Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice

Abstract

Antineutrophil cytoplasmic autoantibodies (ANCAs) are identified in the circulation of approximately 80% of patients with pauci-immune necrotizing and crescentic glomerulonephritis and systemic small vessel vasculitis, such as microscopic polyangiitis and Wegener granulomatosis. The most common antigen target for ANCAs is myeloperoxidase (MPO), which is found in neutrophils and monocytes. We report definitive experimental animal evidence that ANCAs are pathogenic. MPO knockout (Mpo–/–) mice were immunized with mouse MPO. Splenocytes from these mice or from control mice were injected intravenously into recombinase-activating gene-2–deficient (Rag2–/–) mice, which lack functioning B lymphocytes and T lymphocytes. All mice that received splenocytes developed mild to moderate glomerular immune deposits, but only mice that received 1 × 108 or 5 × 107 anti-MPO splenocytes developed severe necrotizing and crescentic glomerulonephritis, granulomatous inflammation, and systemic necrotizing vasculitis, including necrotizing arteritis and hemorrhagic pulmonary capillaritis. To test the pathogenic potential of antibodies alone, purified anti-MPO IgG or control IgG was injected intravenously into Rag2–/– mice and wild-type mice. Mice that received anti-MPO IgG but not mice that received control IgG developed focal necrotizing and crescentic glomerulonephritis with a paucity of glomerular Ig deposition. Thus, anti-MPO IgG alone was able to cause pauci-immune glomerular necrosis and crescent formation in the absence of functional T or B lymphocytes in Rag2–/– mice and in the presence of an intact immune system in wild-type C57BL/6J mice. This animal model offers strong support for a direct pathogenic role for ANCA IgG in human glomerulonephritis and vasculitis

Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: A long‐term followup study

“…In addition, ANCA activate other cells in vitro, such as monocytes and endothelial cells (7). Finally, in vivo experimental data also suggest an important role for ANCA in the pathophysiology of vasculitis (8,9). Certain drugs have been linked to the induction of ANCA and the onset of ANCA-associated vasculitis (AAV) (10).…”

Antineutrophil cytoplasmic antibodies reacting with human neutrophil elastase as a diagnostic marker for cocaine‐induced midline destructive lesions but not autoimmune vasculitis

“…Classic ANCA reacting with PR3 and pANCA reacting with MPO have become accepted diagnostic tools in the evaluation of patients with Wegener's granulomatosis (WG) and patients with microscopic polyangiitis (MPA) (9). Evidence is mounting that these specific antibodies not only are disease markers but also are pathogenic of small-vessel vasculitis, the characteristic histopathologic hallmark of these disorders (10,11).…”

Febrile temperatures control antineutrophil cytoplasmic autoantibody–induced neutrophil activation via inhibition of phosphatidylinositol 3‐kinase/Akt

“…The activation of neutrophils by ANCAs induces respiratory burst activity and the release of toxic granule proteins (3). Recently, the passive transfer of anti-MPO mAb from MPO-deficient mice into wild-type mice resulted in systemic vasculitis, and the clinical manifestations included necrotizing pauciimmune glomerulonephritis (25). Moreover, neutrophil depletion completely prevented this disease in another mouse model, thus firmly establishing the role of ANCAs and neutrophils in the induction of vasculitis (12).…”