Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 15, Pages 6317-6322Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0610434104
Keywords
autoimmune disease; receptor editing
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Accumulating evidence indicates that epigenetic alterations contribute to exacerbated activation or deregulation of the mechanisms that maintain tolerance to self-antigens in patients with lupus, a systemic autoimmune disease that can be triggered by medications taken to treat a variety of conditions. Here, we tested the effect of hydralazine, an anti hypertensive drug that triggers lupus, on receptor editing, a chief mechanism of B lymphocyte tolerance to self-antigens. Using mice expressing transgenic human Igs, we found that hydralazine impairs up-regulation of RAG-2 gene expression and reduces secondary Ig gene rearrangements. Receptor editing was also partially abolished in a dose-dependent manner by a specific inhibitor of MEK1/2. Adoptive transfer of bone marrow B cells pretreated with hydralazine or with a MEK inhibitor to naive syngeneic mice resulted in autoantibody production. We conclude that, by disrupting receptor editing, hydralazine subverts B lymphocyte tolerance to self and contributes to generation of pathogenic autoreactivity. We also postulate that inhibition of the Erk signaling pathway contributes to the pathogenesis of hydralazine-induced lupus and idiopathic human lupus.
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