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Increased Positive Selection of B1 Cells and Reduced B Cell Tolerance to Intracellular Antigens in c1q-Deficient Mice¹

Helen Ferry^*, Paul K. Potter, Tanya L. Crockford^*, Anastasia Nijnik^*, Michael R. Ehrenstein, Mark J. Walport^2,, Marina Botto and Richard J. Cornall^3,*

^* Henry Wellcome Building for Molecular Physiology, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom; Rheumatology Section, Imperial College Faculty of Medicine, London, United Kingdom; and Department of Medicine, University College, London, United Kingdom

Inherited deficiency of early components of the classical complement pathway is strongly associated with the targeting of intracellular self Ags in systemic lupus erythematosus, but the reasons for this association are debated. In this study, we show that C1q deficiency increases the positive selection of B1b B cells and IgM autoantibodies by an intracellular self Ag, which is exposed on dying cells, and decreases the negative selection of autoreactive conventional B cells by the same Ag. These effects are specific to intracellular Ag because C1q deficiency does not affect negative selection by extracellular self Ag or increase the positive selection of naive B cells. The B1-derived IgM autoantibody binds to the intracellular Ag when it is expressed on dying cells, leading to fixation of C1q and clearance of cells by phagocytosis. These findings suggest that the positive selection of autoreactive B1 cells by self Ags may contribute to the IgM and C1q-dependent clearance of dying cells in a feedback loop that limits exposure of conventional B cells to immunogenic self Ags. We show that exposure of intracellular Ag leads to the activation of conventional B cells, when there is a source of T cell help in vivo.

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 by the Wellcome Trust.

² Current address: Wellcome Trust, London NW1 2BE, U.K.

³ Address correspondence and reprint requests to Dr. Richard J. Cornall, Henry Wellcome Building for Molecular Physiology, Roosevelt Drive, Oxford OX3 7BN, U.K. E-mail address: richard.cornall{at}ndm.ox.ac.uk

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; PC, phosphorylcholine; BM, bone marrow; CI, confidence interval; FO, follicular; FSC, forward light scatter; HEL, hen egg lysozyme; int, intermediate; mHEL-KK, intracellular membrane-bound form of HEL; MZ, marginal zone; sHEL, soluble HEL; WT, wild type.