Anti-neutrophil cytoplasmic antibodies and effector CD4+ cells play nonredundant roles in anti-myeloperoxidase crescentic glomerulonephritis

• Published in: Journal of the American Society of Nephrology 2006-07, Vol.17 (7), p.1940-1949
• Main Authors: RUTH, Amanda-Jane, RICHARD KITCHING, A, KWAN, Rain Y. Q, ODOBASIC, Dragana, OOI, Joshua D. K, TIMOSHANKO, Jennifer R, HICKEY, Michael J, HOLDSWORTH, Stephen R
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Antineutrophil Cytoplasmic - physiology; Autoimmunity; Biological and medical sciences; CD4-Positive T-Lymphocytes - physiology; Glomerulonephritis; Glomerulonephritis - enzymology; Glomerulonephritis - immunology; Glomerulonephritis - pathology; Kidney - immunology; Kidney - pathology; Medical sciences; Mice; Mice, Inbred C57BL; Nephrology. Urinary tract diseases; Nephropathies. Renovascular diseases. Renal failure; Neutrophils - physiology; Peroxidase - immunology; Peroxidase - metabolism
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2006020108

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.