Prolactin alters the mechanisms of B cell tolerance induction

Abstract

Objective: 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.Methods: 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 κ/λ 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.Results: 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‐γ 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 κ/λ 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.Conclusion: 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.