title: Hormonal milieu at time of B cell activation controls duration of autoantibody response.
abstract: A strong gender bias is seen in many autoimmune diseases including systemic lupus erythematosus (SLE). To investigate the basis for the female preponderance in SLE, we have been studying BALB/c mice in which B cells express the R4A heavy chain of an anti-DNA antibody in association with an endogenous light chain repertoire (R4Atg mice). In unmanipulated mice, approximately 5% of B cells express the R4A transgene. R4Atg mice do not spontaneously develop elevated serum titers of anti-DNA antibodies. Administration of either estradiol (E2) or prolactin (Pr) results in escape from tolerance of autoreactive B cells, expressed as an increase in transgene-expressing B cells and elevated serum titers of anti-DNA antibodies. We previously demonstrated that autoreactive B cells maturing in an estrogenic milieu develop as marginal zone (MZ) B cells; when these same B cells mature in the presence of increased prolactin, they develop as follicular (Fo) B cells. To determine the long term consequence of this differential maturation of DNA-reactive B cells, we treated R4Atg BALB/c mice with E2 or Pr for 6 weeks until serum titers of anti-DNA antibody were high, at which time hormonal exposure was discontinued. In E2-treated mice, the anti-DNA titers remained high even 3 months after discontinuation of hormone exposure. Nascent B cells underwent normal tolerance induction, but existing autoreactive MZ B cells persisted and continued to secrete autoantibody. In contrast, Pr caused only a short-term increase in anti-DNA antibody titers. By 3 months after cessation of hormone treatment, serum anti-DNA antibody titers and B cell subsets were indistinguishable from those in placebo (P) treated mice. These findings suggest that autoantibody responses are sustained for variable lengths of time depending on the B cell subset producing the autoantibodies. This observation may be relevant to understanding the heterogeneous presentation of patients with SLE and to the design of therapies targeting specific B-cell populations in autoimmune disease.
authors.affiliation: Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Jeganathan
authors.affiliation: Division of Rheumatology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Peeva
authors.affiliation: Center for Autoimmune and Musculoskeletal Disease, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA. Electronic address: bdiamond@nshs.edu.
authors.forename: Betty
authors.initials: B
authors.lastname: Diamond
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D004958:Estradiol / Q000235:genetics / Q000276:immunology*; D005260:Female; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D011388:Prolactin / Q000235:genetics / Q000276:immunology*
chemical_list: D000974:Antibodies, Antinuclear; D007143:Immunoglobulin Heavy Chains; D004958:Estradiol; D011388:Prolactin
keywords: Autoantibodies; Autoreactive; B cells; anti-DNA antibody