DNA mimics a self-protein that may be a target for some anti-DNA antibodies in systemic lupus erythematosus.
Recent studies suggest that some anti-DNA Abs in systemic lupus erythematosus may actually be Abs to specific proteins and that binding to dsDNA is a nonspecific cross-reactive event. To identify such proteins that bind to anti-DNA Abs, a cDNA expression library from human placenta was screened with mAb 3E10, a pathogenic anti-dsDNA Ab. MAb 3E10 was shown to bind to a 44-amino-acid fragment of HP8, a newly identified protein with amino acid sequence homology to the family of SPARC extracellular matrix proteins. To determine if Ab binding to both dsDNA and HP8 protein occurs through a common binding site, and therefore represents molecular mimicry, the Ab binding domains for protein and DNA were mapped. Chain recombinations between mAb 3E10 and a non-anti-DNA mAb showed that both the heavy and the light chains of mAb 3E10 were essential for anti-dsDNA and anti-HP8 reactivity. Mutagenesis experiments demonstrated that dsDNA and HP8 shared several critical binding residues located in all three complementarity-determining regions of mAb 3E10 VH. Moreover, Abs to HP8 were demonstrated in the sera of a subset of lupus patients. These results indicate that DNA mimics the HP8 protein in binding a lupus Ab, and that this protein may be a target for a subpopulation of anti-dsDNA Abs in systemic lupus erythematosus.
Department of Medicine, Veterans Affairs Medical Center, Sepulveda, CA 91343.
D J
DJ
Zack
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Yamamoto
A L
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Wong
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Stempniak
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French
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Weisbart
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D001324:Autoantigens / Q000737:chemistry / Q000276:immunology*; D001327:Autoimmune Diseases / Q000276:immunology*; D001483:Base Sequence; D001666:Binding Sites, Antibody; D022762:CCAAT-Enhancer-Binding Proteins; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D004247:DNA / Q000737:chemistry / Q000276:immunology*; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000276:immunology*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011993:Recombinant Fusion Proteins / Q000276:immunology; D011995:Recombination, Genetic; D014157:Transcription Factors
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D001324:Autoantigens; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D004247:DNA