Inhibition of caspase-3-mediated poly(ADP-ribose) polymerase (PARP) apoptotic cleavage by human PARP autoantibodies and effect on cells undergoing apoptosis.
Autoantibodies directed to nuclear antigens are serological hallmarks of autoimmune rheumatic diseases such as systemic lupus erythematosus. Although much more is known about the molecular identity and functions of targeted self-antigens, with few exceptions, evidence that autoantibodies to these targets have a particular function and contribute directly to the pathological process is lacking. Here we show that human autoantibodies reacting with the zinc fingers of poly(ADP-ribose) polymerase involved in the recognition of damaged DNA totally prevent the cleavage of poly(ADP-ribose) polymerase by caspase-3, a process that normally occurs during early apoptosis. Furthermore, these antibodies, which are frequent in certain autoimmune rheumatic and bowel diseases, affect the characteristic features of apoptosis and increase cell survival ex vivo. This new observation is important, because failure to remove autoimmune or abnormal cells can give rise to prolonged autoimmune stimulation and tumor formation.
Decker
P
P
Institut de Biologie Moléculaire et Cellulaire, Unité Propre de Recherche 9021, Centre National de la Recherche Scientifique, 67084 Strasbourg, France.
Isenberg
D
D
Muller
S
S
D000918:Antibody Specificity; D017209:Apoptosis; D001323:Autoantibodies / Q000494:pharmacology*; D001327:Autoimmune Diseases / Q000209:etiology; D053148:Caspase 3; D061945:Caspase Inhibitors; D020134:Catalytic Domain / Q000276:immunology; D018922:HL-60 Cells; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D011065:Poly(ADP-ribose) Polymerases / Q000276:immunology* / Q000378:metabolism*; D016335:Zinc Fingers / Q000276:immunology
D001323:Autoantibodies; D061945:Caspase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C505407:CASP3 protein, human; D053148:Caspase 3