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Abstract: PO1460

Maturation of Decay Accelerating Activity Response Across the Natural History of C3 Glomerulopathy

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Culek, Christopher, University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, Iowa, United States
  • Smith, Richard J., University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, Iowa, United States
  • Nester, Carla Marie, University of Iowa Molecular Otolaryngology and Renal Research Laboratories, Iowa City, Iowa, United States
Background

C3 Glomerulopathy (C3G) is an ultra-rare complement-mediated renal disease characterized by dysregulation of the alternative pathway (AP) of complement. Dysregulation is often driven by a nephritic factor (C3Nef), an autoantibody to the C3 convertase (C3BbB) of the AP. We hypothesized that the properties of Nefs change over time and that changes will be associated with changes in underlying complement dysregulation.

Methods

IgG was purified from normal human serum and from sera collected across six time points of a well characterized C3G patient. Using SPR (Biacore), the C3 convertase (C3bBb) was formed on a CM5 sensor chip. Purified test or control IgG was injected to form the Nef-C3bBb complex. The ability of native complement regulators to decay the Nef-C3bBb complex was assessed by injecting Decay Accelerating Factor (DAF), Complement Receptor 1 (CR1), Factor H (FH), or control reagent. Residual C3bBb was determined by the ratio of post- to pre-regulated convertase. Data were compared to time-associated complement biomarker results.

Results

The presence of Nef conferred resistance to the normal decay accelerating activity (DAA) by DAF, CR1, and FH. Resistance to DAA was highest in the earliest sample (S1, p= 0.0001), with a reduction in subsequent samples. This change was independent of Nef titer and coincident with reduced complement activity. Low DAF resistance was maintained in later samples, whereas CR1 and FH resistance gradually increased.

Conclusion

Nef-stabilized C3bBb resistance to native DAA proteins matures over time and is independent of Nef titer. Changes in response to regulators is accompanied by a relative change in underlying complement dysregulation as reflected by complement biomarkers. How this variance (in time and across regulators) impacts disease course and outcome in patients with C3G or whether the phenomenon represents a novel treatment target warrants further study.

Funding

  • NIDDK Support