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− FoxP3brightCD25bright) 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.
Highlights
Estrogens are well-known regulators of the immune responses and several lines of evidence support a key role for them in the development or progression of numerous diseases, including autoimmune disorders [1,2,3,4,5]
A substantial female predominance exists in systemic sclerosis (SSc), with a female-to-male ratio ranging from 3:1 to 14:1 [10], suggesting that female sex hormones such as estrogen may play a role in disease pathogenesis
In order to evaluate whether the presence of anti-ERa antibodies plays a role in the clinical course of the disease, we divided SSc patients into subgroups according to the presence of serum anti-ERa antibodies and examined the demographic and clinical parameters in each group
Summary
Estrogens are well-known regulators of the immune responses and several lines of evidence support a key role for them in the development or progression of numerous diseases, including autoimmune disorders [1,2,3,4,5]. The expression of functional membrane-associated ERa in different cell types including human lymphocytes has been suggested [6,7,8] and autoantibodies specific to ERa have been detected in sera from patients with systemic lupus erythematosus (SLE) [9]. These anti-ERa antibodies behave as true estrogen agonist and are able to induce cell activation and apoptotic cell death in resting lymphocytes as well as proliferation of anti-CD3 activated T cells. The aim of this study was to evaluate anti-ERa serum immunoreactivity in patients with SSc and to assess the possible relationship between the presence of anti-ERa antibodies and the clinical and immunological features of the disease
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