Autoimmunity to the p53 protein is a feature of systemic lupus erythematosus (SLE) related to anti-DNA antibodies.
The induction of anti-DNA autoantibodies in systemic lupus erythematosus (SLE) patients is problematic because mammalian DNA is poorly immunogenic at best. Here we demonstrate a chain of connected antibodies in SLE patient sera that could account for the induction of anti-DNA antibody, and possibly for some of the pathogenic features of SLE. We now report that SLE patients, in addition to anti-DNA, produce antibodies to the carboxy-terminal domain of the tumour suppressor molecule p53; this p53 domain recognizes damaged DNA. Hence, these anti-p53 antibodies could mimic damaged DNA immunologically. Indeed, SLE sera do contain anti-idiotypic antibodies to a prototypic anti-p53 antibody. Moreover, SLE anti-DNA antibodies also recognize this type of anti-p53 antibody. Indeed, binding of affinity-purified anti-DNA both to DNA and to the anti-p53 antibody could be blocked by a p53 peptide derived from the DNA-binding domain. This mimicry of the p53 DNA-binding domain by the SLE anti-DNA antibodies is functional: activation of the p53 molecule could be inhibited by such anti-DNA antibodies. Thus, anti-DNA antibodies may arise in SLE patients by a chain of idiotypic autoimmunity centered around p53 autoimmunity. The SLE anti-DNA and anti-p53 antibodies can functionally block p53 activation, and so could affect apoptosis.
Herkel
J
J
I. Department of Medicine, Johannes Gutenberg University, 55101 Mainz, Germany.
Mimran
A
A
Erez
N
N
Kam
N
N
Lohse
A W
AW
Märker-Hermann
E
E
Rotter
V
V
Cohen
I R
IR
D000974:Antibodies, Antinuclear / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000276:immunology; D006801:Humans; D007130:Immunoglobulin Idiotypes / Q000096:biosynthesis / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology*; D018716:Molecular Mimicry / Q000276:immunology; D010455:Peptides / Q000276:immunology; D017433:Protein Structure, Secondary; D016159:Tumor Suppressor Protein p53 / Q000276:immunology*
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D004268:DNA-Binding Proteins; D007130:Immunoglobulin Idiotypes; D010455:Peptides; D016159:Tumor Suppressor Protein p53