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.

• Authors: Masako Otani, Junichiro Nakata, Masao Kihara, Valérie Leroy, Solange Moll, Yoshinao Wada, Shozo Izui
• Journal: Journal of the American Society of Nephrology : JASN (J Am Soc Nephrol) Vol. 23 Issue 3 Pg. 438-46 (Mar 2012) ISSN: 1533-3450 [Electronic] United States
• PMID: 22193386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Complement C3
• Immunoglobulin A
• Immunoglobulin Allotypes
• Immunoglobulin G
• glycosylated IgA
• Rheumatoid Factor

Topics

• Amino Acid Sequence
• Animals
• Antibodies, Monoclonal (adverse effects, analysis)
• Complement C3 (metabolism)
• Disease Models, Animal
• Glomerulonephritis (etiology, metabolism, pathology)
• Glomerulonephritis, IGA (etiology, metabolism, pathology)
• Hybridomas (metabolism)
• Immunoglobulin A (immunology, metabolism)
• Immunoglobulin Allotypes (metabolism)
• Immunoglobulin G (immunology, metabolism)
• Mice
• Mice, Inbred BALB C
• Molecular Sequence Data
• Rheumatoid Factor (metabolism)