Systemic lupus erythematosus in mice, spontaneous and induced, is associated with autoimmunity to the C-terminal domain of p53 that recognizes damaged DNA.
The tumor suppressor molecule p53 features a regulatory domain at the C terminus that recognizes damaged DNA. Since damaged DNA might be involved in activating anti-DNA autoantibodies, we tested whether autoimmunity to the C terminus of p53 might mark murine systemic lupus erythematosus (SLE). We now report that MRL / MpJ-Fas(lpr) mice, which spontaneously develop SLE, produce antibodies both to the C terminus of p53 and to a monoclonal antibody (PAb-421) that binds the p53 C terminus. Anti-idiotypic antibodies to PAb-421 (sampled as monoclonal antibodies) could also bind DNA. Thus, the PAb-421 antibody mimics DNA, and the anti-idiotypic antibody to PAb-421 mimics the p53 DNA-binding site. This mimicry was functional; immunization of BALB / c mice to PAb-421 induced anti-DNA antibodies and antibodies to the C terminus of p53, and most of the mice developed an SLE-like disease. Immunization of C57BL / 6 mice to PAb-421 induced antibodies to p53, but not to its C-terminal domain. The C57BL / 6 mice also did not develop anti-DNA antibodies or the SLE-like disease. Thus, network autoimmunity to the domain of p53 that recognizes damaged DNA can be a pathogenic feature in SLE in genetically susceptible strains of mice.
Herkel
J
J
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Erez-Alon
N
N
Mimran
A
A
Wolkowicz
R
R
Harmelin
A
A
Ruiz
P
P
Rotter
V
V
Cohen
I R
IR
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D000974:Antibodies, Antinuclear / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000276:immunology; D000953:Antigens, Protozoan / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology*; D003421:Crithidia / Q000235:genetics / Q000276:immunology; D004247:DNA / Q000235:genetics / Q000276:immunology; D004249:DNA Damage; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry / Q000276:immunology; D005260:Female; D007114:Immunization; D007074:Immunoglobulin G / Q000276:immunology; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000276:immunology*
D000888:Antibodies, Anti-Idiotypic; D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D000953:Antigens, Protozoan; D001323:Autoantibodies; D000939:Epitopes; D007074:Immunoglobulin G; D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D004247:DNA