Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice (1)
Associated with circulating antineutrophil cytoplasmic autoantibodies (ANCA) are specific for antigens in the primary granules of neutrophils and the peroxidase positive lysosome of monocyte. Two main antigens are identified as myeloperoxidase (MPO) and proteinase 3 (PR3).
MPO was purified from WEHI-3 cells (a murine myeloid cell line). MPO-/- mice were immunized with 10 ug MPO emulfied with complete Freund’s adjuvant on day 0 followed by booter immunization with incomplete Freund’s adjuvant on day 21 and 31. Rag2-/- mice which are lacking T or B lymphocytes were used as donors.
Anti-MPO splenocytes from MPO immunized MPO-/- mice elevated BUN and serum creatinine dose dependently. These mice also showed severe necrotizing and crescentic glomerulonephritis.
Purified IgG produced by splenocytes from MPO immunized mice were injected donor mice at the dose of 50 ug/g body weight. By day 3, Rag2-/- mice that received anti-MPO IgG already had developed hematuria, proteinuria, and leukocyturia, which persisted until sacrificat day 6.
They showed 13.2 % of glomeruli with necrosis and 10.8 % of cresents. B6 mice, likewise, showed 4.7% of glomeruli with necrosis and 3.3 % of cresents. Anti-MPO IgG induces glomeular necrosis and cresents in Rag-/- mice and in the presence of a competent immune system in WT B6 mice.
The pathogenesis of pauci-immune ANCA associated glomerulonephritis is distinct from that for immune complex glomerulonephritis or anti-GBM glomerulonephritis. This distinct pathogenesis involves ANCA-induced activation of neutrophils and monocytes which were activated with ANCA IgG. ANCA IgG activates cytokine-primed neutrophils to release injurious oxygen metabolites and proteinase, followed by inducing IL-1, IL-8 and leukotrienes.