Aggravation of anti-myeloperoxidase antibody-induced glomerulonephritis by bacterial lipopolysaccharide: role of tumor necrosis factor-alpha.
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.
Department of Clinical and Experimental Immunology, Cardiovascular Research Institute Maastricht, University Maastricht, PO Box 616, 6200 MD Maastricht, The Netherlands.
Dennis
D
Huugen
Hong
H
Xiao
Anita
A
van Esch
Ronald J
RJ
Falk
Carine J
CJ
Peutz-Kootstra
Wim A
WA
Buurman
Jan Willem Cohen
JW
Tervaert
J Charles
JC
Jennette
Peter
P
Heeringa
D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005921:Glomerulonephritis / Q000276:immunology* / Q000473:pathology; D066298:In Vitro Techniques; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D009504:Neutrophils / Q000276:immunology; D009195:Peroxidase / Q000097:blood / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology; D014657:Vasculitis / Q000276:immunology / Q000473:pathology
D019268:Antibodies, Antineutrophil Cytoplasmic; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D009195:Peroxidase