A peptide DNA surrogate accelerates autoimmune manifestations and nephritis in lupus-prone mice.
Lupus-associated anti-DNA Abs display features of Ag selection, yet the triggering Ag in the disease is unknown. We previously demonstrated that the peptide DWEYSVWLSN is bound by a pathogenic anti-DNA Ab, and that immunization of nonautoimmune mice with this peptide induces autoantibodies and renal Ig deposition. To elucidate differences in the induced B cell responses in mice genetically predisposed to autoimmunity, young (NZB x NZW)F(1) mice were immunized with this peptide DNA mimetope. DWEYSVWLSN-immunized mice had significantly increased IgG anti-dsDNA, anti-laminin, and anti-cardiolipin Ab titers compared with controls. In addition, glomerular histopathology in the form of endocapillary disease and crescent formation was markedly more severe in DWEYSVWLSN-immunized mice. Analysis of mAbs from DWEYSVWLSN-immunized mice revealed that anti-peptide Abs were often cross-reactive with DNA. Genetic elements used in the Ab response in immunized mice were homologous to those used in the spontaneous anti-DNA response in (NZB x NZW)F(1) mice, as well as in other, experimentally induced anti-DNA Abs. Our results indicate that peptide immunization can induce a molecular genetic response common to a variety of stimuli that break tolerance to mammalian dsDNA. Based on the similarity between spontaneously arising anti-DNA Abs and several types of induced anti-DNA Abs, we suggest that there may be more than a single Ag that can trigger systemic lupus erythematosus.
Beger
Erik
E
Department of Medicine, Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Deocharan
Bisram
B
Edelman
Morris
M
Erblich
Bryna
B
Gu
Yun
Y
Putterman
Chaim
C
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000378:metabolism; D002999:Clone Cells; D003429:Cross Reactions; D004247:DNA / Q000276:immunology*; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D020022:Genetic Predisposition to Disease; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D007279:Injections, Subcutaneous; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008814:Mice, Inbred NZB; D018716:Molecular Mimicry / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000008:administration & dosage* / Q000276:immunology* / Q000378:metabolism; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology
D000974:Antibodies, Antinuclear; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D009842:Oligopeptides; D019444:Vaccines, DNA; D004247:DNA