Autoantibodies to estrogen receptor α in systemic sclerosis (SSc) as pathogenetic determinants and markers of progression

Abstract

Systemic sclerosis (SSc) is a multisystem autoimmune disease of unknown etiology characterized by inflammation, autoantibody production, and fibrosis. It predominantly affects women, this suggesting that female sex hormones such as estrogens may play a role in disease pathogenesis. However, up to date, the role of estrogens in SSc has been scarcely explored. The activity of estrogens is mediated either by transcription activity of the intracellular estrogen receptors (ER), ERα and ERβ, or by membrane-associated ER. Since the presence of autoantibodies to ERα and their role as estrogen agonists interfering with T lymphocyte homeostasis were demonstrated in other autoimmune diseases, we wanted to ascertain whether anti-ERα antibodies were detectable in sera from patients with SSc. We detected anti-ERα antibody serum immunoreactivity in 42% of patients with SSc (30 out of 71 analyzed). Importantly, a significant association was found between anti-ERα antibody values and key clinical parameters of disease activity and severity. Fittingly, anti-ERα antibody levels were also significantly associated with alterations of immunological features of SSc patients, including increased T cell apoptotic susceptibility and changes in T regulatory cells (Treg) homeostasis. In particular, the percentage of activated Treg (CD4(+)CD45RA(-) FoxP3(bright)CD25(bright)) was significantly higher in anti-ERα antibody positive patients than in anti-ERα antibody negative patients. Taken together our data clearly indicate that anti-ERα antibodies, probably via the involvement of membrane-associated ER, can represent: i) promising markers for SSc progression but, also, ii) functional modulators of the SSc patients' immune system.

Figure 1. Evaluation of serum anti-ERα antibody titer in patients with SSc and healthy donors.

(A) Anti-ERα antibodies in SSc patients (n = 71) and in sex- and age-matched healthy donors (HD, n = 90). Samples were considered positive if the optical density (OD) at 490 nm was higher than the cutoff value of an OD at 490 nm of 0.2 (broken line). The cut-off value was defined as 3 SD above the mean OD at 490 nm in healthy donors. Circles represent individual samples. P<0.0001 mean OD at 490 nm in patients with SSc vs. healthy donors (Mann-Whitney U-test). (B) Correlation between anti-ERα antibody levels and the EScSG activity index in SSc (n = 71). (C) Correlation between anti-ERα antibody levels and the percentage of circulating Treg (CD4⁺CD25⁺FoxP3⁺) and (D) that of activated Treg (aTreg, CD4⁺CD45RA⁻ FoxP3^brightCD25^bright) in SSc (n = 34). The rho and P values shown in panels B–D were determined using the Spearman’s rank correlation analysis. Solid lines represent best fits as estimated by linear regression analysis.