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* Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106;
University of Wales College of Medicine, Cardiff, United Kingdom; and
Department of Medicine, Evans Biomedical Research Center, Boston University Medical Center, Boston, MA 02215
Decay-accelerating factor (DAF or CD55) and CD59 are regulators that protect self cells from C3b deposition and C5b-9 assembly on their surfaces. Their relative roles in protecting glomeruli in immune-mediated renal diseases in vivo are unknown. We induced nephrotoxic serum (NTS) nephritis in Daf1-/-, CD59a-/-, Daf1-/-CD59a-/-, and wild-type (WT) mice by administering NTS IgG. After 18 h, we assessed proteinuria, and performed histological, immunohistochemical, and electron microscopic analyses of kidneys. Twenty-four mice in each group were studied. Baseline albuminuria in the Daf1-/-, CD59a-/-, and Daf1-/-CD59a-/- mice was 82, 83, and 139 as compared with 92 µg/mg creatinine in the WT controls (p > 0.1). After NTS, albuminuria in CD59a-/- and WT mice (186 ± 154 and 183 ± 137 µg/mg creatinine, p > 0.1) was similar. In contrast, Daf1-/- mice developed severe albuminuria (378 ± 520, p < 0.05) that was further exacerbated in Daf1-/-CD59a-/- mice (577 ± 785 µg/mg creatinine, p < 0.05). Glomerular histology showed essentially no infiltrating leukocytes in any group. In contrast, electron microscopy revealed prominent podocyte foot process effacement in Daf1-/- mice with more widespread and severe damage in the double knockouts compared with only mild focal changes in CD59a-/- or WT mice. In all animals, deposition of administered (sheep) NTS Ig was equivalent. This contrasted with marked deposition of both C3 and C9 in Daf1-/-CD59a-/- and Daf1-/- mice, which was evident as early as 2 h post-NTS injection. The results support the proposition that in autoantibody-mediated nephritis, DAF serves as the primary barrier to classical pathway-mediated injury, while CD59 limits consequent C5b-9-mediated cell damage.
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