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* Laboratory of Viral Immunobiology, Christopher H. Browne Center for Immunology and Immune Diseases, Rockefeller University, New York, NY 10021;
Institut für Immunologie,
Klinik für Innere Medizin III, and
Institut für Medizinische Mik-robiologie, Universitätsklinikum Jena, Jena, Germany;
¶ Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; and
|| Institut für Medizinische Immunologie, Charitè Universitätsmedizin Berlin, Berlin, Germany
EBV is a candidate trigger of rheumatoid arthritis (RA). We determined both EBV-specific T cell and B cell responses and cell-associated EBV DNA copies in patients with RA and demographically matched healthy virus carriers. Patients with RA showed increased and broadened IgG responses to lytic and latent EBV-encoded Ags and 7-fold higher levels of EBV copy numbers in circulating blood cells. Additionally, patients with RA exhibited substantial expansions of CD8+ T cells specific for pooled EBV Ags expressed during both B cell transformation and productive viral replication and the frequency of CD8+ T cells specific for these Ags correlated with cellular EBV copy numbers. In contrast, CD4+ T cell responses to EBV and T cell responses to human CMV Ags were unchanged, altogether arguing against a defective control of latent EBV infection in RA. Our data show that the regulation of EBV infection is perturbed in RA and suggest that increased EBV-specific effector T cell and Ab responses are driven by an elevated EBV load in RA.
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1 J.D.L. is a recipient of the Dana Foundation and Irvington Institute’s Human Immunology Fellowship from the Cancer Research Institute and is supported by a Pilot Grant from the National Multiple Sclerosis Society (PP1145) and an Institutional Clinical and Translational Science Pilot and Collaborative Project Grant (to the Rockefeller University Hospital). C.M. is supported by the Dana Foundation’s Neuroimmunology Program, the Arnold and Mabel Beckman Foundation, the Alexandrine and Alexander Sinsheimer Foundation, the Burroughs Wellcome Fund, the Starr Foundation, the National Cancer Institute (R01CA108609 and R01CA101741), the National Institute of Allergy and Infectious Diseases (RFP-NIH-NIAID-DAIDS-BAA-06-19), the Foundation for the National Institutes of Health (Grand Challenges in Global Health), and an Institutional Clinical and Translational Science Award (to the Rockefeller University Hospital). T.K. is supported by the Deutsche Forschungsgemeinschaft (SFB 604 C5) and the Gemeinnützige Hertie-Stiftung (1.319.110/03/03). J.S. and J.I.C. are supported by the intramural research program of the National Institute of Allergy and Infectious Diseases. J.S. is partially supported by the Japan Herpes Virus Infection Forum.
2 J.D.L. and O.F. contributed equally to this work and share first authorship.
3 T.K. and C.M. contributed equally to this work and share senior authorship.
4 Address correspondence and reprint requests to Dr. Christian Münz, Christopher H. Browne Center for Immunology and Immune Diseases, Rockefeller University, Box 390, 1230 York Avenue, New York, NY 10021. E-mail address: munzc{at}rockefeller.edu
5 Abbreviations used in this paper: RA, rheumatoid arthritis; EA, early Ags; EBNA, EBV nuclear Ag; Flu-HA, influenza hemagglutinin peptide; HCMV, human CMV; HD, healthy donors; SEB, Staphylococcus enterotoxin B; VCA, viral capsid Ag.
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