Bromocriptine restores tolerance in estrogen-treated mice

J Clin Invest. 2000 Dec;106(11):1373-9. doi: 10.1172/JCI10420.


Estrogen can modulate autoimmunity in certain models of systemic lupus erythematosus. Recently, we have shown that it can mediate survival and activation of anti-DNA B cells in a mouse transgenic for the heavy chain of a pathogenic anti-DNA antibody. To identify whether estrogen effects reflect increased prolactin secretion, we characterized B-cell autoreactivity in transgenic mice given both bromocriptine (an inhibitor of prolactin secretion) and estradiol. Treatment of mice with estradiol plus bromocriptine led to reduced titers of anti-DNA antibodies and diminished IgG deposition in kidneys compared with treatment with estradiol alone. However, mice treated with estradiol plus bromocriptine showed an expansion of transgene-expressing B cells and enhanced Bcl-2 expression, similar to those of estradiol-treated mice. We identified anergic high-affinity anti-DNA B cells in mice treated with estradiol plus bromocriptine, and we showed by molecular analysis of anti-DNA hybridomas that their B cells derive from a naive repertoire. Thus, the estradiol-induced breakdown in B-cell tolerance can be abrogated by bromocriptine, which induces anergy in the high-affinity DNA-reactive B cells. These studies demonstrate that some of the effects of estrogen on naive autoreactive B cells require the presence of prolactin and, thus, suggest potential therapeutic interventions in lupus.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies, Antinuclear / genetics
  • Antibodies, Antinuclear / immunology
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism
  • Bromocriptine / pharmacology*
  • Estradiol / pharmacology*
  • Female
  • Hybridomas / immunology
  • Immune Tolerance / drug effects*
  • Immune Tolerance / immunology
  • Immunoglobulin G / immunology
  • Immunohistochemistry
  • Kidney / drug effects
  • Kidney / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism


  • Antibodies, Antinuclear
  • Immunoglobulin G
  • Proto-Oncogene Proteins c-bcl-2
  • Bromocriptine
  • Estradiol