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Blood, 1 May 2008, Vol. 111, No. 9, pp. 4559-4570. Prepublished online as a Blood First Edition Paper on November 9, 2007; DOI 10.1182/blood-2007-05-092825. This Article Full Text Full Text (PDF) Supplemental Figure All Versions of this Article: blood-2007-05-092825v1 111/9/4559    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Margutti, P. Articles by Ortona, E. Search for Related Content PubMed PubMed Citation Articles by Margutti, P. Articles by Ortona, E. Related Collections Hemostasis, Thrombosis, and Vascular Biology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY Autoantibodies to the C-terminal subunit of RLIP76 induce oxidative stress and endothelial cell apoptosis in immune-mediated vascular diseases and atherosclerosis Paola Margutti1, Paola Matarrese2, Fabrizio Conti3, Tania Colasanti1, Federica Delunardo1, Antonella Capozzi4, Tina Garofalo4, Elisabetta Profumo1, Rachele Riganò1, Alessandra Siracusano1, Cristiano Alessandri3, Bruno Salvati5, Guido Valesini3, Walter Malorni2, Maurizio Sorice4, and Elena Ortona1 1 Dipartimento di Malattie Infettive, Parassitarie e Immunomediate, and 2 Dipartimento del Farmaco, Istituto Superiore di Sanità (ISS), Rome; 3 Dipartimento di Clinica e Terapia Medica, Cattedra di Reumatologia, 4 Dipartimento di Medicina Sperimentale, and 5 Dipartimento di Scienze Chirurgiche, Università Sapienza, Rome, Italy 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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