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.

Autoantibodies to the C-terminal subunit of RLIP76 induce oxidative stress and endothelial cell apoptosis in immune-mediated vascular diseases and atherosclerosis / P., Margutti; P., Matarrese; Conti, Fabrizio; Colasanti, Tania; F., Delunardo; Capozzi, Antonella; Garofalo, Tina; E., Profumo; R., Rigano; A., Siracusano; Alessandri, Cristiano; Salvati, Bruno; Valesini, Guido; W., Malorni; Sorice, Maurizio; E., Ortona. - In: BLOOD. - ISSN 0006-4971. - STAMPA. - 111:9(2008), pp. 4559-4570. [10.1182/blood-2007-05-092825]

Autoantibodies to the C-terminal subunit of RLIP76 induce oxidative stress and endothelial cell apoptosis in immune-mediated vascular diseases and atherosclerosis

CONTI, FABRIZIO;COLASANTI, TANIA;CAPOZZI, ANTONELLA;GAROFALO, TINA;ALESSANDRI, cristiano;SALVATI, Bruno;VALESINI, Guido;SORICE, Maurizio;
2008

Abstract

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.
2008
systemic lupus erythematosus; psychiatric manifestations; lipid peroxidation
01 Pubblicazione su rivista::01a Articolo in rivista
Autoantibodies to the C-terminal subunit of RLIP76 induce oxidative stress and endothelial cell apoptosis in immune-mediated vascular diseases and atherosclerosis / P., Margutti; P., Matarrese; Conti, Fabrizio; Colasanti, Tania; F., Delunardo; Capozzi, Antonella; Garofalo, Tina; E., Profumo; R., Rigano; A., Siracusano; Alessandri, Cristiano; Salvati, Bruno; Valesini, Guido; W., Malorni; Sorice, Maurizio; E., Ortona. - In: BLOOD. - ISSN 0006-4971. - STAMPA. - 111:9(2008), pp. 4559-4570. [10.1182/blood-2007-05-092825]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/227861
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