Bromocriptine restores tolerance in estrogen-treated mice.
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.
Peeva
E
E
Department of Medicine, and. Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA.
Grimaldi
C
C
Spatz
L
L
Diamond
B
B
D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D001971:Bromocriptine / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology*; D005260:Female; D006825:Hybridomas / Q000276:immunology; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D007150:Immunohistochemistry; D007668:Kidney / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism
D000974:Antibodies, Antinuclear; D007074:Immunoglobulin G; D019253:Proto-Oncogene Proteins c-bcl-2; D001971:Bromocriptine; D004958:Estradiol