Antigen-specific B cells are required as APCs and autoantibody-producing cells for induction of severe autoimmune arthritis.
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 lambda 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.
O'Neill
Shannon K
SK
Department of Immunology/Microbiology, Rush University medical Center, Cohn Research Building, Chicago, IL 60612, USA.
Shlomchik
Mark J
MJ
Glant
Tibor T
TT
Cao
Yanxia
Y
Doodes
Paul D
PD
Finnegan
Alison
A
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology*; D001169:Arthritis, Experimental / Q000209:etiology* / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000096:biosynthesis*; D001324:Autoantigens / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D005260:Female; D005803:Genes, Immunoglobulin; D007075:Immunoglobulin M / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D008822:Mice, Transgenic; D011509:Proteoglycans / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D007075:Immunoglobulin M; D011509:Proteoglycans