title: Antibodies to several citrullinated antigens are enriched in the joints of rheumatoid arthritis patients.
abstract: OBJECTIVE
  High titers of specific anti-citrullinated protein antibodies (ACPAs) are frequently present in the serum of rheumatoid arthritis (RA) patients, but their presence in synovial fluid is less well characterized. The purpose of this study was to compare the levels of antibody to 4 well-defined citrullinated candidate RA autoantigens in serum and synovial fluid and to determine whether antibodies to one citrullinated antigen are dominant over another. Furthermore, we studied their relationships with mutated citrullinated vimentin (MCV), a newly identified RA-specific serum assay, and the classic cyclic citrullinated peptide (CCP) in the synovial fluid of well-defined HLA-DR groups.
  
  
  METHODS
  Paired serum and synovial fluid samples from 290 RA patients and serum samples from 100 age- and sex-matched healthy controls were analyzed for the presence of anti-MCV and anti-CCP antibodies and for reactivity to citrullinated fibrinogen, alpha-enolase, type II collagen, and vimentin. A total of 219 of the 290 patients were genotyped for the HLA-DR shared epitope alleles.
  
  
  RESULTS
  Significantly higher proportions of antibodies against all RA-associated citrullinated antigens were found in synovial fluid as compared with serum. This was also true for the MCV and CCP responses but not for non-RA-associated anti-tetanus toxoid antibodies. As expected, we found a high correlation between citrullinated vimentin and MCV responses. All synovial fluid ACPAs were predominantly associated with HLA-DRB1*04 alleles and were confined to the CCP+/MCV+ subset of patients.
  
  
  CONCLUSIONS
  MCV and CCP positivity represent a similar subset of RA patients, whereas ACPAs with different fine specificities fall into subgroups of anti-CCP+/anti-MCV+ patients. The levels of all specific ACPAs were elevated in synovial fluid, suggesting that there is local antibody production and/or retention of ACPAs at the site of inflammation governed by RA-predisposing genes.
authors.affiliation: Karolinska University Hospital, Karolinska Institutet at Solna, Stockholm, Sweden.
authors.forename: Omri
authors.initials: O
authors.lastname: Snir
authors.forename: Mona
authors.initials: M
authors.lastname: Widhe
authors.forename: Monika
authors.initials: M
authors.lastname: Hermansson
authors.forename: Caroline
authors.initials: C
authors.lastname: von Spee
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
authors.forename: Sanne
authors.initials: S
authors.lastname: Hensen
authors.forename: Karin
authors.initials: K
authors.lastname: Lundberg
authors.forename: Ake
authors.initials: A
authors.lastname: Engström
authors.forename: Patrick J W
authors.initials: PJ
authors.lastname: Venables
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Vivianne
authors.initials: V
authors.lastname: Malmström
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood*; D001324:Autoantigens / Q000276:immunology; D014408:Biomarkers, Tumor / Q000276:immunology; D002956:Citrulline / Q000737:chemistry / Q000276:immunology*; D024043:Collagen Type II / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005340:Fibrinogen / Q000737:chemistry / Q000276:immunology; D005838:Genotype; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010456:Peptides, Cyclic / Q000276:immunology*; D010751:Phosphopyruvate Hydratase / Q000276:immunology; D013582:Synovial Fluid / Q000276:immunology*; D025521:Tumor Suppressor Proteins / Q000276:immunology; D014746:Vimentin / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D014408:Biomarkers, Tumor; D024043:Collagen Type II; D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; D010456:Peptides, Cyclic; D025521:Tumor Suppressor Proteins; D014746:Vimentin; C487763:cyclic citrullinated peptide; D002956:Citrulline; D005340:Fibrinogen; C095157:ENO1 protein, human; D010751:Phosphopyruvate Hydratase