Autoantibodies to estrogen receptor α interfere with T lymphocyte homeostasis and are associated with disease activity in systemic lupus erythematosus (original) (raw)
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Biology of Sex Differences, 2016
Background: Current evidence indicates that estrogens, in particular 17β-estradiol (E2), play a crucial role in the gender bias of autoimmune diseases although the underlying molecular mechanisms have not yet been fully elucidated. Immune cells have estrogen receptors (ERs), i.e., ERα and ERβ, that play pro-and anti-inflammatory functions, respectively, and the presence of one estrogen receptor (ER) subtype over the other might change estrogen effects, promoting or dampening inflammation. In this study, we contributed to define the influences of E2 on T cells from female patients with systemic lupus erythematosus (SLE), a representative autoimmune disease characterized by a higher prevalence in women than in men (female/male ratio 9:1). Particularly, our aim was to evaluate whether alterations of ERα and ERβ expression in T cells from female SLE patients may impact lymphocyte sensitivity to E2 and anti-ERα antibody (anti-ERα Ab) stimulation interfering with cell signaling and display a direct clinical effect. Methods: Sixty-one premenopausal female patients with SLE and 40 age-matched healthy donors were recruited. Patients were divided into two groups based on the SLE Disease Activity Index 2000 (SLEDAI-2K) (i.e., <6 and ≥6). ER expression was evaluated in T lymphocytes by flow cytometry, immunofluorescence, and Western blot analyses. Serum anti-ERα Ab levels were analyzed by enzyme-linked immunosorbent assay (ELISA). ER-dependent signaling pathways were measured by a phosphoprotein detection kit.
International Immunopharmacology, 2001
Ž Estrogens are believed to play a role in the etiology of both human and murine systemic lupus erythematosus lupus;. SLE , presumably through the agency of their cellular receptor proteins. There is now considerable interest in the molecular mechanism of action of estrogens in immune tissues, particularly with regard to autoimmune disorders, which are generally more prevalent in women. In this laboratory, an attempt is being made to characterize estrogen receptors in murine models of SLE and to try and relate this to estrogen receptor function in vivo. The initial aim was to compare binding properties of estrogen receptors in brain, reproductive and immune tissues of BALBrc and MRLrMP-lprrlpr mice. The latter strain Ž. spontaneously develops an autoimmune disease resembling human systemic lupus erythematosus lupus; SLE. It is hypothesized that estradiol, through its receptors, mediates the progression of murine SLE, and that in autoimmune disease, the estrogen receptor is functionally andror structurally changed. Initial studies suggest that there are differences in estrogen receptors between BALBrc mice, which do not get autoimmune disease, and two strains that do, MRLrMP-lprrlpr and NZBrW mice. In MRL mice, these differences may be reflected in impaired priming of the progesterone receptor.
Estrogen Receptor Signaling and Its Relationship to Cytokines in Systemic Lupus Erythematosus
Journal of Biomedicine and Biotechnology, 2010
Dysregulation of cytokines is among the main abnormalities in Systemic Lupus Erythematosus (SLE). However, although, estrogens, which are known to be involved in lupus disease, influence cytokine production, the underlying molecular mechanisms remain poorly defined. Recent evidence demonstrates the presence of estrogen receptor in various cell types of the immune system, while divergent effects of estrogens on the cytokine regulation are thought to be implicated. In this paper, we provide an overview of the current knowledge as to how estrogen-induced modulation of cytokine production in SLE is mediated by the estrogen receptor while simultaneously clarifying various aspects of estrogen receptor signaling in this disease. The estrogen receptor subtypes, their structure, and the mode of action of estrogens by gene activation and via extranuclear effects are briefly presented. Results regarding the possible correlation between estrogen receptor gene polymorphisms and quantitative chan...
Estrogen and progesterone receptors in murine models of systemic lupus erythematosus
International Immunopharmacology, 2001
Ž Estrogens are believed to play a role in the etiology of both human and murine systemic lupus erythematosus lupus;. SLE , presumably through the agency of their cellular receptor proteins. There is now considerable interest in the molecular mechanism of action of estrogens in immune tissues, particularly with regard to autoimmune disorders, which are generally more prevalent in women. In this laboratory, an attempt is being made to characterize estrogen receptors in murine models of SLE and to try and relate this to estrogen receptor function in vivo. The initial aim was to compare binding properties of estrogen receptors in brain, reproductive and immune tissues of BALBrc and MRLrMP-lprrlpr mice. The latter strain Ž. spontaneously develops an autoimmune disease resembling human systemic lupus erythematosus lupus; SLE. It is hypothesized that estradiol, through its receptors, mediates the progression of murine SLE, and that in autoimmune disease, the estrogen receptor is functionally andror structurally changed. Initial studies suggest that there are differences in estrogen receptors between BALBrc mice, which do not get autoimmune disease, and two strains that do, MRLrMP-lprrlpr and NZBrW mice. In MRL mice, these differences may be reflected in impaired priming of the progesterone receptor.
Estrogens and autoimmune diseases
ANNALS-NEW …
Abstract: Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone (and glucocorticoids) as natural immune-suppressors . Several physiological, pathological, and therapeutic conditions ...
Estrogen receptor-α deficiency attenuates autoimmune disease in (NZB × NZW)F1 mice
Genes and Immunity, 2008
Estrogens promote lupus in humans and some mouse models of this disease. Nonetheless, little is known about the role of estrogen receptors in lupus pathogenesis. Here, we report that in females on the lupus-prone (NZB Â NZW)F 1 background, disruption of estrogen receptor-a (ERa or Esr1) attenuated glomerulonephritis and increased survival. ERa deficiency also retarded development of anti-histone/DNA antibodies, suggesting that ERa promotes loss of immunologic tolerance. Furthermore, ERa deficiency in (NZB Â NZW)F 1 females attenuated the subsequent development of anti-double-stranded DNA (dsDNA) IgG antibodies, which are associated with glomerulonephritis in this model. We provide evidence that ERa may promote lupus, at least in part, by inducing interferon-g, an estrogen-regulated cytokine that impacts this disease. ERa deficiency in (NZB Â NZW)F 1 males increased survival and reduced anti-dsDNA antibodies, suggesting that ERa also modulates lupus in males. These studies demonstrate that ERa, rather than ERb, plays a major role in regulating autoimmunity in (NZB Â NZW)F 1 mice. Furthermore, our results suggest for the first time that ERa promotes lupus, at least in part, by impacting the initial loss of tolerance. These data suggest that targeted therapy disrupting ERa, most likely within the immune system, may be effective in the prevention and/or treatment of lupus.
Estrogen, estrogen-like molecules and autoimmune diseases
Autoimmunity Reviews, 2020
In western countries, the slope of autoimmune disease (AD) incidence is increasing and affects 5-8% of the population. Mainly prevalent in women, these pathologies are due to thymic tolerance processes breakdown. The female sex hormone, estrogen, is involved in this AD female susceptibility. However, predisposition factors have to act in concert with unknown triggering environmental factors (virus, microbiota, pollution) to initiate AD. Individuals are exposed to various environmental compounds that display endocrine disruption abilities. The cellular effects of some of these molecules may be mediated through the aryl hydrocarbon receptor (AhR). Here, we review the effects of these molecules on the homeostasis of the thymic cells, the immune tolerance intrinsic factors (transcription factors, epigenetic marks) and on the immune tolerance extrinsic factors (microbiota, virus sensibility). This review highlights the contribution of estrogen and endocrine disruptors on the dysregulation of mechanisms sustaining AD development. The family of autoimmune diseases (AD) encompasses > 80 different chronic diseases, such as systemic lupus erythematosus (SLE), primary Sjӧgren's syndrome (SjS), rheumatoid arthritis (RA) and myasthenia gravis (MG). These pathologies affect 5 to 8% of the population, and their incidence is rising in industrialized countries. AD are more prevalent in women than in men and remain the fourth leading cause of illness for women [1-4]. The main role of the immune system is to distinguish self from nonself-components. A highly controlled process of establishing tolerance to self-antigens is set up in immune tissues (thymus and bone marrow) in order to maintain tissue and organ integrity. To effect this, the immune system must be able to identify autoreactive T-cells and eliminate them; otherwise autoimmune reactions can occur. Brooks has summarized this process into three key stages: 1) A breaking in central and peripheral mechanisms of tolerance to self-components; 2) defective immunoregulatory tools (defects in regulatory T-cells (Treg) and T helper cells 17 (Th17)); and 3) exposure to environmental induction factors. In this case, the adaptive immune response (via T-cells and B-cells) overreacts and may target the selfmolecules [5]. Numerous data corroborate that AD may arise when diverse events are combined to stimulate inflammation and finally activate abnormal immune signal reactions to targeted tissues or organs. Clear intrinsic factors are involved in disease progression, among them genetic factors single-nucleotide polymorphism (i.e., MHC genotypes), sex hormones and X chromosome inactivity defects. The contributions of extrinsic components have emerged from epidemiologic studies and investigations in monozygotic twins who display disease with incomplete concordance [6]. Hence, exposure to viruses [7], diet-related factors (vitamin D or gut microbiota), UV radiation, melatonin, lifestyle (job),
Clinical Reviews in Allergy & Immunology, 2011
Early studies of the immune system disclosed that, generally, females exhibit stronger responses to a variety of antigens than males. Perhaps as a result of this response, women are more prone to developing autoimmune diseases than men. Yet, the precise cellular and molecular mechanisms remain under investigation. Recently, interferongamma and the related pro-inflammatory interleukin-12 were found to be under effects of sex steroid hormones, with potential implications in regulating immune cells and autoimmune responses. In B lymphocytes, functional binding sites for estrogen receptors were identified in the promoter of the gene encoding activation-induced deaminase, an enzyme required for somatic hypermutation, and class-switch recombination. The observation that estrogen exerts direct impacts on antibody affinity-maturation provides a potential mechanism that could account for generating pathogenic highaffinity auto-antibodies. Further deciphering the multi-faceted influences of sex hormones on the responsiveness of immune cells could lead to novel therapeutic interventions for autoimmunity management.