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Abstract: FR-PO842

TLR7-GalNAcT2 Axis Modulated IgA1 O-Glycosylation in Patients with IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Zheng, Nuoyan, The first affiliated hospital of Sun Yat-sen University, Guangzhou, China
  • Yu, Xueqing, Department of Nephrology, Guangdong Provincial People's Hospital, Guangzhou, China
Background

IgA nephropathy (IgAN) was featured with galactose deficient-IgA1 (Gd-IgA1) complex deposit in kidney of patients. O-glycosyltransferases were responsible for O-glycan synthesis, which made them crucial for the production of Gd-IgA1. Toll-like receptors (TLRs) were shown to be related with pathogenesis of IgAN. The underlying mechanism between TLRs and the production of Gd-IgA1 was not known yet.

Methods

Biopsy proven IgAN patients with clinical features of primary IgAN, MCD, MN, LN were enrolled in this study. Paraffin-embedded sections of kidney biopsies were subjected to immunofluorescence staining for analysis of TLR7 expression. Peripheral blood mononuclear cells (PBMCs) were prepared and used for real-time PCR analysis or cell-culture experiments.

Results

Here we found that TLR7 proteins were abundantly presented in infiltrated leukocytes in kidney of IgA patients (n=90), as compared with healthy donors and patients with MCD or MN. The mean fluorescence intensity of TLR7 was associated with renal function deterioration. Renal expression of TLR7 protein was evidently presently in CD19+ B cells. Moreover, mRNA levels of TLR7 were significantly correlated with those of GalNAcT2 in PBMCs and they were both increased in B cells of IgAN patients. After activation with TLR7 ligand-R848, PBMCs from IgAN patients secret more Gd-IgA1 molecules than controls and expression GalNAcT2 was increased in sorted B cells from IgAN patients. Over-expression of TLR7 led to up-regulated expression of GalNAcT2, whereas knockdown-expression of TLR7 led to down-regulated expression of GalNAcT2. Over-expression of GalNAcT2 in B cells resulted in augmented synthesis of Gd-IgA1 molecules, but not total IgA1 molecules.

Conclusion

Taken together, the abundant presence of TLR7 play important roles in pathogenesis of IgA nephropathy, by promoting GalNAcT2 expression in B cells and later the synthesis of Gd-IgA1 molecules.

Funding

  • Government Support - Non-U.S.