The role of anti-alpha-enolase autoantibodies in pathogenicity of autoimmune-mediated retinopathy.
Autoantibodies against alpha-enolase, a glycolytic enzyme, have been frequently associated with visual loss and retinal degeneration in patients with autoimmune and cancer-associated retinopathy; however their role in the pathogenicity of retinopathy has not been fully explained. Thus, we examined the causative role of anti-enolase antibodies on retinal cells. In the in vitro studies reported here, we found that Enol-1 monoclonal antibody against alpha-enolase significantly inhibited the catalytic function of enolase, which resulted in the depletion of glycolytic ATP. Enol-1 significantly increased intracellular Ca(2+), which led to Bax translocation to the mitochondria, and the release of cytochrome c into the cytoplasm--events that correlated with the initiation of apoptosis. Normal IgG did not induce intracellular calcium or reduce cytosolic ATP. L-type voltage-gated calcium channel blockers (nifedipine, D-cis-diltiazem, and verapamil) were effective in blocking the Ab-induced intracellular Ca(2+) rise and induction of Bax. Based on these findings we propose that chronic access of autoantibodies to the retina results in the inhibition of enolase catalytic function, depletion of ATP, and elevation in intracellular Ca(2+), leading to deregulation of glycolysis in retinal neurons and their destruction.
Magrys
Agnieszka
A
Neurological Sciences Institute, Oregon Health and Science University, Beaverton, Oregon 97006, USA.
Anekonda
Thimmappa
T
Ren
Gaoying
G
Adamus
Grazyna
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000502:physiology; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006019:Glycolysis; D009474:Neurons / Q000378:metabolism*; D010751:Phosphopyruvate Hydratase / Q000276:immunology*; D051381:Rats; D012164:Retinal Diseases / Q000276:immunology*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D000255:Adenosine Triphosphate; D010751:Phosphopyruvate Hydratase; D002118:Calcium