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(American Journal of Pathology. 2005;167:47-58.)
© 2005 American Society for Investigative Pathology

Aggravation of Anti-Myeloperoxidase Antibody-Induced Glomerulonephritis by Bacterial Lipopolysaccharide

Role of Tumor Necrosis Factor-{alpha}

Dennis Huugen*, Hong Xiao{dagger}, Anita van Esch*, Ronald J. Falk{dagger}{ddagger}, Carine J. Peutz-Kootstra§, Wim A. Buurman, Jan Willem Cohen Tervaert*, J. Charles Jennette{dagger} and Peter Heeringa*

From the Departments of Clinical and Experimental Immunology,* Pathology,§ and General Surgery, Cardiovascular Research Institute Maastricht, University Maastricht, The Netherlands; and the Departments of Pathology and Laboratory Medicine{dagger} and Medicine and Hypertension,{ddagger} University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

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.




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