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Abstract: SA-PO842

Characterization of IgA1-Containing Circulating Immune Complexes in Patients with IgA Nephropathy with Progressive vs. Nonprogressive Disease

Session Information

Category: Glomerular Diseases

  • 1401 Glomerular Diseases: From Inflammation to Fibrosis

Authors

  • Gurganus, Graham, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Hall, Stacy D., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Huang, Zhi qiang, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Maillard, Nicolas, Hospital and University Jean Monnet of Saint-Etienne, Saint-Etienne, France
  • Moldoveanu, Zina, University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Rizk, Dana V., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Julian, Bruce A., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Renfrow, Matthew B., University of Alabama at Birmingham, Birmingham, Alabama, United States
  • Novak, Jan, University of Alabama at Birmingham, Birmingham, Alabama, United States
Background


IgA nephropathy (IgAN) is an autoimmune disease wherein circulating immune complexes (CIC) deposit in the glomeruli and induce mesangioproliferative injury. These CIC contain IgA1 with some O-glycans deficient in galactose (Gd-IgA1) bound by IgG autoantibodies (AuAb) specific for Gd-IgA1. Serum levels of Gd-IgA1 and IgG AuAb predict disease progression, but little is known about characteristics of the CIC. Here, we analyzed the mesangioproliferative capacity and composition of CIC from patients with progressive vs. non-progressive IgAN.

Methods


CIC from sera of IgAN patients with progressive (IgAN-P; n=3) or non-progressive (IgAN-Np; n=2) disease were isolated by size-exclusion chromatography (SEC). IgAN-P were defined as having eGFR loss (2021 CKD Epi formula) >2 ml/min/1.73 m2 per year. Median follow up was 13 years. Mesangioproliferative activity of CIC was assessed by using cultured primary human mesangial cells (MC). Jacalin affinity chromatography was used to deplete total serum IgA1 before SEC. Serum levels of IgA, Gd-IgA1, and IgG AuAb were determined by ELISA and CIC composition was assessed by SDS-PAGE/immunoblotting with antibodies specific for IgA, IgG, or complement C3.

Results

CIC of molecular mass (Mr) >700 kDa stimulated proliferation of MC. These CIC contained IgA, IgG, and C3. Most of C3 in these CIC was covalently associated with IgG and IgA, presumably through a thioester bond. Immunoblotting of CIC electrophoretically separated under reducing conditions revealed C3, C3b, and iC3b. CIC from IgAN-P exhibited greater mesangioproliferative activity compared to CIC from IgAN-Np. Jacalin removed these stimulatory CIC from serum, and the corresponding SEC fractions were devoid of IgA, IgG, and C3.

Conclusion

IgAN CIC with Mr >700 kDa that stimulated cellular proliferation of MC contained IgA1 with IgG and covalently attached C3. Jacalin affinity chromatography confirmed association of IgA1 with C3 and IgG. Moreover, IgAN-P had more active CIC compared to IgAN-Np CIC. Future studies will determine similarities and differences in the composition and amounts of these CIC associated with disease severity and/or progression.

Funding

  • NIDDK Support