Prolactin alters the mechanisms of B cell tolerance induction

Persistently elevated serum prolactin levels interfere with B cell tolerance induction by impairing BCR-mediated clonal deletion, deregulating receptor editing, and decreasing the threshold for activation of anergic B cells, thereby promoting autoreactivity.

Effects of prolactin on splenic B cell subsets were studied in female BALB/c mice. B cell receptor (BCR)-mediated apoptosis and proliferation of transitional B cells were analyzed by flow cytometry. Expression of apoptotic genes was examined by microarrays and real-time polymerase chain reaction analysis. B cells coexpressing kappa/lambda light chains were assessed by flow cytometry and immunohistochemistry. Activation status of transitional type 3 (T3) B cells was evaluated by BCR-induced calcium influx studies.

Autoimmune diseases predominantly affect women, suggesting that female sex hormones may play a role in the pathogenesis of such diseases. We have previously shown that persistent mild-to-moderate elevations in serum prolactin levels induce a break in self tolerance in mice with a BALB/c genetic background. The aim of this study was to evaluate the effects of hyperprolactinemia on the mechanisms of B cell tolerance induction.

BCR-mediated apoptosis of the T1 B cell subset, a major checkpoint for negative selection of autoreactive specificities, was decreased in prolactin-treated mice. Microarray studies indicated that this event may be mediated by the prolactin-induced up-regulation of the antiapoptotic gene interferon-gamma receptor type II and down-regulation of the proapoptotic gene Trp63. Prolactin treatment also altered the amount of receptor editing, as indicated by the increased number of transitional B cells coexpressing kappa/lambda light chains. Additionally, hyperprolactinemia modified the level of B cell anergy by increasing the degree of BCR-induced calcium influx in the T3 B cells.