title: 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 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.
  
  
  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-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Albert Einstein College of Medicine, Bronx, New York, USA.
authors.forename: Subhrajit
authors.initials: S
authors.lastname: Saha
authors.forename: Juana
authors.initials: J
authors.lastname: Gonzalez
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rosenfeld
authors.forename: Harold
authors.initials: H
authors.lastname: Keiser
authors.forename: Elena
authors.initials: E
authors.lastname: Peeva
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000473:pathology / Q000502:physiology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005260:Female; D006966:Hyperprolactinemia / Q000473:pathology / Q000503:physiopathology*; D007108:Immune Tolerance / Q000502:physiology*; D007145:Immunoglobulin kappa-Chains / Q000502:physiology; D007146:Immunoglobulin lambda-Chains / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D010750:Phosphoproteins / Q000502:physiology; D011388:Prolactin / Q000502:physiology*; D017471:Receptors, Interferon / Q000502:physiology; D015534:Trans-Activators / Q000502:physiology; D000096743:Interferon gamma Receptor
chemical_list: D007145:Immunoglobulin kappa-Chains; D007146:Immunoglobulin lambda-Chains; D010750:Phosphoproteins; D011388:Prolactin; D017471:Receptors, Interferon; D015534:Trans-Activators; D000096743:Interferon gamma Receptor; C486419:Trp63 protein, mouse