Abstract: TH-PO017

Complement Activation Is Not Required for MPO-ANCA Induced Pulmonary Granulomatosis in Mice

Session Information

Category: Glomerular

  • 1001 Glomerular: Basic/Experimental Immunology and Inflammation

Authors

  • Xiao, Hong, University of North Carolina at Chapel Hill, Chapel hill, North Carolina, United States
  • Hu, Peiqi, University of North Carolina at Chapel Hill, Chapel hill, North Carolina, United States
  • Alba, Marco A., University of North Carolina at Chapel Hill, Chapel hill, North Carolina, United States
  • Falk, Ronald J., University of North Carolina at Chapel Hill, Chapel hill, North Carolina, United States
  • Jennette, J. Charles, University of North Carolina at Chapel Hill, Chapel hill, North Carolina, United States
Background

We previously developed an animal model of human pauci-immune crescentic glomerulonephritis (CGN) caused by myeloperoxidase (MPO) specific antineutrophil cytoplasmic autoantibodies (MPO-ANCA) by i.v. injection of mice with antibodies specific for mouse MPO. The induction of CGN by injection of anti-MPO IgG required activation of the alternative complement pathway, and was prevented in deficient in complement factor B (CFB) or C5. We now have developed a model of ANCA pulmonary granulomatosis that mimics granulomatosis with polyangiitis caused by i.v. injection of anti-MPO IgG after intratracheal spray of lipopolysacarride (LPS).

Methods

9-11 wk-old B6 WT, CFB-/- and C5-/- mice were treated with an intratracheal spray of LPS (5ug) at day 0, plus two doses of anti-MPO IgG, i.v. (75ug/g BW) at day0 and day1. Mice were sacrificed at day7. Kidney and lung tissues were obtained for pathologic examination.

Results

With this regimen, all B6 WT mice (n=5) developed CGN (mean 20% glomeruli with crescents) and pulmonary necrotizing granulomatous lesions (mean scores = 2.6 out of 3). All CFB-/- (n=3) and C5-/- (n=4) mice developed pulmonary necrotizing granulomatous lesions (mean scores = 3) but none developed CGN. Negative control WT mice that received LPS alone (n=6), and MPO-/- mice that received LPS and anti-MPO (n=3) developed no CGN or pulmonary granulomatosis.

Conclusion

Absence of CFB or C5 protects from anti-MPO induced CGN but not anti-MPO induced pulmonary granulomatosis, indicating complement activation is not required for MPO-ANCA induced pulmonary granulomatosis in mice. These interesting and potentially impactful observations suggest that although both necrotizing CGN and necrotizing pulmonary granulomatosis are caused by MPO-ANCA, the mediators are different, and, thus optimum therapy for the kidney disease may differ from optimum therapy for the lung disease. For example, although blockade of alternative pathway activation may be effective adjunct therapy for ANCA CGN, it may have no effect on ANCA granulomatous disease.

Funding

  • NIDDK Support