title: Increased proteasome activator 28 gamma (PA28γ) levels are unspecific but correlate with disease activity in rheumatoid arthritis.
abstract: BACKGROUND
  PA28γ (also known as Ki, REG gamma, PMSE3), a member of the ubiquitin-and ATP-independent proteasome activator family 11S, has been proved to show proteasome-dependent and -independent effects on several proteins including tumor suppressor p53, cyclin-dependent kinase inhibitor p21 and steroid receptor co-activator 3 (SCR-3). Interestingly, PA28γ is overexpressed in pathological tissue of various cancers affecting e. g. breast, bowl and thyroids. Furthermore, anti-PA28γ autoantibodies have been linked to several autoimmune disorders. The aim of this study was to develop and evaluate a novel and sensitive PA28γ sandwich ELISA for the quantification of PA28γ serum levels in patients with cancer and autoimmune diseases for diagnostic and prognostic purposes.
  
  
  METHODS
  PA28γ-specific polyclonal antibodies and recombinant His-tagged PA28γ were purified and used to develop a sandwich ELISA for the detection of circulating PA28γ. With this new assay, PA28γ serum levels of patients with various cancers, rheumatoid arthritis (RA), Sjögren's syndrome (SS), adult-onset Still's disease (AOSD) and different connective-tissue diseases (CTD) were compared with healthy control subjects. Anti-PA28γ autoantibodies were additionally confirmed using a newly developed microbead assay.
  
  
  RESULTS
  The developed PA28γ sandwich ELISA showed a high specificity with a detection limit of 3 ng/ml. A significant up-regulation of circulating PA28γ was detected in the sera of patients with cancer, RA, SS and CTD. A significant correlation was observed dependent on age as well as anti-PA28γ autoantibody levels with circulating PA28γ protein levels. Furthermore, PA28γ serum levels showed a correlation with disease activity in patients with RA under treatment with the T-cell directed biological compound abatacept according to disease activity score 28 (DAS28) and erythrocyte sedimentation rate (ESR).
  
  
  CONCLUSIONS
  The application of PA28γ as a novel biomarker for diagnostic purposes of a specific disease is limited, since elevated levels were observed in different disorders. However, the correlation with disease activity in patients with RA suggests a prognostic value, which needs to be addressed by further studies. Therefore our results show that PA28γ is a useful marker which should be included in studies related to novel treatments, e.g. abatacept.
authors.forename: Melanie
authors.initials: M
authors.lastname: Gruner
authors.forename: Anja
authors.initials: A
authors.lastname: Moncsek
authors.forename: Stefan
authors.initials: S
authors.lastname: Rödiger
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kühnhardt
authors.affiliation: Department of Rheumatology and Clinical Immunology and Autoinflammatory Reference Centre at Charité, Charité-Universitätsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany. eugen.feist@charite.de.
authors.forename: Eugen
authors.initials: E
authors.lastname: Feist
authors.forename: Ralf
authors.initials: R
authors.lastname: Stohwasser
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood* / Q000175:diagnosis*; D001324:Autoantigens / Q000096:biosynthesis / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D005500:Follow-Up Studies; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000096:biosynthesis / Q000097:blood*; D015854:Up-Regulation / Q000502:physiology
chemical_list: D001324:Autoantigens; D015415:Biomarkers; C099558:Ki antigen; D046988:Proteasome Endopeptidase Complex