Determination of the Role of Estrogen Receptors and Estrogen Regulated Genes in B cell Autoreactivity. Addendum.

摘要

Systemic lupus erythematosus is an autoimmune disease that occurs preferentially in women. We have developed a murine model in which BALB/c 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 (BALB/c) strain and an estrogen-nonresponsive (C57Bl/6) strain, we have found that estrogen upregulates p202b, an anti-apoptotic factor, and itpkb, a molecular that limits the release of calcium stores, in BALB/c mice protecting autoreactive B cells from BCR-triggered apoptosis and impairing negative selection during B cell development.