Contribution of BAFF and DNA‐containing Immune Complexes to the Generation of DNA‐reactive B cells

We have reported that 17β‐estradiol (E2) treatment of BALB/c mice that express a transgene‐encoded heavy chain of a nephritogenic anti‐DNA antibody (R4A) induces a lupus‐like phenotype as demonstrated by the presence of serum anti‐dsDNA antibody titers, an expansion of DNA‐reactive B cells and immune complex (IC) deposition in the kidney. We have recently shown that E2 treated mice display increased expression of BAFF mRNA. BAFF is an important regulator of B cell maturation and survival, rescuing self‐reactive B cells from anergy in mice. Furthermore, increased serum levels of BAFF have been reported in patients with SLE and RA. We propose that E2 results in the production of DNA‐containing ICs, which trigger the increased expression of BAFF, facilitating in turn the survival and activation of DNA‐reactive B cells. Consistent with this hypothesis BAFF blockade impaired the generation of anti‐DNA secreting B cells in E2 treated mice. To see if BAFF induction resulted from the action of DNA‐containing immune complexes, we administered DNAse to E2‐treated mice and demonstrated a reduction in BAFF expression. Taken together, these data demonstrate that a feedback loop exists in which DNA‐containing ICs induce expression of BAFF, which enhances the maturation and survival of DNA‐reactive B cells. Thus, targeted therapies that interfere with BAFF signals or IC formation may prove to be useful treatments for SLE.