Published ahead of print on February 14, 2008, doi:10.1164/rccm.200707-1015OC Am. J. Respir. Crit. Care Med., Volume 177, Number 10, May 2008, 1128-1134 A more recent version of this article appeared on May 15, 2008
Submitted on July 10, 2007 Identification of Target Antigens of Anti-fibroblast Antibodies in Pulmonary Arterial HypertensionBenjamin Terrier1,1 Faculty of Medicine, Paris Descartes Univeristy, Paris, France, 2 Laboratory of Proteomics, Institut Cochin, Universite Paris Descartes, Paris, France; INSERM U567, Paris, France, 3 Faculty of Medicne, Department of Pneumology and French Reference Center for pulmonary arterial hypertension, Antoin-Beclere Hospital, Assistance Publique-Hopitaux de Paris, Paris Sud University, Clamart, France, 4 Faculty of Medicine, Department of Internal Medicine and French Reference Center for necrotizing vasculitides and systemic sclerosis, Cochin Hospital, Paris Descartes University, Paris, France, 5 Faculty of Medicine, Paris Descartes Univeristy, Paris, France; Faculty of Medicine, Department of Internal Medicine and French Reference Center for necrotizing vasculitides and systemic sclerosis, Cochin Hospital, Paris Descartes University, Paris, France * To whom correspondence should be addressed. E-mail: luc.mouthon{at}cch.aphp.fr.
Background. Pulmonary arterial hypertension (PAH) may be classified as idiopathic (IPAH) or familial (FPAH) or associated with various conditions and exposures such as dexfenfluramine intake (Dex-PAH) or systemic sclerosis (SSc-PAH). Since fibroblast dysfunction has been identified in SSc and IPAH and anti-fibroblast antibodies (AFAs) with a pathogenic role have been detected in the serum of SSc patients, we used a proteomic approach combining 2-D electrophoresis and immunoblotting to identify the target antigens of AFAs in such patients. Patients and methods. Sera from 24 patients with IPAH, 6 with FPAH, 6 with Dex-PAH and 12 with SSc-PAH were collected. We pooled sera from sets of 3 patients with PAH classification and SSc-PAH based on autoantibody profile. Sera from 14 healthy blood donors were also pooled and used as a control. Results. Serum IgG antibodies in the pools of patients with IPAH (n=8), FPAH (n=2), Dex-PAH (n=2) and SSc-PAH (n=4) recognized 103±31, 63±20, 78±11 and 81±12 protein spots, respectively, whereas serum IgG antibodies from healthy controls recognized 43±22 protein spots. Twenty-one protein spots were specifically recognized by the serum IgG antibodies from PAH patients. We identified 16 of the protein spots as vimentin, calumenin, tropomyosin 1, heat-shock proteins 27 and 70, glucose-6-phosphate-dehydrogenase, PI3-kinase, DAP kinase and others. These proteins are involved in regulation of cytoskeletal function, cell contraction, oxidative stress, cell energy metabolism and other key cellular pathways. Conclusion. AFAs detected in patients with PAH recognize cellular targets playing key roles in cell biology and maintenance of homeostasis. Key words: fibroblast, antigens, autoantibodies, pulmonary arterial hypertension
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