Natural history of murine lupus. Modulation by sex hormones

Talal, Norman

doi:10.1002/art.1780210908

Cited by 23 publications

(11 citation statements)

References 32 publications

(3 reference statements)

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“…Testosterone and other sex hormones also have known immunomodulatory effects [21–24]. In murine lupus, manipulating sex hormones via classic ovariectomy and castration experiments demonstrated clear roles for E2 and T2 in exacerbating or ameliorating, respectively, lupus disease expression [25]. However, results from studies where ERα was knocked out are not as clear-cut.…”

Section: Discussionmentioning

confidence: 99%

Complete knockout of estrogen receptor alpha is not directly protective in murine lupus

Scott

Wirth

Eudaly

et al. 2017

Clinical Immunology

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Systemic lupus erythematosus (SLE) is a chronic and potentially severe autoimmune disease that disproportionately affects women. Despite a known role for hormonal factors impacting autoimmunity and disease pathogenesis, the specific mechanisms of action remain poorly understood. Our laboratory previously backcrossed “estrogen receptor alpha knockout (ERαKO)” mice onto the NZM2410 lupus prone background to generate NZM/ERαKO mice. This original ERαKO mouse, developed in the mid-1990s and utilized in hundreds of published studies, is not in fact ERα null. They express an N-terminally truncated ERα, and are considered a functional KO. They have physiologic deficiencies including infertility due to disruption of a critical activation domain (AF-1) at the N terminus of ERα, required for most classic estrogen (E2) actions. We demonstrated that female NZM/ERαKO mice had significantly less renal disease and significantly prolonged survival compared to WT littermates despite similar serum levels of autoantibodies and glomerular immune complex deposition. Herein, we present results of experiments using a lupus prone true ERα−/− mice (deletional KO mice on the NZM2410 background), surprisingly finding that these animals were not protected if they were ovariectomized, even if E2-repleted, suggesting that another hormonal component confers protection, possibly testosterone, rather than the absence of the full-length ERα.

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Section: Discussionmentioning

confidence: 99%

Complete knockout of estrogen receptor alpha is not directly protective in murine lupus

Scott

Wirth

Eudaly

et al. 2017

Clinical Immunology

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“…At present, the precise role of estrogens in the etiology of lacrimal gland inflammation and aqueous-deficient dry eye in SjS is unknown. Estrogens have been shown to accelerate (Homo-Delarche et al, 1991; Olsen and Kovacs, 1996; Roubinian et al, 1978; Talal, 1978), and anti-estrogens (Auborn et al, 2003; Nelson and Steinberg, 1987; Sthoeger et al, 2003; Wu et al, 2000) and selective estrogen receptor modulators (Apelgren et al, 1996) to retard, systemic disease processes in mouse models of SjS. Estrogens are also known to enhance the polyclonal B cell activation, autoantibody formation and tissue abnormalities encountered in SjS (Ahmed et al, 1989; Carlsten et al, 1990; Sato and Sullivan, 1994).…”

Section: Discussionmentioning

confidence: 99%

Does estrogen deficiency cause lacrimal gland inflammation and aqueous-deficient dry eye in mice?

Darabad¹,

Suzuki²,

Richards³

et al. 2014

Experimental Eye Research

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Researchers have proposed that estrogen deficiency will lead to a Sjögren's syndrome (SjS)-like lacrimal gland inflammation, aqueous tear deficiency and dry eye. The purpose of this study was to determine whether this proposal is correct. Lacrimal glands were obtained from adult, age-matched wild type (WT) and aromatase knockout (ArKO) mice, in which estrogen synthesis is completely eliminated. Tissues were also obtained from autoimmune MRL/Mp-lpr/lpr (MRL/lpr) mice as inflammation controls. Tear volumes in WT and ArKO mice were measured and glands were processed for molecular biological and histological evaluation. Our results demonstrate that estrogen absence does not lead to a SjS-like inflammation in lacrimal tissue or to an aqueous-deficient dry eye. There was no upregulation of genes associated with inflammatory pathways in lacrimal glands of male or female ArKO mice. Such inflammatory activity was prominent in autoimmune MRL/lpr tissues. We also found no evidence of inflammation in lacrimal gland tissue sections of estrogen-deficient mice, and tear volumes of ArKO males were actually increased as compared to those WT controls. Interestingly, our study did show that estrogen absence influences the expression of thousands of lacrimal gland genes, and that this impact is sex- and genotype-specific. Our findings demonstrate that estrogen absence is not a risk factor for the development of SjS-like lacrimal gland inflammation or for aqueous-deficient dry eye in mice.

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“…The female NZBWF1 mouse is a well-established model of SLE with prevalent hypertension and renal injury 19–25 . Mice were randomly divided into 4 groups: control mice administered an isotype control (Control/IgG) or the monoclonal antibody to mouse CD3 (Control/Anti-CD3), and SLE mice administered isotype control (SLE/IgG) or the antibody to CD3 (SLE/Anti-CD3).…”

Section: Methodsmentioning

confidence: 99%

Anti-CD3 antibody therapy attenuates the progression of hypertension in female mice with systemic lupus erythematosus

Mathis

Taylor

Ryan

2017

Pharmacological Research

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Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder with prevalent hypertension that significantly contributes to the mortality in this patient population. Pre-clinical and clinical evidence suggests that anti-CD3 antibody therapy may attenuate the development of autoimmune diseases like SLE. However, it is unclear whether this treatment impacts the development of the prevalent hypertension associated with SLE. The present study was designed to determine whether anti-CD3 antibody treatment attenuates the progression of hypertension in female SLE mice with already established renal disease (albuminuria ≥ 100 mg/dL). Female SLE (NZBWF1) and control (NZW) mice were administered either an antibody to CD3ε, a component of the T cell receptor complex expressed on all T cells, or IgG antibody (isotype control) for up to 4 weeks (intranasal; 25 μg/week). Spleen weight was lower in SLE mice treated with anti-CD3 antibody than in IgG-treated SLE mice, suggesting that immune system hyperactivity is decreased. Circulating anti-dsDNA autoantibodies were increased in SLE mice compared to controls and were blunted in the anti-CD3-treated SLE mice. The development of hypertension was attenuated in anti-CD3 treated mice with SLE independently of changes in renal injury (assessed by urinary albumin). These data suggest anti-CD3 therapy during autoimmune disease may have added clinical benefit to attenuate cardiovascular risk factors like hypertension.

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Natural history of murine lupus. Modulation by sex hormones

Cited by 23 publications

References 32 publications

Complete knockout of estrogen receptor alpha is not directly protective in murine lupus

Complete knockout of estrogen receptor alpha is not directly protective in murine lupus

Does estrogen deficiency cause lacrimal gland inflammation and aqueous-deficient dry eye in mice?

Anti-CD3 antibody therapy attenuates the progression of hypertension in female mice with systemic lupus erythematosus

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