title: Myeloperoxidase (MPO)-specific CD4+ T cells contribute to MPO-anti-neutrophil cytoplasmic antibody (ANCA) associated glomerulonephritis.
abstract: Autoimmunity to the neutrophil enzyme myeloperoxidase (MPO) is an important cause of rapidly progressive glomerulonephritis, but the relative roles of MPO-specific anti-neutrophil cytoplasmic antibodies (MPO-ANCA) and autoreactive effector MPO-specific CD4(+) T cells are unclear. We confirmed that passive transfer of murine MPO-ANCA to agammaglobulinemic μMT mice immunized with OVA induces glomerular injury with capillary wall thickening, fibrinoid necrosis, mesangial cell proliferation, and periglomerular cell infiltration. Preimmunization of μMT mice with MPO induced MPO-specific CD4(+) T cells and significantly enhanced renal injury after MPO-ANCA transfer. CD4(+) T cell depletion prevented this augmentation of injury, confirming the importance of effector T cells in the development of MPO-ANCA associated glomerulonephritis. Therefore, MPO-ANCA can induce glomerulonephritis through both direct humoral mechanisms (recruitment of neutrophils and deposition of MPO) and indirectly by initiating MPO deposition in glomeruli, thereby directing effector CD4(+) T cell mediated injury. To confirm and support this data, we transferred T cells from MPO-immunized Mpo(-/-)μMT mice into Rag1(-/-) mice (control mice received ovalbumin specific T cells) and triggered injury by passive MPO-ANCA. Renal injury was significantly greater in mice transferred with T cells from MPO-immunized mice. These current studies demonstrate that MPO-ANCA induces injury via both humoral and cell mediated immune mechanisms.
authors.affiliation: Center for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Victoria, Australia.
authors.forename: Poh-Yi
authors.initials: PY
authors.lastname: Gan
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ooi
mesh_terms: D000818:Animals; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D005260:Female; D005434:Flow Cytometry; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007114:Immunization; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007148:Immunoglobulin mu-Chains / Q000235:genetics / Q000276:immunology; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D010047:Ovalbumin / Q000276:immunology; D009195:Peroxidase / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D019268:Antibodies, Antineutrophil Cytoplasmic; D007075:Immunoglobulin M; D007148:Immunoglobulin mu-Chains; D010047:Ovalbumin; D009195:Peroxidase