Estradiol in Systemic Lupus Erythematosus

Abstract

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune polymorphous disease that primarily affects women of reproductive age. This gender disparity has suggested the importance of investigating the role of reproductive hormones in the pathogenesis of the disease. Estradiol, the most potent form of estrogen, plays a key role in shaping the immune system including the production of lymphocytes, the peripheral differentiation of regulatory T cells (T-regs), antibody production, and the complement and interferon systems, and has been studied in the pathogenesis of systemic lupus erythematosus (SLE). It operates by binding to estrogen receptors (ERs) α and β, initiating cellular responses including alterations in gene expression. Regulatory T cells are instrumental in preserving immunological self-tolerance and moderating immune responses. Estradiol’s serum levels correlate with the expansion of CD4+CD25+ and FoxP3+ in healthy females. However, this response is reduced in lupus patients. Estradiol also interacts with microRNAs (miRNAs) in gene regulation. Hsa-miR-10b-5p, a miRNA targeting SRSF1, is overexpressed in SLE patients and its levels increase with exposure to estrogens. Other miRNAs also show correlation with plasma Estradiol levels. The precise role of Estradiol in the pathogenesis of SLE remains complex and multifaceted and is a topic for further research.

INTRODUCTION

Systemic Lupus Erythematosus (SLE) is a chronic autoimmune polymorphous disease that affects different organs and systems, with varying levels of severity. It affects primarily women of reproductive age, sometimes starting as early as teenage years, (1) with varying prevalences around the world ranging from 15.9 to 110.85 per 100.000 persons for women with a female-to-male ratio as high as 10:1. The highest prevalence in men was observed in the United Arab Emirates (58.2 per 100.000 persons) (2). This gender disparity in SLE suggests a potential link with female reproductive hormones and previous publications support this theory (3-5). As a result, estradiol has increasingly become the subject of intensive research scrutiny. Several potential mechanisms of action and effects of sexual hormones have been hypothesized and investigated in the context of lupus. This discussion will highlight a few such pathways and recent interesting scientific publications.

Estradiol and regulatory T cells

The possibility that estrogens might contribute to collagen diseases has been considered since the 1930s-1940s. Estradiol (17β-estradiol), one of the most potent and biologically active form of estrogen (6,7), plays a key role in shaping the immune system. This includes production of lymphocytes, the peripheral differentiation of regulatory T cells (T-regs), antibody production, and the complement and interferon systems. All these elements are significant in SLE pathogenesis (8-11).

Estradiol operates mainly by binding to estrogen receptors (ERs) α and β which are located in the nucleus of target cells throughout the body and can induce direct genomic effects by binding to DNA sequences or it can indirectly regulate gene expression through intracellular signaling pathways, leading to non-genomic effects. However, these receptors can have varying transcriptional roles. They can form either heterodimers or homodimers and can even suppress each other’s functions. When co-expressed, ERβ acts as a negative regulator of Erα signaling, inhibiting transcription (12, 13). Through ERα signaling, Estradiol also plays a role in downregulating the autoimmune regulator gene (AIRE) which is a key element in central immune tolerance (14). The expression of AIRE is also influenced by other reproductive hormones: decreased by progesterone and increased by dihydrotestosterone (15). Is it plausible that the gender bias in SLE could be attributed to issues related to steroid receptor action (16)?

Regulatory T cells are instrumental in preserving immunological self-tolerance and moderating various immune responses (3, 17). A specific, naturally occurring type of T-regs, known as CD25+CD4+ regulatory T cells, have demonstrated their capacity to suppress the activation and development of self-reactive T cells. If the population of these T-regs is reduced or their function is compromised or inhibited, it can trigger the emergence of a range of organ-specific autoimmune diseases, including SLE. FoxP3 is a regulatory gene and transcription factor found both in mice and humans involved in the production of T-regs (18-20). Estradiol appears to be playing a significant role here, as its serum levels have been found to correlate with the expansion of CD4+CD25+ and FoxP3+ in healthy females. It has also been shown capable of stimulating the differentiation of CD25+ cells and FoxP3 expression levels in mice, as well as demonstrating its potential to protect against autoimmune disease (4, 11).

In healthy individuals, the addition of Estradiol at physiological levels to CD4+ T-regs resulted in an increase in the number of T-regs and expression of FoxP3. However, this response was reduced in both female and male lupus patients, leading to a significant decrease in the percentages of CD4+FoxP3+ and CD8+FoxP3+ T cells compared to healthy controls. Interestingly, in female lupus patients, plasma testosterone levels significantly correlated with the expression of FoxP3. This emphasizes these patients’ inability to normally increase the number of T-regs in response to Estradiol while indicating that androgens may positively regulate FoxP3 (4).

Estradiol and microRNA in gene regulation of lupus patients cells

Serine/Arginine splicing factor 1 (SRSF1) is an RNA binding protein involved in gene expression and control, particularly those genes involved in cytokine production and lymphocyte signaling (21, 22). When SRSF1 is deleted from the T cells in mice, it results in an overactive immune system that exhibits characteristics of autoimmune diseases and exacerbates nephritis (23, 24). In the T cells of lupus patients, T cells show reduced expression of SRSF1 compared to healthy controls, and this decrease is associated with a more severe progression of the disease (25).

MicroRNAs (miRNAs) are noncoding RNAs that play a role in regulating gene expression. Hsa-miR-10b-5p is a miRNA targeting SRSF1 and its overexpression leads to a down-regulation of SRSF1, potentially leading to a hyperactive immune system with autoimmune features (as described above). In SLE patients, Has-miR-10b-5p levels are increased regardless of disease activity and exposure to estrogens further increases the levels of this miRNA in human T cells, possibly leading to reduced levels of SRSF1 (26).

Several other miRNAs, namely miR21, miR25, and miR186 have been identified as potential regulators of immune responses in SLE patients. They were found to be significantly elevated in the mononuclear cells of lupus patients and positively correlated with plasma Estradiol levels (27).

Low levels of miR146a (which has anti-inflammatory properties) with TRAF6 protein overexpression, as well as low levels of miR654 with MIF (macrophage migration inhibitory factor) overexpression, were found to correlate with disease activity in lupus nephritis patients. These can potentially serve as predictors for the progression to end-stage renal disease (27-29). However, the role of Estradiol in the expression of these miRNAs is yet to be determined.

The relationship between lupus and Estradiol has been the subject of extensive research and debate, but its existence is undeniable. While there are intriguing associations between hormonal fluctuations and SLE onset, activity and risk of flare seen in both observational, interventional and systematic review studies (hormone replacement therapies) (30, 31), the precise role of Estradiol in the pathogenesis of the disease remains complex, multifaceted and a topic for future research.

Conflict of interest

The authors declare that they have no conflict of interest.