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J. Exp. Med.,
Volume 188, Number 7, October 5, 1998 1353-1358
By
From the * Department of Medicine, Section of Nephrology, The University of Chicago, Chicago,
Illinois 60637; and the Crry (complement receptor 1-related protein/gene y) is a key cellular complement regulator in
rodents. It is also present in Fx1A, the renal tubular preparation used to immunize rats to induce active Heymann nephritis (HN), a model of membranous nephropathy. We hypothesized
that rats immunized with anti-Fx1A develop autoantibodies (auto-Abs) to Crry as well as to the
megalin-containing HN antigenic complex, and that anti-Crry Abs promote the development
of injury in HN by neutralizing the complement regulatory activity of Crry. Rats immunized
with Fx1A lacking Crry remained free of proteinuria and glomerular deposits of C3 during a
10-wk follow-up despite typical granular immunoglobulin (Ig)G deposits in glomeruli. Anti-Fx1A auto-Abs were present in their sera at levels that were not different from sera pooled
from proteinuric rats with HN induced with nephritogenic Fx1A. Passive administration of
sheep anti-Crry Abs to rats immunized with Crry-deficient Fx1A led to proteinuria and glomerular C3 deposition, which were not seen in such rats injected with preimmune IgG, nor in
rats with collagen-induced arthritis injected with anti-Crry IgG. To directly examine the role
of Crry in HN, rats were immunized with Crry-deficient Fx1A reconstituted with rCrry. This
led to typical HN, with 8 out of 15 rats developing proteinuria within 14 wk. Moreover, the
extent of glomerular C3 deposition correlated with proteinuria, and anti-Crry Abs were
present in glomerular eluates. Thus, Crry is a key nephritogenic immunogen in Fx1A. Formation of neutralizing auto-Abs to Crry impairs its function, leading to unrestricted complement
activation by Abs reactive with the HN antigenic complex on the epithelial cell surface.
Evans Department of Medicine and Clinical Research, Renal Section,
Boston University Medical Center, Boston, Massachusetts 02118
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