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

Huugen, D., Xiao, H., van Esch, A., Falk, RJ., Peutz-Kootstra, CJ., Buurman, WA., Tervaert, JWC., Jennette, JC. & Heeringa, P., Jul-2005, In : The American Journal of Pathology. 167, 1, p. 47-58 12 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • D Huugen
  • H Xiao
  • A van Esch
  • RJ Falk
  • CJ Peutz-Kootstra
  • WA Buurman
  • JWC Tervaert
  • JC Jennette
  • P Heeringa

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.

Original languageEnglish
Pages (from-to)47-58
Number of pages12
JournalThe American Journal of Pathology
Volume167
Issue number1
Publication statusPublished - Jul-2005

    Keywords

  • ANTINEUTROPHIL CYTOPLASMIC ANTIBODIES, HUMAN ENDOTHELIAL-CELLS, CRESCENTIC GLOMERULONEPHRITIS, WEGENERS-GRANULOMATOSIS, MONOCLONAL-ANTIBODIES, SYSTEMIC VASCULITIS, NEUTROPHILS, MYELOPEROXIDASE, MICE, AUTOANTIBODIES

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