Gender Differences in Autoimmune Diseases: Estrogen Increases Calcineurin Expression in Systemic Lupus Erythematosus

doi:10.1006/clin.1998.4604

Clinical Immunology and Immunopathology

Volume 89, Issue 2, November 1998, Pages 171-180

Clinical Immunology ...

https://doi.org/10.1006/clin.1998.4604 Get rights and content

Abstract

Systemic lupus erythematosus (SLE) predominantly affects women (9:1 compared to men) of childbearing age and often decreases its intensity in postmenopausal women, suggesting that sex hormones play a role in its pathogenesis. Comparison of steady-state levels of calcineurin mRNA using RNase protection assays revealed increased calcineurin expression in response to estradiol in cultured T cells from nine female lupus patients. Calcineurin mRNA levels did not increase significantly in T cells from eight age-matched normal control female volunteers. Estrogen-dependent calcineurin mRNA increased in a dose-dependent fashion, while progesterone and dexamethasone did not increase calcineurin mRNA in patient cells. Lupus T cell calcineurin mRNA increased in response to estradiol at 6 h but not at 3 h. Calcineurin phosphatase activity increased in lupus T cell extracts after incubation of cells with estradiol, while phosphatase activity in normal T cells was unaffected by estrogen. Calcineurin expression in T cells from patients with vasculitis and rheumatoid arthritis taking medications similar to those taken by the lupus patients was unaffected by estradiol. This study provides the first evidence for a molecular marker of estrogen action in lupus patients and suggests that estrogen-dependent changes in lupus T cell calcineurin could alter proinflammatory cytokine gene regulation and T–B cell interactions.

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Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension.
PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed.
The potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against cardiovascular risk factors in adulthood. In addition, increasing evidence suggests that estrogen may have distinct temporal effects on cardiovascular risk factors during SLE.
Data from experimental models of lupus suggest that estrogens may have an important permissive role for developing SLE early in life. However, their role in adulthood remains unclear, particularly for the effect on cardiovascular disease and its risk factors. Additional work is needed to understand the effect of estrogens in human SLE, and preclinical studies in experimental models of SLE may contribute important mechanistic insight to further advance the field.
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SLE is a chronic autoimmune inflammatory disorder that predominantly affects young women. Based on this observation, it has been speculated that sex steroids, particularly estrogens, contribute to SLE disease progression. Young women with SLE are at an increased risk for the development of hypertension yet the reasons for this are unclear. One potential mechanism for the increased risk of hypertension during SLE is the chronic inflammation caused by immune complex mediated tissue injury. Estrogens are known to have an immunomodulatory role that can lead to the production of characteristic autoantibodies important for immune complex formation. Therefore, it is conceivable that during SLE estrogens contribute to tissue injury, increased inflammation and hypertension. This brief review discusses the increased risk for hypertension during SLE, the role of estrogens in immune system function, evidence for estrogens in SLE, and a possible link between estrogens and SLE hypertension.
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Citation Excerpt :
The expression of calcineurin mRNA is also greater in patients with SLE than in healthy individuals. This allows T cells to prepare to increase the expression of cytokines and make their interaction with the B cells more efficient [122,20,125]. Patients with SLE show immunereactivity to their own antigens as their lymphocytes are exposed and stimulated by intracellular components of the individual him/herself due to accelerated apoptosis and the incorrect clearing of waste products.
Autoimmune diseases occur more in women than in men, and this may be attributable to the role of estrogens. Androgens promote autoimmune diseases with a profile of type 1 cytokines, such as rheumatoid arthritis, whereas estrogens promote autoimmune diseases with a type 2 cytokine profile, like systemic lupus erythematosus. Both androgens and estrogens regulate the Th1/Th2 balance. Type 1 autoimmune diseases are improved when decrease type 1 cytokines (i.e. during fasting), or when there is a rise in type 2 cytokines (increased estrogens, as in pregnancy). Type 2 autoimmune diseases improve when type 2 cytokines are diminished (decreased estrogen, as in post-partum period) or when type 1 response is stimulated.
The induction of the lupus phenotype by estrogen is via an estrogen receptor-α-dependent pathway
2010, Clinical Immunology
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In another study, it was shown that estrogen exposure directly activated T cells via cell membrane ER [19]. It was further observed that calcineurin, CD40L expression, PP2B phosphatase activity, NF-κB activity and FoxP3 expression were increased in T cells cultured with E-2 [20–23], and the activation of these T cells was ER dependent [24]. B cell development in the bone marrow has been shown to be modified by exposure to estrogen [25], which resulted in the ER-dependent up-regulation of several genes involved in cell activation and survival [26–28].
In order to investigate the roles of ER subtypes in the estrogen-induced lupus phenotype, ERα-deficient (ERα^−/−) and wild-type mice (WT) were injected monthly with estradiol (E-2) starting at 8 weeks. In WT mice, E-2 treatment induced a lupus phenotype, with accelerated death and increased kidney damage, as well as Th2-type serum cytokine and autoantibody production. In contrast, only minimal changes were observed in ERα^−/− mice after E-2 treatment. In a separate study, we found that in immune cells of autoimmune-prone SNF₁ and non-autoimmune DBF₁ mice, both ERα and ERβ were differentially expressed and modulated by E-2. In SNF₁ mice, there were more CD4⁺ and CD8⁺ T cells constitutively expressing ERα, and the percentages of ERα+ dendritic cells and macrophages were increased after E-2 exposure compared to DBF₁ mice. Taken together, these observations strongly suggest a role for ERα in E-2-induced development of the lupus phenotype.
Gender Differences in Autoimmune Diseases. Immune Mechanisms and Clinical Applications
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This chapter updates and adds new information to complement and extend previous reviews on gender differences in autoimmunity. It starts with general remarks on what is new in sex hormones and autoimmunity. It then discusses genes and sex differences with respect to autoimmune diseases, immune mediators, and signals that are under the influence of sex hormones, and updates the information on estrogen receptors (ER), both ERα and ERβ. The chapter discusses immune modulation following activation and/or blocking of estrogen receptors and the subsequent expression of the autoimmune state. In this chapter, recent work was selected that dealt with hormones and gender differences in autoimmunity. The interplay between sex hormones and the cellular–humoral–cytokine factors that could influence the expression of autoimmune diseases is discussed. Specific autoimmune diseases with female predominance are discussed with emphasis on systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren syndrome (SS), and neurologic diseases, particularly those with established animal models. Current and future applications of the basic information in the field of hormones and gender are outlined with emphasis on possible future therapeutic applications in autoimmune diseases with female predominance.

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^☆: This research was supported in part by grants from the Sarah Morrison fund, Evans Endowment fund, Coleman Trust fund, St Luke's Foundation, and the University of Missouri Research Board.

^☆☆: R. D. Lahita

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Regular ArticleGender Differences in Autoimmune Diseases: Estrogen Increases Calcineurin Expression in Systemic Lupus Erythematosus☆,☆☆

Abstract

Clin. Immunol. Immunopathol.

Curr. Opin. Immunol.

Cell

Cell

Clin. Immunol. Immunopath.

Anal. Biochem.

Methods Enzymol.

J. Biol. Chem.

Cell

Cell

Sex hormones as immune modulators of disease

Ann. N. Y. Acad. Sci.

Estrogen, the immune response and autoimmunity

Clin. Exp. Rheumatol.

Hormonal modulation in SLE

Arthritis Rheum.

Effect of pregnancy on course of systemic lupus erythematosus

JAMA

Oral contraceptives and systemic lupus erythematosus

Arthritis Rheum.

Sex hormones in systemic lupus erythematosus: A controversy for modern times

J. Rheumatol.

Oestrogens, bones and systemic lupus erythematosus

Lupus

Oral contraceptives and systemic lupus erythematosus

Arthritis Rheum.

Why women

Lupus

Gonadal steroids and immunity

Endocrinol. Rev.

Sex steroid receptors in peripheral T cells: Absence of androgen receptors and restriction of estrogen receptors to OKT8 positive cells

J. Immunol.

Oestrogen and human T lymphocytes: Presence of specific receptors in the T-suppressor/cytotoxic subset

Scand. J. Immunol.

Presence of estrogen binding sites on macrophage-like synoviocytes and CD8+++

Arthritis Rheum.

Peripheral blood T cells and monocytes, and B cell lines derived from lupus patients express estrogen receptor transcripts similar to those of normal controls

J. Rheumatol.

Oestrogen influences CD4+in vivoin vitro

Immunology

Effect of estradiol on cytokine secretion

J. Immunol.

The T cell enigma in lupus

Arthritis Rheum.

Overview of cellular immune function in systemic lupus erythematosus

Systemic Lupus Erythematosus

Mode of action of tacrolimus (FK506): Molecular and cellular mechanisms

Ther. Drug Monitoring

Molecular and genetic insights into T cell antigen receptor structure and function

Annu. Rev. Genet.

Immune cell biochemical abnormalities in systemic lupus erythematosus

Clin. Exp. Rheumatol.

Regular Article
Gender Differences in Autoimmune Diseases: Estrogen Increases Calcineurin Expression in Systemic Lupus Erythematosus☆,☆☆

Presence of estrogen binding sites on macrophage-like synoviocytes and CD8⁺⁺⁺

Oestrogen influences CD4⁺in vivoin vitro