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Antigen-Specific B Cells Are Required as APCs and Autoantibody-Producing Cells for Induction of Severe Autoimmune Arthritis¹

Shannon K. O’Neill^*, Mark J. Shlomchik, Tibor T. Glant, Yanxia Cao, Paul D. Doodes^* and Alison Finnegan^2,*,

^* Department of Immunology/Microbiology, Departments of Biochemistry and of Orthopedic Surgery, Section of Biochemistry and Molecular Biology, and Department of Internal Medicine, Section of Rheumatology, Rush University Medical Center, Cohn Research Building, Chicago, IL 60612; and Department of Laboratory Medicine, Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510

B cells play an important role in rheumatoid arthritis, but whether they are required as autoantibody-producing cells as well as APCs has not been determined. We assessed B cell autoantibody and APC functions in a murine model of autoimmune arthritis, proteoglycan (PG)-induced arthritis, using both B cell-deficient mice and Ig-deficient mice (mIgM) mice that express an H chain transgene encoding for membrane-bound, but not secreted, IgM. The IgH transgene, when paired with endogenous L chain, recognizes the hapten 4-hydroxy-3-nitro-phenyl acetyl and is expressed on 1–4% of B cells. B cell-deficient and mIgM mice do not develop arthritis after immunization with PG. In adoptive transfer of PG-induced arthritis into SCID mice, T cells from mIgM mice immunized with PG were unable to transfer disease even when B cells from PG-immunized wild-type mice were provided, suggesting that the T cells were not adequately primed and that Ag-specific B cells may be required. In fact, when PG was directly targeted to the B cell Ig receptor through a conjugate of 4-hydroxy-3-nitrophenyl acetyl-PG, T cells in mIgM mice were activated and competent to transfer arthritis. Such T cells caused mild arthritis in the absence of autoantibody, demonstrating a direct pathogenic role for T cells activated by Ag-specific B cells. Transfer of arthritic serum alone induced only mild and transient arthritis. However, both autoreactive T cells and autoantibody are required to cause severe arthritis, indicating that both B cell-mediated effector pathways contribute synergistically to autoimmune disease.

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