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Published online 28 February 2005 doi:10.1084/jem.20042251
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 201, Number 5, 703-711
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ARTICLE

 Defective B cell tolerance checkpoints in systemic lupus erythematosus

Sergey Yurasov1,2, Hedda Wardemann1, Johanna Hammersen1, Makoto Tsuiji1, Eric Meffre1,3, Virginia Pascual5, and Michel C. Nussenzweig1,4

1 Laboratory of Molecular Immunology, The Rockefeller University
2 Department of Pediatrics, Memorial Sloan-Kettering Cancer Center
3 Hospital for Special Surgery and Weill Medical College of Cornell University, New York, NY 10021
4 Howard Hughes Medical Institute, New York, NY 10021
5 Baylor Institute for Immunology Research, Dallas, TX 75204

CORRESPONDENCE Michel C. Nussenzweig: nussen{at}mail.rockefeller.edu

A cardinal feature of systemic lupus erythematosus (SLE) is the development of autoantibodies. The first autoantibodies described in patients with SLE were those specific for nuclei and DNA, but subsequent work has shown that individuals with this disease produce a panoply of different autoantibodies. Thus, one of the constant features of SLE is a profound breakdown in tolerance in the antibody system. The appearance of self-reactive antibodies in SLE precedes clinical disease, but where in the B cell pathway tolerance is first broken has not been defined. In healthy humans, autoantibodies are removed from the B cell repertoire in two discrete early checkpoints in B cell development. We found these checkpoints to be defective in three adolescent patients with SLE. 25–50% of the mature naive B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5–20% in controls. We conclude that SLE is associated with abnormal early B cell tolerance.

Abbreviations used: aa, amino acids; ANA, antinuclear antibody; IFA, indirect immunofluorescence assay; IgH, Ig heavy; IgL, Ig light; SLE, systemic lupus erythematosus; PS, phosphatidylserine.

S. Yurasov and H. Wardemann contributed equally to this work.


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