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 ter minus that recognizes damaged DNA. Since damaged DNA might be involved in a ctivating anti-DNA autoantibodies, we tested whether autoimmunity to the C terminus of p53 might mark murine systemic lupus erythematosus (SLE). We no w report that MRL/MpJ-Fas(lpr) mice, which spontaneously develop SLE, produ ce antibodies both to the C terminus of p53 and to a monoclonal antibody (P Ab-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 m ice 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 o f C57BL/6 mice to PAb-421 induced antibodies to p53, but not to its C-termi nal domain. The C57BL/6 mice also did not develop anti-DNA antibodies or th e SLE-like disease. Thus, network autoimmunity to the domain of p53 that re cognizes damaged DNA can be a pathogenic feature in SLE in genetically susc eptible strains of mice.