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Cutting Edge: Complement (C3d)-Linked Antigens Break B Cell Anergy

Taras Lyubchenko^1,*, Joseph M. Dal Porto^1,, V. Michael Holers^*, and John C. Cambier^2,

^* Division of Rheumatology, Department of Medicine, University of Colorado School of Medicine, Denver, CO 802602; and Department of Immunology, University of Colorado School of Medicine and National Jewish Medical and Research Center, Denver, CO 80206

C3dg adducts of Ag can coligate complement receptor type 2 (CR2; CD21) and the B cell Ag receptor. This interaction significantly amplifies BCR-mediated signals in Ag-naive wild-type mice, lowering the threshold for B cell activation and the generation of humoral immune responses as much as 1000-fold. In this study we demonstrate that CR2-mediated complementation of BCR signals can also overcome B cell anergy. Unlike Ag alone, BCR/CR2 costimulation (Ars-CCG/C3dg complexes) of anergic Ars/A1 B cells led to Ca²⁺ mobilization in vitro and the production of autoantibodies in vivo. Interestingly, the in vivo immune response of anergic cells occurs without the formation of germinal centers. These results suggest that the Ag unresponsiveness of anergic B cells can be overcome by cross-reactive (self-mimicking) Ags that have been complement-opsonized. This mechanism may place individuals exposed to complement-fixing bacteria at risk for autoimmunity.

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 T.L. and J.D. contributed equally to this work.

² Address correspondence and reprint requests to Dr. John C. Cambier, Department of Immunology, K803A, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, Colorado 80206. E-mail address: cambierj{at}njc.org

³ Abbreviations used in this paper: CR2, complement receptor 2; AFC, Ab-forming cell; AM, acetoxymethyl ester; Ars, p-azophenylarsonate; CCG, chicken -globulin; GC, germinal center; PNA, peanut agglutinin; PtdInsP3, phosphatidylinositol 3,4,5-trisphosphate; Tg, transgenic.