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Abstract: PO1420

LFA-1 (CD11a/CD18) and Mac-1 (CD11b/CD18) Are Important for Mediating Myeloperoxidase-ANCA Glomerulonephritis in a Preclinical Mouse Model

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Gou, Shen-Ju, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Hu, Peiqi, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Xiao, Hong, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Hu, Yanglin, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Alba, Marco A., The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Falk, Ronald J., The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
  • Jennette, J. Charles, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States
Background

Neutrophils play a critical role in the pathogenesis of necrotizing crescentic glomerulonephritis (NCGN) caused by anti-neutrophil cytoplasmic autoantibodies (ANCA). LFA-1 and Mac-1 are β2-integrins that have critical synergistic roles in neutrophil-mediated inflammation. In this study, we investigated the role of LFA-1 and Mac-1 in murine NCGN induced by mouse anti-mouse MPO, which is histopathologically indistinguishable from human ANCA NCGN.

Methods

Anti-MPO IgG was purified from sera of MPO knock out (KO) mice immunized with murine MPO. Mice with KO of LFA-1 or Mac-1, and normal wild-type C57BL/6j mice (WT B6) were injected i.v. with 50ug/g body weight anti-MPO IgG. Circulating anti-MPO IgG (MPO-ANCA) was monitored by ELISA. Proteinuria, hematuria and leukocyturia were monitored, and mice were sacrificed at day 6 and kidney tissue obtained for pathologic examination. MPO-ANCA-induced neutrophil activation was assayed in vitro.

Results

At day 6, WTB6 (n=8), LFA-1 KO (n=8) and Mac-1 KO (n=9) mice that received anti-MPO IgG had similar levels of circulating MPO-ANCA. All WT B6 mice developed hematuria and NCGN with mean 13.9% glomeruli with crescents and 5.3% with necrosis. In contrast, LFA-1 KO mice and Mac-1 KO mice had normal urine and substantially reduced NCGN (Table).
In vitro assays showed that anti-MPO IgG caused similar activation of neutrophils from LFA-1 KO, Mac-1 KO and WT mice.

Conclusion

Depletion of LFA-1 or Mac-1 blocks MPO-ANCA induced NCGN in mice, thus both of these β2-integrins are required for ANCA disease induction. Depletion of LFA-1 or Mac-1 does not block MPO-ANCA induced neutrophil activation. These observations indicate that blockade of either of these β2-integrins abrogates MPO-ANCA NCGN by inhibiting the recruitment of neutrophils that is required to induce inflammatory vascular injury in ANCA disease. These data suggest that pharmacologic blockade of β2-integrins may have a therapeutic role in ANCA disease.

Anti-MPO IgG-Induecd Glomerular Lesions in Different Strains of Mice
 Crescents/glomerulusNecrosis/glomerulus
B6 WT (n=8)13.9% 5.3%
B6 Mac-1 KO (n=9)2.9% (p<0.001)0.7% (p=0.003)
B6 LFA-1 KO (n=8)0.9% (p<0.001)0.0% (p<0.001)

Funding

  • NIDDK Support