Estrogen Receptor a Regulation of Lupus Development &Pathogenesis

PROJECT SUMMARY/ABSTRACT
Estrogens promote the development and progression of lupus, a chronic autoimmune disease
affecting an estimated 1.5 million Americans, 90-95% of whom are women. Estrogens are
thought to promote lupus by facilitating loss of immunologic tolerance and enhancing
autoantibody production. However, the molecular pathways through which estrogens exert
these effects have not been defined. Further, the relative contributions of estrogen receptors
ER and ER in mediating the effects of estrogens on lupus are not presently delineated.
Because both ER and ER are expressed in the immune cell lineages that contribute to lupus,
the identification of the specific lineages and cell types that must express each receptor to
achieve estrogen-induced enhancement of lupus remains a major unanswered question at
present. Susceptibility to lupus is modulated by genetic factors. The action of some lupus
susceptibility loci in mice is more pronounced in females, and our preliminary data indicate
estrogen contributes to this gender difference. However, concrete evidence implicating estrogen
receptors in modulating lupus susceptibility loci is lacking. To understand how estrogens
enhance lupus, it is essential to identify the genetic factors that synergize with estrogens to
promote lupus, and to determine the cell types and pathways through which estrogens augment
the immune response to nuclear autoantigens. A long term goal of our laboratory is to
understand how genetic and hormonal factors interact to influence lupus in order to facilitate the
development of novel therapies in the treatment of lupus. The objective of this application is to
determine how ER promotes lupus in the (NZB x NZW)F1 mouse. Our central hypothesis is
that ER acts in a B and T cell intrinsic manner to augment lupus by synergizing with genetic
factors and promoting cellular processes that enhance loss of tolerance and maturation of IgG+
DNA-reactive B cells. This hypothesis is based upon our preliminary data demonstrating that
ER deficiency in (NZB x NZW)F1 mice diminishes loss of tolerance, reduces levels of anti-
dsDNA IgG antibodies and attenuates development of lupus nephritis. To test this hypothesis
we will 1) Identify the lupus susceptibility loci whose activity is modulated by ER , 2) Identify the
cell lineage(s) in which ER must be expressed to achieve ER -dependent acceleration of
lupus and 3) Identify ER -regulated processes that promote production of anti-DNA IgG
antibodies. Our rationale for this research is that understanding how ER signaling promotes
lupus will provide information crucial to development of therapies to prevent and treat lupus.