Bone marrow-derived cells are sufficient and necessary targets to mediate glomerulonephritis and vasculitis induced by anti-myeloperoxidase antibodies

Abstract

Clinical and experimental evidence indicate that ANCA cause pauci-immune necrotizing and crescentic glomerulonephritis (NCGN) and systemic small vessel vasculitis in humans. One of the major target antigens for ANCA is myeloperoxidase (MPO). An animal model that closely resembles the human disease is induced by intravenous injection of anti-MPO IgG into mice. The likely primary pathogenic targets for the anti-MPO IgG are circulating neutrophils and monocytes, although other cells have been implicated, including endothelial cells and epithelial cells. Herein is reported a new model for anti-MPO-mediated glomerulonephritis and vasculitis that further documents the pathogenic potential of ANCA and demonstrates that bone marrow (BM)-derived cells are sufficient targets to cause anti-MPO disease in the absence of MPO in other cell type. MPO knockout (Mpo-/-) mice that were immunized with mouse MPO were exposed to irradiation and received a transplant of Mpo+/+ or Mpo-/- BM. Engraftment in mice with circulating anti-MPO resulted in development of pauci-immune NCGN in all mice and pulmonary capillaritis and splenic necrotizing arteritis in some. Anti-MPO IgG also was introduced intravenously into chimeric mice by transplantation of Mpo+/+ BM into irradiated Mpo-/- mice or Mpo-/- BM into irradiated Mpo+/+ mice. Chimeric Mpo-/- mice with circulating MPO-positive neutrophils developed NCGN, whereas chimeric Mpo+/+ mice with circulating MPO-negative neutrophils did not, thereby indicating that BM-derived cells are not only sufficient but also necessary for induction of anti-MPO disease. This novel animal model further documents ANCA IgG interactions with neutrophils as a cause of ANCA-associated glomerulonephritis and vasculitis.