Autoantibodies to estrogen receptor α interfere with T lymphocyte homeostasis and are associated with disease activity in systemic lupus erythematosus

Abstract

Objective. Estrogens influence many physiologic processes and are also implicated in the development or progression of numerous diseases, including autoimmune disorders. Aberrations of lymphocyte homeostasis that lead to the production of multiple pathogenic autoantibodies, including autoantibodies specific to estrogen receptor (ER), have been detected in the peripheral blood of patients with systemic lupus erythematosus (SLE). This study was undertaken to assess the presence of both anti-ER␣ and anti-ER␤ antibodies in sera from patients with SLE, to analyze the effect of these antibodies on peripheral blood T lymphocyte homeostasis, and to evaluate their role as determinants of disease pathogenesis and progression.Methods. Anti-ER antibody serum immunoreactivity was analyzed by enzyme-linked immunosorbent assay in samples from 86 patients with SLE and 95 healthy donors. Phenotypic and functional analyses were performed by flow cytometry and Western blotting.Results. Anti-ER␣ antibodies were present in 45% of the patients with SLE, whereas anti-ER␤ antibodies were undetectable. In healthy donors, anti-ER␣ antibodies induced cell activation and consequent apoptotic cell death in resting lymphocytes as well as proliferation of anti-CD3-stimulated T lymphocytes. A significant association between anti-ER␣ antibody values and clinical parameters, i.e., the SLE Disease Activity Index and arthritis, was found.Conclusion. Our data suggest that anti-ER␣ autoantibodies interfere with T lymphocyte homeostasis and are significantly associated with lupus disease activity.The involvement of estrogens, which influence many physiologic processes, has been shown in the development or progression of several autoimmune disorders (1-4). There is evidence that 17␤-estradiol directly modulates the development and function of immune cells, although the mechanism by which this might occur is not well understood (5,6). The primary mechanism of 17␤-estradiol activity is mediated by transcription activity of the intracellular estrogen receptors (ERs), ER␣ and ER␤, to produce genomic effects (7). A variety of cellular responses to physiologic concentrations of 17␤-estradiol occur rapidly, within seconds to a few minutes. These rapid estrogen-mediated effects (referred to as nongenomic) are triggered through the activation of membrane-associated ER and are independent of transcription pathways and protein synthesis.

Sex affects immunity

“…Both males and females with SLE have reduced levels of testosterone [3]. Autoantibodies to ERa are present in 45% of SLE patients, implicated in altering T cell homeostasis and contributing to disease [85].…”

Joint involvement in patients affected by systemic lupus erythematosus: application of the swollen to tender joint count ratio

“…Moreover, STR seems to be more sensitive than SLEDAI-2K in capturing joint involvement. SLE is a systemic autoimmune disease characterized by a multi-factorial etiology, a broad autoantibody profile and het- erogeneous clinical features (8)(9)(10)(11). The therapeutic strategy in SLE patients should include the control of disease activity and the prevention of chronic damage (12,13).…”

Membrane lipid rafts and estrogenic signalling: a functional role in the modulation of cell homeostasis

“…Our group, by using epitope-binding technologies, reported the cell surface expression of a functionally active ERa46 isoform, but not of ERb, on lymphocytes, demonstrating that E2 level fluctuations may be associated with a prompt lymphocyte response [77]. The activation of this mERa significantly increased the apoptotic levels of resting T lymphocytes, the proliferation of activated T lymphocytes and the IFN-c production by NK cells [77,78]. Schneider et al [79] showed that both ERa and ERb were expressed on the plasmatic membrane of mouse splenocytes and they were reported to be associated with lipid raft and/or caveolar fractions.…”