Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha

Am J Pathol. 2005 Jul;167(1):47-58. doi: 10.1016/s0002-9440(10)62952-5.


Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, and idiopathic pauci-immune necrotizing crescentic glomerulonephritis are associated with myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (ANCAs). Clinical and experimental evidence indicates that ANCA and proinflammatory stimuli of infectious origin act synergistically to cause vasculitis. We tested this hypothesis in a recently developed mouse model of anti-MPO IgG-induced glomerulonephritis by using bacterial lipopolysaccharide (LPS) as the proinflammatory stimulus. Systemic administration of LPS dose dependently increased renal injury induced by anti-MPO IgG as demonstrated by increased glomerular crescent formation and glomerular necrosis. In the early phase, LPS enhanced anti-MPO IgG-induced glomerular neutrophil accumulation. Furthermore, a transient induction of circulating tumor necrosis factor (TNF)-alpha levels, followed by a marked increase in circulating MPO levels, was observed on administration of LPS. In vitro, anti-MPO IgG induced a respiratory burst in murine neutrophils only after priming with TNF-alpha. Finally, anti-TNF-alpha treatment attenuated, but did not prevent, the LPS-mediated aggravation of anti-MPO IgG-induced glomerulonephritis. In conclusion, our study demonstrates that ANCA and proinflammatory stimuli act synergistically to induce vasculitic disease and suggests potential benefits of inhibiting TNF-alpha bioactivity in treating human ANCA-associated necrotizing crescentic glomerulonephritis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Antineutrophil Cytoplasmic / immunology*
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / pathology
  • In Vitro Techniques
  • Lipopolysaccharides / immunology*
  • Mice
  • Neutrophils / immunology
  • Peroxidase / blood
  • Peroxidase / immunology*
  • Tumor Necrosis Factor-alpha / analysis
  • Tumor Necrosis Factor-alpha / immunology
  • Vasculitis / immunology
  • Vasculitis / pathology


  • Antibodies, Antineutrophil Cytoplasmic
  • Lipopolysaccharides
  • Tumor Necrosis Factor-alpha
  • Peroxidase