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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 (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 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. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 31, 2007 Accepted October 31, 2007 Autoantibodies to the C-terminal subunit of RLIP76 induce oxidative stress and endothelial cell apoptosis in immune-mediated vascular diseases and atherosclerosis Paola Margutti, Paola Matarrese, Fabrizio Conti, Tania Colasanti, Federica Delunardo, Antonella Capozzi, Tina Garofalo, Elisabetta Profumo, Rachele Rigano, Alessandra Siracusano, Cristiano Alessandri, Bruno Salvati, Guido Valesini, Walter Malorni, Maurizio Sorice, and Elena Ortona* Dipartimento di Malattie Infettive, Parassitarie e Immunomediate, Istituto Superiore di Sanita, Rome, Italy Dipartimento del Farmaco, Istituto Superiore di Sanita, Rome, Italy Dipartimento di Clinica e Terapia Medica, Cattedra di Reumatologia, Universita "Sapienza", Rome, Italy Dipartimento di Medicina Sperimentale, Universita "Sapienza", Rome, Italy Dipartimento di Scienze Chirurgiche, Universita "Sapienza", Rome, Italy * Corresponding author; email: elena.ortona{at}iss.it. 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 Behcet'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 Behcet's 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 JNK (C-Jun NH2 Kinase) signaling, 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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