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Abstract: TH-PO820

TLR9 Activation Is Involved in Aberrant IgA Glycosylation via APRIL- and IL-6-Mediated Pathways in IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Makita, Yuko, Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
  • Suzuki, Hitoshi, Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
  • Kano, Toshiki, Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
  • Julian, Bruce A., Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Novak, Jan, Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Suzuki, Yusuke, Department of Nephrology, Juntendo University Faculty of Medicine, Tokyo, Japan
Background

Toll-like receptors (TLRs) play a key role in the pathogenesis of IgA nephropathy (IgAN). Galactose-deficient IgA1 (Gd-IgA1) is involved in development of the disease. However, the mechanisms driving Gd-IgA1 production have not been fully elucidated. Although previous reports indicated a proliferation-inducing ligand (APRIL) and IL-6 may be involved in Gd-IgA1 synthesis in IgAN, the mechanisms leading to the overproduction of Gd-IgA1 and subsequent formation of Gd-IgA1 containing ICs are still unclear.

Methods

IgAN prone ddY mice were divided into two groups with CpG-ODN (TLR9 ligand) immunization (n=18) or without (n=18). CpG-ODN was injected intraperitoneally 3 times a week for 12 weeks. Renal pathology and serum levels of aberrantly glycosylated IgA, IgG-IgA ICs, APRIL and IL-6 were evaluated after 12 weeks. We also examined the mechanisms of production of Gd-IgA1 in human IgA1-secreting cells.

Results

Injection of ddY mice with CpG-ODN increased production of aberrantly glycosylated IgA and IgG-IgA ICs, resulting in exacerbated kidney injury (P<0.05). Serum levels of APRIL correlated with serum levels of aberrantly glycosylated IgA and IgG-IgA IC (P<0.05). CpG-ODN stimulation induced production of aberrantly glycosylated IgA in splenocytes of ddY mice through increase of APRIL and IL-6. In human IgA1-secreting cells, TLR9 activation enhanced Gd-IgA1 production via increase of APRIL and IL-6. Production of Gd-IgA1 was partly reduced by siRNA for APRIL and/or anti-IL-6.

Conclusion

TLR9 stimulation enhanced synthesis of nephritogenic IgA through overproduction of APRIL and IL-6 in IgAN. Moreover, the present study clarified the crosstalk between APRIL and IL-6, of note APRIL and IL-6 independently promote the production of aberrantly glycosylated IgA.