Autoantibodies to the C-terminal subunit of RLIP76 induce oxidative stress and endothelial cell apoptosis in immune-mediated vascular diseases and atherosclerosis.
Although detection of autoantibodies in the peripheral blood from patients with immune-mediated endothelial dysfunctions has so far failed to provide tools of diagnostic or pathogenetic value, putative bioindicators include anti-endothelial cell antibodies, a heterogeneous family of antibodies that react with autoantigens expressed by endothelial cells. In this study, to identify endothelial autoantigens involved in the autoimmune processes causing endothelial damage, we screened a human microvascular endothelial cell cDNA library with sera from patients with Behçet's disease. We identified antibodies to the C-terminus of Ral binding protein1 (RLIP76), a protein that catalyzes the ATP-dependent transport of glutathione (GSH) conjugates including GSH-4-hydroxy-t-2,3-nonenal, in the serum of a significant percentage of patients with various diseases characterized by immune-mediated endothelial dysfunction, including Behçet disease, systemic sclerosis, systemic lupus erythematosus and carotid atherosclerosis. These autoantibodies increased intracellular levels of 4-hydroxy-t-2,3-nonenal, decreased levels of GSH and activated C-Jun NH2 Kinase signaling (JNK), thus inducing oxidative stress-mediated endothelial cell apoptosis. The dietary antioxidant alpha-tocopherol counteracted endothelial cell demise. These findings suggest that autoantibodies to RLIP76 play a pathogenetic role in immune-mediated vascular diseases and represent a valuable peripheral blood bioindicator of atherosclerosis and immune-mediated vascular diseases.
Margutti
Paola
P
Dipartimento di Malattie Infettive, Parassitarie e Immunomediate, Istituto Superiore di Sanità, Rome, Italy.
Matarrese
Paola
P
Conti
Fabrizio
F
Colasanti
Tania
T
Delunardo
Federica
F
Capozzi
Antonella
A
Garofalo
Tina
T
Profumo
Elisabetta
E
Riganò
Rachele
R
Siracusano
Alessandra
A
Alessandri
Cristiano
C
Salvati
Bruno
B
Valesini
Guido
G
Malorni
Walter
W
Sorice
Maurizio
M
Ortona
Elena
E
D018528:ATP-Binding Cassette Transporters / Q000276:immunology*; D000328:Adult; D000368:Aged; D017209:Apoptosis; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D005260:Female; D020690:GTPase-Activating Proteins / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000276:immunology*; D021122:Protein Subunits; D015398:Signal Transduction; D014652:Vascular Diseases / Q000209:etiology / Q000276:immunology*; D024502:alpha-Tocopherol / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D001323:Autoantibodies; D020690:GTPase-Activating Proteins; D021122:Protein Subunits; C095637:RALBP1 protein, human; D024502:alpha-Tocopherol