Anti-neutrophil cytoplasmic antibodies and effector CD4+ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis.
Most humans with microscopic polyarteritis and anti-myeloperoxidase (anti-MPO), anti-neutrophil cytoplasmic antibodies (ANCA) develop "pauci-immune" crescentic glomerulonephritis. For dissection of the roles of ANCA and cell-mediated effectors in microscopic polyarteritis, experimental autoimmune anti-MPO glomerulonephritis was induced by immunizing C57BL/6 mice with human MPO. Autoimmunity to mouse MPO (ANCA and CD4+ cell reactivity) was induced. Challenge with anti-glomerular basement membrane globulin resulted in accumulation of neutrophils, CD4+ cells and macrophages, and significant numbers of crescentic glomeruli compared with similarly challenged control-immunized mice. MPO-deficient (Mpo(-/-)) mice immunized with MPO developed similar immune responses to MPO but failed to recruit effector cells to glomeruli or develop significant crescent formation, suggesting that MPO is acting as a planted glomerular autoantigen. Effector CD4+ cell depletion in this model attenuated crescentic glomerulonephritis and effector cell influx without altering ANCA titers. However, B cell-deficient mice, with no ANCA, still developed severe crescentic glomerulonephritis with accumulation of effector cells. Intravital microscopy studies demonstrated that passive transfer of sera from MPO-immunized Mpo(-/-) mice to LPS-primed mice rapidly induced glomerular neutrophil accumulation and release of MPO. These studies provide in vivo evidence in a relevant vascular bed for both humoral and cellular anti-MPO responses as key inducers of injury. ANCA induces glomerular neutrophil infiltration and MPO deposition. Subsequently, anti-MPO CD4+ cells recognize MPO as a planted glomerular antigen and act with macrophages to amplify severe glomerular injury.
Ruth
Amanda-Jane
AJ
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, VIC 3168, Australia.
Kitching
A Richard
AR
Kwan
Rain Y Q
RY
Odobasic
Dragana
D
Ooi
Joshua D K
JD
Timoshanko
Jennifer R
JR
Hickey
Michael J
MJ
Holdsworth
Stephen R
SR
D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000502:physiology*; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D005921:Glomerulonephritis / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D007668:Kidney / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000502:physiology*; D009195:Peroxidase / Q000276:immunology* / Q000378:metabolism
D019268:Antibodies, Antineutrophil Cytoplasmic; D009195:Peroxidase