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Suppression of Proteoglycan-Induced Arthritis by Anti-CD20 B Cell Depletion Therapy Is Mediated by Reduction in Autoantibodies and CD4⁺ T Cell Reactivity¹

Keith Hamel^*, Paul Doodes^*, Yanxia Cao, Yumei Wang, Jeffrey Martinson^*, Robert Dunn, Marilyn R. Kehry, Balint Farkas and Alison Finnegan^2,*,

^* Department of Immunology and Microbiology, Department of Internal Medicine, Section of Rheumatology, and Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612; and Biogen Idec, San Diego, CA 92122

B cells have been implicated in the pathogenesis of rheumatoid arthritis (RA) since the discovery of RA as an autoimmune disease. There is renewed interest in B cells in RA based on the clinical efficacy of B cell depletion therapy in RA patients. Although, reduced titers of rheumatoid factor and anti-cyclic citrullinated peptide Abs are recorded, the mechanisms that convey clinical improvement are incompletely understood. In the proteoglycan-induced arthritis (PGIA) mouse model of RA, we reported that Ag-specific B cells have two important functions in the development of arthritis. PG-specific B cells are required as autoantibody-producing cells as well as Ag-specific APCs. Herein we report on the effects of anti-CD20 mAb B cell depletion therapy in PGIA. Mice were sensitized to PG and treated with anti-CD20 Ab at a time when PG-specific autoantibodies and T cell activation were evident but before acute arthritis. In mice treated with anti-CD20 mAb, development of arthritis was significantly reduced in comparison to control mAb-treated mice. B cell depletion reduced the PG-specific autoantibody response. Furthermore, there was a significant reduction in the PG-specific CD4⁺ T cell recall response as well as significantly fewer PG-specific CD4⁺ T cells producing IFN- and IL-17, but not IL-4. The reduction in PG-specific T cells was confirmed by the inability of CD4⁺ T cells from B cell-depleted mice to adoptively transfer disease into SCID mice. Overall, B cell depletion during PGIA significantly reduced disease and inhibited both autoreactive B cell and T cell function.

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 research was supported by National Institutes of Health Grant AR47657 (to A.F.).

² Address correspondence and reprint requests to Dr. Alison Finnegan, Department of Medicine, Section of Rheumatology, Rush University Medical Center, 1735 West Harrison Avenue, Chicago, IL 60612. E-mail address: Alison_Finnegan{at}rush.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; CIA, collagen-induced arthritis; PG, proteoglycan; PGIA, proteoglycan-induced arthritis; RF, rheumatoid factor; SLE, systemic lupus erythematosus.

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