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Cutting Edge: Anti-Tumor Necrosis Factor Therapy in Rheumatoid Arthritis Inhibits Memory B Lymphocytes via Effects on Lymphoid Germinal Centers and Follicular Dendritic Cell Networks¹

Jennifer H. Anolik^2,*, Rajan Ravikumar^*, Jennifer Barnard^*, Teresa Owen^*, Anthony Almudevar, Eric C. B. Milner^*, Chase H. Miller, Paul O. Dutcher, James A. Hadley and Iñaki Sanz^2,*

^* Department of Medicine, Division of Allergy, Immunology, and Rheumatology, Department of Biostatistics, and Department of Otorhinolaryngology, University of Rochester, Rochester, NY 14642

Rheumatoid arthritis (RA) is mediated by a proinflammatory cytokine network with TNF at its apex. Accordingly, drugs that block TNF have demonstrated significant efficacy in the treatment of RA. A great deal of experimental evidence also strongly implicates B cells in the pathogenesis of RA. Yet, it remains unclear whether these two important players and the therapies that target them are mechanistically linked. In this study we demonstrate that RA patients on anti-TNF (etanercept) display a paucity of follicular dendritic cell networks and germinal center (GC) structures accompanied by a reduction in CD38⁺ GC B cells and peripheral blood memory B cell lymphopenia compared with healthy controls and RA patients on methotrexate. This study provides initial evidence in humans to support the notion that anti-TNF treatment disrupts GC reactions at least in part via effects on follicular dendritic cells.

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 work was supported in part by grants to J.H.A from National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (K08 AR048303), the Lupus Foundation of America, the Lupus Research Institute, and the Alliance for Lupus Research and by grants to I.S. from the U19 Autoimmunity Center of Excellence (R01 AI049660-01A1 and AI56390) and Center for Biodefense of Immunocompromised Populations (N01-AI50029).

² Address correspondence and reprint requests to Dr. Jennifer Anolik or Dr. Iñaki Sanz, Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester, 601 Elmwood Avenue, Box 695, Rochester, NY 14642. E-mail addresses: jennifer_anolik{at}urmc.rochester.edu or ignacio_sanz{at}urmc.rochester.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; FDC, follicular dendritic cell; GC, germinal center, LT, lymphotoxin; MTX, methotrexate; PB, peripheral blood.