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Shared immunological targets in the lungs and joints of patients with rheumatoid arthritis: identification and validation
  1. A Jimmy Ytterberg1,2,
  2. Vijay Joshua1,
  3. Gudrun Reynisdottir1,
  4. Nataliya K Tarasova2,
  5. Dorothea Rutishauser2,
  6. Elena Ossipova1,
  7. Aase Haj Hensvold1,
  8. Anders Eklund3,
  9. C Magnus Sköld3,
  10. Johan Grunewald3,
  11. Vivianne Malmström1,
  12. Per Johan Jakobsson1,
  13. Johan Rönnelid4,
  14. Leonid Padyukov1,
  15. Roman A Zubarev2,
  16. Lars Klareskog1,
  17. Anca I Catrina1
  1. 1Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden
  2. 2Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
  3. 3Division of Respiratory Medicine, Department of Medicine, Karolinska Institutet, and Center for Molecular Medicine (CMM), Karolinska University Hospital, Stockholm, Sweden
  4. 4Clinical Immunology Unit, Uppsala University, Uppsala, Sweden
  1. Correspondence to Dr Anca Catrina Dr Jimmy Ytterberg, Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Karolinska Institutet, Stockholm S-17176, Sweden; anca.catrina{at}ki.se; jimmy.ytterberg@ki.se

Abstract

Objectives Immunological events in the lungs might trigger production of anti-citrullinated protein antibodies during early rheumatoid arthritis (RA). We investigated the presence of shared immunological citrullinated targets in joints and lungs of patients with RA.

Patients and methods Proteins extracted from bronchial (n=6) and synovial (n=7) biopsy specimens from patients with RA were investigated by mass spectrometry-based proteomics. One candidate peptide was synthesised and used to investigate by ELISA the presence of antibodies in patients with RA (n=393), healthy controls (n=152) and disease controls (n=236). HLA-DRB1 shared epitope (SE) alleles were detected in patients with RA.

Results Ten citrullinated peptides belonging to seven proteins were identified, with two peptides shared between the synovial and bronchial biopsy samples. Further analysis, using accurate mass and retention time, enabled detection of eight citrullinated peptides in synovial and seven in bronchial biopsy specimens, with five peptides shared between the synovial and bronchial biopsy specimens. Two citrullinated vimentin (cit-vim) peptides were detected in the majority of synovial and lung tissues. Antibodies to a synthesised cit-vim peptide candidate (covering both cit-vim peptides identified in vivo) were present in 1.8% of healthy controls, 15% of patients with RA, and 3.4% of disease controls. Antibodies to cit-vim peptide were associated with the presence of the SE alleles in RA.

Conclusions Identical citrullinated peptides are present in bronchial and synovial tissues, which may be used as immunological targets for antibodies of patients with RA. The data provide further support for a link between lungs and joints in RA and identify potential targets for immunity that may mediate this link.

  • Ant-CCP
  • Early Rheumatoid Arthritis
  • Rheumatoid Arthritis

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