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Antigenic triggers and molecular targets for anti-double-stranded DNA antibodies

X Qing

The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA

E Beger

The Division of Rheumatology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA

C Putterman

The Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA; The Division of Rheumatology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA; Division of Rheumatology, Ullmann 1223, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USAputterma{at}aecom.yu.edu

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 auto antibody 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 -actinin. High titers of anti--actinin antibodies were present in the sera and kidney eluates of lupus mice with active disease. Binding to -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 -actinin is a cross-reactive renal target for the pathogenic anti-dsDNA autoantibody response in lupus mice.

Key Words: SLE • phage libraries • peptide mimetopes • lupus nephritis • -actinin

Lupus, Vol. 11, No. 12, 865-871 (2002)
DOI: 10.1191/0961203302lu308rr


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