mice constitutively expressing the 6-19 IgA RF transgene (Tg) in order to obtain 6-19 IgA RF glycovariants bearing O-glycans, the extent and composition of which were different from those of the wildtype (WT) 6-19 IgA RF mAb. The analysis of these different [6][7][8][9][10][11][12][13][14][15][16][17][18][19] IgA RF variants compared with the WT 6-19 IgA RF mAb indicates that the extent of O-glycosylation, even if the glycans are highly galactosylated, is an important factor determining the nephritogenic activity of 6-19 IgA RF mAbs.…”

Induction of IgA Deposits and Glomerulonephritis by IgA Rheumatoid Factor

“…In this issue of JASN, Otani et al 1 describe an interesting murine model for studies of IgA-associated GN. The authors explore the nephritogenic potential of two different monoclonal IgA rheumatoid factors (designated as [6][7][8][9][10][11][12][13][14][15][16][17][18][19] IgA and 46-42 IgA) specific for murine IgG2a in relation to potential differences in glycosylation of these IgA antibodies.…”