Hormonal milieu at time of B cell activation controls duration of autoantibody response

J Autoimmun. 2014 Sep;53:46-54. doi: 10.1016/j.jaut.2014.02.007. Epub 2014 Mar 28.

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.

Keywords: Autoantibodies; Autoreactive; B cells; anti-DNA antibody.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Antinuclear / genetics
  • Antibodies, Antinuclear / immunology
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / pathology
  • Estradiol / genetics
  • Estradiol / immunology*
  • Female
  • Immunoglobulin Heavy Chains / genetics
  • Immunoglobulin Heavy Chains / immunology
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology*
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Transgenic
  • Prolactin / genetics
  • Prolactin / immunology*

Substances

  • Antibodies, Antinuclear
  • Immunoglobulin Heavy Chains
  • Estradiol
  • Prolactin