ASN's Mission

To create a world without kidney diseases, the ASN Alliance for Kidney Health elevates care by educating and informing, driving breakthroughs and innovation, and advocating for policies that create transformative changes in kidney medicine throughout the world.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on X

Kidney Week

Please note that you are viewing an archived section from 2021 and some content may be unavailable. To unlock all content for 2021, please visit the archives.

Abstract: PO1449

Propensity of Immunoglobulin A Self-Aggregation via "Tailpiece" Cysteine 471 and Therapeutic Use of Existing Drug Cysteamine to Treat IgA Nephropathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Xie, Xinfang, Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China, Xi'an, China
  • Gao, Li, Department of Cardiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
  • Liu, Pan, Department of Medicine-Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
  • Lv, Jicheng, Renal Division, Department of Medicine, Peking University First Hospital, Beijing China; Institute of Nephrology, Peking University, Beijing, China
  • Lu, Wanhong, Department of Nephrology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China, Xi'an, China
  • Zhang, Hong, Renal Division, Department of Medicine, Peking University First Hospital, Beijing China; Institute of Nephrology, Peking University, Beijing, China
  • Jin, Jing, Department of Medicine-Nephrology and Hypertension, Feinberg Cardiovascular and Renal Research Institute, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
Background

IgA nephropathy (IgAN) is caused by deposition of circulatory IgA1 in the kidney. Hypo-galactosylated IgA1 has the propensity to form poly-IgA1 complexes that are prone to deposition. In IgA1 protein sequence, there are features required for the assembly of dimeric mucosal IgA1, including “tailpiece” Cys471 residue of the heavy chain in participating disulfide bonds with J-chain subunit in IgA1 dimer. In monomeric IgA1 with the absence of J-chain, this free Cys471 is susceptible to oxidation-induced disulfide with other IgA monomers.

Methods

Poly-IgA1 isolated from the plasma of IgAN patients was analyzed for intermolecular disulfide connections. Cysteine residues of Cys311 and Cys471 of IgA1 were mutated to determine their participation in IgA1-IgA1 disulfide bond formation. Cysteine-reducing drugs cysteamine and WR-1065 were tested for effects on IgA1 aggregation and on kidney deposition.

Results

High-molecular-weight IgA1 complexes were susceptible to reducing condition, suggesting disulfide-linkages in poly-IgA1 complexes. Mutagenesis confirmed Cys471’s participation in IgA1 self-aggregation, which could be disassembled by aminothiol drugs cysteamine and WR-1065. Administration of cysteamine to murine models of IgAN reduced the level of IgA1 deposition in the glomerulus.

Conclusion

IgA1 tailpiece contributes to the propensity of IgA1 monomer to self-aggregate via intermolecular disulfide bonds. Our results revealed a novel molecular mechanism for aberrant formation of IgA aggregates, to which repurposed cystinosis drug cysteamine was efficacious in preventing renal IgA deposition.

‘Tailpiece’ Cysteine-471 involved in IgA self aggregation, cysteamine treatment lowers poly-IgA contents in vitro and its renal deposition in vivo.