Determination of the Role of Estrogen Receptors and Estrogen Regulated Genes in B cell Autoreactivity. Addendum
Final rept. 1 Jul 2011
FEINSTEIN INST FOR MEDICAL RESEARCH MANHASSET NY
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Systemic lupus erythematosus is an autoimmune disease that occurs preferentially in women. We have developed a murine model in which BALBc non-spontaneously autoimmune mice harbor a transgene encoding the heavy chain of an anti-DNA antibody. Using this model, we have shown that B cell expression of the estrogen receptor ER mediates an estrogeninduced loss of B cell tolerance. This occurs through a reduced B cell receptor BCR signal strength in transitional B cells and the presence of DNA is required to mediate positive selection of the autoreactive B cells. Moreover, estrogen-induced autoimmunity depends on the genetic background. Exploiting the availability of an estrogen-responsive BALBc strain and an estrogen-nonresponsive C57Bl6 strain, we have found that estrogen upregulates p202b, an anti-apoptotic factor, and itpkb, a molecular that limits the release of calcium stores, in BALBc mice protecting autoreactive B cells from BCR-triggered apoptosis and impairing negative selection during B cell development.
- Anatomy and Physiology
- Medicine and Medical Research