Specific presence of intracellular citrullinated proteins in rheumatoid arthritis synovium: relevance to antifilaggrin autoantibodies

Arthritis Rheum. 2001 Oct;44(10):2255-62. doi: 10.1002/1529-0131(200110)44:10<2255::aid-art388>3.0.co;2-#.


Objective: To investigate the presence of citrullinated proteins in the synovial membrane of patients with rheumatoid arthritis (RA) and controls, and to analyze a possible relationship with antifilaggrin autoantibody (AFA) reactivity.

Methods: Synovial biopsy samples were obtained from 88 consecutive patients undergoing needle arthroscopy for knee synovitis associated with RA (n = 36), spondylarthropathy (n = 35), osteoarthritis (n = 9), or other diagnoses (n = 8). Tissue sections were stained with 2 different anticitrulline polyclonal antibodies and an antifilaggrin monoclonal antibody (mAb). The phenotype of citrulline-positive cells and the colocalization with affinity-purified AFA were investigated by double immunofluorescence on frozen sections.

Results: Studies with the first antibody showed that citrulline is expressed intracellularly in the lining and sublining layers of RA synovial tissue. Staining with the second antibody, monospecific for proteins containing modified citrulline, and with anti-inducible nitric oxide synthetase confirmed the presence of citrullinated proteins rather than free citrulline in the synovium. Citrulline-positive cells were detected in 50% of the RA patients (18 of 36) but in none of the controls (0 of 52). The anticitrulline reactivity colocalized with affinity-purified AFA reactivity, although stainings with the antifilaggrin mAb indicated the absence of filaggrin in the synovium.

Conclusion: Intracellular citrullinated proteins, which are not recognized by an antifilaggrin mAb, are expressed in RA but not in control synovium. The high specificity of this finding and the colocalization with AFA reactivity boost the interest in citrullinated proteins as possible triggers of autoimmune responses in RA. Moreover, this is the first description of a specific histologic marker for RA synovium.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / metabolism*
  • Arthritis, Rheumatoid / pathology
  • Citrulline
  • Female
  • Filaggrin Proteins
  • Humans
  • Intermediate Filament Proteins / analysis
  • Intermediate Filament Proteins / immunology
  • Male
  • Middle Aged
  • Proteins / analysis*
  • Proteins / immunology
  • Synovial Membrane / immunology
  • Synovial Membrane / metabolism*
  • Synovial Membrane / pathology


  • FLG protein, human
  • Filaggrin Proteins
  • Intermediate Filament Proteins
  • Proteins
  • Citrulline