Anti-Neutrophil Cytoplasmic Antibodies and Effector CD4 Cells Play Nonredundant Roles in Anti-Myeloperoxidase Crescentic Glomerulonephritis(1)
MPO-ANCA–associated “pauci-immune” crescentic GN in humans therefore may be a three-step process involving the loss of tolerance and acquisition of autoimmunity to MPO, MPO-ANCA–induced glomerular localization and degranulation of neutrophils that release MPO and induce injury, and CD4+ effector responses to MPO inducing severe GN with crescent formation.
Experimental autoimmune anti-MPO crescentic GN was induced by sensitizing 8- to 10-wk-old male WT mice with 10ug of human MPO in complete Freund adjuvant. Ten days after immunization, mice were administered 32 mg of sheep anti-mouse glomerular basement membrane (GBM) globulin intravenously in two divided doses and killed humanely on days 4, 5, 7, and10. C57BL/6 WT mice immunized with hMPO developed high anti-hMPO antibody titers and dermal DTH responses to hMPO, demonstrating the establishment of both B and T cell responsiveness to hMPO.
C57BL/6 WT mice received hMPO and sheep anti-mouse GBM antibodies developed Crescent formation was significantly greater in MPO-immunized mice compared with BSA-immunized mice at all time points.
Despite circulating MPO-ANCA, glomerular crescent formation was attenuated in CD4-depleted mice by injection of anti-CD4 antibodies compared with control mice. Accumulation of CD4 cells and macrophages in glomeruli was reduced, but glomerular neutrophil numbers were similar levels.
WT mice were pretreated with LPS 4 h before, then injected with sera fromMpo/mice immunized with either MPO or OVA. LPS alone caused minimal accumu-lation of leukocytes in glomeruli, but transfer of anti-MPO sera induced a rapid influx of leukocytes into glomeruli.
Microbial products may induce neutrophil MPO translocation to the cell surface for expressing the link between sepsis and the onset/relapse of ANCA-associated vasculitis. ANCA activates neutrophils in an Fc-dependent manner. Transfer of sera that contained MPO-ANCA not only induced neutrophil accumulation in glomeruli but also induced glomerular MPO deposition.