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Journal of Virology, September 2004, p. 9918-9923, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.9918-9923.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Rheumatoid Factors Induce Signaling from B Cells, Leading to Epstein-Barr Virus and B-Cell Activation

Lixin Yang,1 Masayuki Hakoda,2 Kazuya Iwabuchi,3 Tsuyoshi Takeda,4 Takao Koike,4 Naoyuki Kamatani,5 and Kenzo Takada1*

Department of Tumor Virology, Institute for Genetic Medicine,1 Division of Immunobiology, Institute for Genetic Medicine, Hokkaido University,3 Department of Internal Medicine II, Hokkaido University Graduate School of Medicine, Sapporo,4 Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima,2 Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan5

Received 28 November 2003/ Accepted 16 May 2004

B-cell antigen receptor signaling is initiated upon binding of the antigen to membrane-bound immunoblobulin (Ig), and the anti-Ig antibody (Ab) mimics this signaling. In B cells latently infected with Epstein-Barr virus (EBV), the same signals induce virus activation. We examine here whether rheumatoid factors (RFs), autoantibodies directed against the Fc portion of IgG, induce EBV and B-cell activation. As a source of RFs, RF-producing lymphoblastoid cell line (LCL) clones were isolated from peripheral blood mononuclear cells (PBMC) and synovial cells from patients with rheumatoid arthritis (RA) by EBV transformation. Burkitt's lymphoma-derived Akata cells, which are highly responsive to EBV activation by anti-Ig Abs, were used for the assay of EBV activation. Akata cells expressed IgG3 as membrane-bound Ig. RFs from a synovium-derived LCL were directed to IgG3 and induced EBV activation in 16 to 18% of Akata cells, whereas RFs from another synovium-derived LCL were directed to IgG1 and did not induce EBV activation. Pretreatment of RFs with the purified Fc fragment of human IgG completely abolished EBV activation. Furthermore, B-cell activation was assessed by incorporation of [3H]thymidine. RFs from synovium-derived LCLs efficiently induced B-cell activation, and the addition of CD40 ligand had a synergistic effect. On the other hand, RFs from PBMC-derived LCLs were polyreactive, had a lower affinity to IgG, and did not induce EBV and B-cell activation. The present findings imply a possible role for RFs as EBV and B-cell activators.

* Corresponding author. Mailing address: Department of Tumor Virology, Institute for Genetic Medicine, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-0815, Japan. Phone: 81-11-706-5071. Fax: 81-11-706-7540. E-mail: kentaka{at}igm.hokudai.ac.jp.

Journal of Virology, September 2004, p. 9918-9923, Vol. 78, No. 18
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.18.9918-9923.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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