The Journal of Experimental Medicine
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Published 3 November 2003. doi:10.1084/jem.20030279
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© Rockefeller University Press, 0022-1007/2003/11/1415 $5.00
The Journal of Experimental Medicine, Volume 198, Number 9, 1415-1425

The Cellular Location of Self-antigen Determines the Positive and Negative Selection of Autoreactive B Cells

Helen Ferry1, Margaret Jones2, David J. Vaux3, Ian S.D. Roberts4 and Richard J. Cornall1

1 Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK
2 The Leukaemia Research Fund Immunodiagnostics Unit, University of Oxford, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK
3 Sir William Dunn School of Pathology, University of Oxford, Oxford, OX1 3ER, UK
4 Department of Cellular Pathology, John Radcliffe Hospital, Headington, Oxford, OX3 9DU, UK

Address correspondence to Richard Cornall, Nuffield Dept. of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK. Phone: 44-1865-221349; Fax: 44-1865-222901; email: richard.cornall{at}ndm.ox.ac.uk

Systemic autoimmune disease is frequently characterized by the production of autoantibodies against widely expressed intracellular self-antigens, whereas B cell tolerance to ubiquitous and highly expressed extracellular antigens is strictly enforced. To test for differences in the B cell response to intracellular and extracellular self-antigens, we sequestered a tolerogenic cell surface antigen intracellularly by addition of a two amino acid endoplasmic reticulum (ER) retention signal. In contrast to cell surface antigen, which causes the deletion of autoreactive B cells, the intracellularly sequestered self-antigen failed to induce B cell tolerance and was instead autoimmunogenic. The intracellular antigen positively selected antigen-binding B cells to differentiate into B1 cells and induced large numbers of IgM autoantibody-secreting plasma cells in a T-independent manner. By analyzing the impact of differences in subcellular distribution independently from other variables, such as B cell receptor affinity, antigen type, or tissue distribution, we have established that intracellular localization of autoantigen predisposes for autoantibody production. These findings help explain why intracellular antigens are targeted in systemic autoimmune diseases.

Key Words: SLE • autoimmunity • self tolerance • B lymphocytes • hen egg lysozyme


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