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B Cell Clonal Expansion and Somatic Hypermutation of Ig Variable Heavy Chain Genes in the Synovial Membrane of Patients with Osteoarthritis¹

Reng-Rong Da^*, Yufen Qin^*, Dominique Baeten and Yiping Zhang^2,*

^* Department of Neurology, University of California Irvine, Irvine, CA 92697; and Division of Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, The Netherlands

Inflammatory mediators have been explored as possible factors in the initiation and/or progression of osteoarthritis (OA). This study shows that synovial infiltration by B lymphocytes is present in almost half of the knee OA cases. The degree of B lymphocyte infiltration is associated with more pronounced synovial inflammation and with the presence of plasma cells and lymphoid follicles in more severe cases. To examine whether these B cells are merely bystanders or could be involved in the pathogenesis of OA, we analyzed the Ig H chain variable region (V_H) genes of B cells recovered from the synovial membrane of five OA patients with marked B cell infiltration. Sequence analysis of CDR3 regions of rearranged VDJ genes revealed clonal or oligoclonal B cell expansions in all cases. Expanded B cell clones in four of five OA patients showed clustered somatic mutations, occurring mainly in the CDRs and with a high replacement-to-silent ratio (>2.9), indicating that these cells are postgerminal center B cells that had been positively selected through their Ag receptor. These data demonstrate the presence in inflamed knee OA synovium of clonally expanded, Ag-driven B cells that may contribute to the development or progression of the disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by a National Institutes of Health Grant RO1 AI 54911.

² Address correspondence and reprint requests to Dr. Yiping Zhang, Department of Neurology, University of California Irvine, 100 Irvine Hall, Irvine, CA 92627. E-mail address: zhangy{at}uci.edu

³ Abbreviations used in this paper: OA, osteoarthritis; V_H, variable H chain; ST, synovial tissue; GC, germinal center; R:S, replacement and silent mutation; FR, framework region; RA, rheumatoid arthritis; SF, synovial fluid.

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