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E receptor 4 and FC gamma receptor pathways [10, 11]. It was also shown that anti-CCP antibodies could activate both the classical and the alternative complement pathways in dose-dependent manners in vitro [12]. In addition, the involvement of ACPA in bone metabolism was identified, giving evidence that anti-citrullinated vimentin antibodies cause osteoclastogenesis in vitro and in vivo in mice after intraperitoneal transfer of purified antibodies [13]. In line with these results, and adding to the concept PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/6833145 of ACPA pathogenicity, ACPA levels were recently described to correlate with the increased presence of neutrophil extracellular traps (NETs) released during NETosis of both circulating and synovial fluid RA neutrophils, and RA NETs could be a source of citrullinated proteins [14]. Since ACPA are detected early in the time-course of the disease and are likely involved in the pathophysiology, one could speculate about the advantage of having a targeted therapy against ACPA. Such treatment might be possible by blocking ACPA with specific peptides, for example using peptides derived from citrullinated fibrinogen. In fact, a similar approach has been used for the blocking of autoantibodies against the cardiac 1-adrenergic receptor. A cyclic peptide (COR-1) that mimics the real epitope structure was shown to prevent autoantibody-mediated myocardial damage in an experimental model of immune cardiomyopathy [15, 16]. Fibrinogen is one of the most extensively characterized ACPA targets. We have previously identified endogenously citrullinated residues at positions 573 and 591 within the fibrinogen chain, and at positions 72 and 74 in the chain from human arthritic synovial tissues, using mass spectrometry (MS) [17]. Previously, several citrullinated and non-citrullinated fibrin-derived peptides from the and chains have Capecitabine been tested for recognition by ACPA [18]. A total of 18 citrullinated peptides out of 71 tested were found to contain epitopes recognized by RA CCPpositive sera. Also, circulating immune complexes containing citrullinated fibrinogen were shown to be present in plasma from CCP-positive RA patients [19]. In the current study, we have analyzed sera from RA patients for ACPA responses against peptides mimicking the endogenously citrullinated epitopes, in the form of citrullinated peptides generated in vitro, and also investigated if these epitopes could be employed to target purified anti-CCP2 immunoglobulin G (IgG) molecules.controls from the Epidemiological Investigation of RA (EIRA) case-control cohort were collected. Control samples were randomly chosen from the Swedish population registry, matching for age, sex, and residential area. All serum and plasma samples were stored at -70 prior to analysis. All patients fulfilled the American College of Rheumatology-European League Against Rheumatism criteria for RA [20]. CCP2-positive RA individuals used for ACPA affinity purification were selected based on having high anti-CCP2 antibody levels (>300 AU/ml, Immunoscan CCPlus?assay, Euro-Diagnostica AB, Sweden). All patients gave written informed consent. This study was approved by the regional ethical committee at the Karolinska Institutet (96-174), and performed in accordance with the Declaration of Helsinki.Peptide identification and synthesisEndogenously citrullinated fibrinogen peptides of the chain, Arg573Cit (563-583) and the chain, Arg72Cit (62-81) and Arg74Cit (62-81), in synovial tissue from RA patients were previously.

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