Human autoantibodies to poly(adenosine diphosphate-ribose) polymerase recognize cross-reactive epitopes associated with the catalytic site of the enzyme.
The factors responsible for the production of autoantibodies against self-components are not well understood. We have identified monospecific human autoantibodies to poly(ADP-ribose) polymerase (ADPRP) in the sera of rheumatic patients. Since this nuclear enzyme has been extensively characterized, and its entire structure is known, we could investigate in detail the epitope specificity of the human autoantibodies, and their effects on the biological functions of the enzyme. All sera with autoantibodies to ADPRP recognized the NAD-binding domain of the enzyme, as demonstrated by either immunoblotting or immunoprecipitation of partially proteolyzed ADPRP. The autoantibodies also inhibited the catalytic activity of the purified enzyme, as measured by the transfer of ADP-ribose from [32P]NAD to either histones or to ADPRP itself. Because comparative structural analyses have shown that the active sites of enzymes are often conserved during evolution, we tested the ability of the autoantibodies to react with ADPRP from lower eukaryotes. The human autoantibodies reacted with ADPRP in cellular extracts from mammalian, avian, amphibian, arthropod, and protozoan cells, and also inhibited the catalytic activity of the various enzymes. Collectively, these experiments indicate that the human autoantibodies to ADPRP recognize a distinct group of evolutionarily conserved antigenic determinants that are closely related to the catalytic site of the enzyme. The results are consistent with the hypothesis that the epitope selectivity of human autoantibodies to ADPRP is influenced by cross-reactive antigens in the external environment.
Yamanaka
H
H
Department of Basic and Clinical Research, Research Institute of Scripps Clinic, La Jolla, California 92037.
Willis
E H
EH
Carson
D A
DA
D000918:Antibody Specificity; D001323:Autoantibodies / Q000276:immunology*; D003429:Cross Reactions; D004247:DNA / Q000378:metabolism; D000939:Epitopes / Q000032:analysis*; D006801:Humans; D011065:Poly(ADP-ribose) Polymerases / Q000276:immunology*; D012216:Rheumatic Diseases / Q000201:enzymology / Q000276:immunology
D001323:Autoantibodies; D000939:Epitopes; D004247:DNA; D011065:Poly(ADP-ribose) Polymerases