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-Actinin Is a Cross-Reactive Renal Target for Pathogenic Anti-DNA Antibodies1
*
Department of Microbiology and Immunology, and
Division of Rheumatology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461
Anti-DNA Abs commonly found in patients with systemic lupus
erythematosus are thought to play an important pathogenic role in lupus
nephritis. Anti-DNA Abs may contribute to renal disease by
cross-reactivity with renal Ags, the identity of which remain elusive.
To identify a target Ag for pathogenic anti-DNA Abs, we performed
Western blotting and immunoprecipitations of mesangial cell lysates
from the lupus-prone MRL-lpr/lpr mouse and a
nonautoimmune BALB/c mouse with the pathogenic anti-DNA Ab R4A. We
found that R4A (but not a nonpathogenic Ab mutant of R4A) binds to and
immunoprecipitates a 100-kDa protein expressed on the cell surface and
in lysates of MRL-lpr/lpr mesangial cells. DNase
treatment of the lysate and of the R4A Ab did not effect binding,
indicating that the binding of R4A to the 100-kDa protein was direct
and not mediated by an antigenic bridge containing DNA. Binding was
greatly diminished in BALB/c lysates, suggesting that Ag expression or
availability at the level of the target organ may be a factor in
determining susceptibility to lupus nephritis. Following identification
of this 100-kDa protein as nonmuscle 
-actinin, binding of R4A to
-actinin was confirmed by Western blot, ELISA, inhibition studies,
and immunofluorescence. High titers of anti--actinin Abs were
present in sera and kidney eluates of lupus mice with active nephritis.
These results indicate that the nephritogenicity of some anti-DNA
Abs may be mediated via cross-reactivity with -actinin. Furthermore,
variations in target Ag display between individuals may underlie
differential susceptibility to anti-DNA Ab-induced renal
disease.
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