Anti-citrullinated protein antibody response after primary EBV infection in kidney transplant patients

PLoS One. 2018 May 10;13(5):e0197219. doi: 10.1371/journal.pone.0197219. eCollection 2018.


Rheumatoid arthritis (RA) is a chronic inflammatory disease of synovial joints, characterized by the presence of the highly disease-specific anti-citrullinated protein antibodies (ACPA) in approximately 70% of patients. Epstein-Barr virus (EBV) has previously been suggested to be involved in the pathophysiology of RA. However, given the high incidence of EBV in the general population and the difficulty of detecting initial infection, providing a direct link between EBV infection and RA development has remained elusive. We hypothesized that primary EBV infection may be a trigger for the development of the ACPA response in vivo. Using a unique cohort of 26 kidney transplant patients with a primary EBV infection, the presence of ACPA before and following infection was determined. No increase in IgG anti-CCP2 titers was detected following EBV infection. IgG anti-CCP2 antibodies were present in two patients and borderline positive in another. These three patients were HLA-DR4 negative. To test whether EBV infection may trigger a non-class switched anti-CCP2 response, IgM anti-CCP2 antibodies were analyzed. No general trend in the IgM anti-CCP2 response was observed following EBV infection. Since two out of the three IgG anti-CCP2 (borderline) positive patients were diagnosed with IgA nephropathy, 23 additional IgA nephropathy patients were tested for IgG anti-CCP2, regardless of their EBV status. All of these patients were IgG anti-CCP2 negative, indicating that IgG anti-CCP2 is not commonly present in IgA nephropathy patients. Collectively, these data do not support the hypothesis that EBV does trigger the highly RA specific ACPA response.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Anti-Citrullinated Protein Antibodies / blood*
  • Epstein-Barr Virus Infections / blood*
  • Epstein-Barr Virus Infections / etiology
  • Female
  • Glomerulonephritis, IGA / blood
  • Glomerulonephritis, IGA / etiology
  • Herpesvirus 4, Human*
  • Humans
  • Kidney Transplantation
  • Male
  • Middle Aged


  • Anti-Citrullinated Protein Antibodies

Grants and funding

Dominique Baeten was supported by a VICI grant from The Netherlands Organization for Scientific Research (NWO), by a Consolidator Grant from the European Research Council (ERC), and by a grant from the Dutch Arthritis Foundation (Reumafonds). There were no conflicts of interest.