Estrogen receptor alpha promotes lupus in (NZB×NZW)F1 mice in a B cell intrinsic manner

Abstract

Lupus is a systemic autoimmune disease characterized by the production of autoreactive antibodies against nuclear antigens. Women are disproportionately affected by lupus, and this sex bias is thought to be due, in large part, to the ability of estrogens to promote lupus pathogenesis. Previously, we have shown that global deletion of estrogen receptor alpha (ERα) significantly attenuated loss of tolerance, immune cell activation, autoantibody production, and the development of lupus nephritis. Here we show that targeted deletion of ERα specifically in B cells retards production of pathogenic autoantibodies and the development of nephritis in lupus-prone (NZB x NZW)F1 mice. Furthermore, we observed that ERα deletion in B cells was associated with decreased B cell activation in young, pre-autoimmune (NZB x NZW)F1 females. Altogether, these data suggest that ERα acts in a B cell-intrinsic manner to control B cell activation, autoantibody production, and lupus nephritis.

Estrogen Receptor Alpha Signaling Is Responsible for the Female Sex Bias in the Loss of Tolerance and Immune Cell Activation Induced by the Lupus Susceptibility Locus Sle1b

“…The B cell intrinsic actions of the Sle1b locus as a whole as well as some individual SLAM family members contained within Sle1b, such as Ly108 and CD84, have been shown to modulate BCR signaling and to promote bypass of the germinal center B cell checkpoint, the formation of spontaneous germinal centers, and the development of anti-chromatin autoantibodies in B6.Sle1b congenic mice (30,31). Likewise, we have shown that the ability ERa to promote loss of tolerance and autoantibody production in the (NZB × NZW)F1 lupus model involves B cell intrinsic action of ERa (13). Estrogens, acting through ERa have also been suggested to modulate BCR signaling (41).…”

Gender Bias in Human Systemic Lupus Erythematosus: A Problem of Steroid Receptor Action?

“…Male mice lacking functional ERα (ERα −/− ) are resistant to developing a lupus phenotype in response to estradiol compared with their wild-type littermates suggesting ERα, rather than ERβ is responsible for inducing a lupus phenotype ( 18 ). This concept is supported by more recent data suggesting ERα promotes SLE in F1 females of a lupus mouse model (NZB × NZW) ( 19 ).…”

Sex Hormones in Acquired Immunity and Autoimmune Disease

“…While global deficiency of ERα in lupus-prone B6.Sle1 mice ameliorates disease ( 142 ), conditional deletion utilizing the Cre-lox technology has shown the effect of ERα in specific immune cells. B cell specific deletion of ERα by crossing ERα flox mice with CD19-Cre mice delayed autoantibody production and lupus nephritis in (NZBxNZW) F1 lupus-prone mice ( 143 ).…”