Antigenic triggers and molecular targets for anti-double-stranded DNA antibodies.
While anti-double-stranded (ds)DNA antibodies are a characteristic serologic hallmark for SLE, the triggering antigen is unknown. Using phage display libraries, we identified DWEYSVWLSN as a peptide mimic of DNA for a pathogenic anti-dsDNA antibody. Peptide immunization of non-autoimmune mice induced anti-dsDNA as well as other lupus-associated antibodies. Molecular analysis of the induced anti-dsDNA antibodies revealed several similarities with anti-dsDNA antibodies that appear spontaneously in lupus mice. Furthermore, lupus-prone mice immunized with this peptide DNA mimic had higher autoantibody titers as well as more severe nephritis. Anti-DNA antibodies may contribute to lupus nephritis via cross-reactivity with renal antigen. Using western blotting of lysates of mesangial cells from a lupus mouse, we found that a pathogenic anti-DNA antibody binds to alpha-actinin. High titers of anti-alpha-actinin antibodies were present in the sera and kidney eluates of lupus mice with active disease. Binding to alpha-actinin was diminished in mesangial cells derived from BALB/c mice, suggesting that target antigen expression may play a role in determining autoantibody binding to the kidney. We conclude that a pathogenic, lupus-like autoantibody response can be induced by a peptide antigen, and that alpha-actinin is a cross-reactive renal target for the pathogenic anti-dsDNA autoantibody response in lupus mice.
Deocharan
B
B
The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Qing
X
X
Beger
E
E
Putterman
C
C
D000185:Actinin / Q000276:immunology; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D004247:DNA / Q000276:immunology*; D006801:Humans; D008181:Lupus Nephritis / Q000276:immunology*
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D000185:Actinin; D004247:DNA