Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse

Svenson, John L.; Eudaly, Jackie; Ruiz, Phil; Korach, Kenneth S.; Gilkeson, Gary S.

doi:10.1016/j.clim.2008.03.508

Cited by 85 publications

(90 citation statements)

References 24 publications

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“…B6/129 mice are mildly autoimmune and thus the lack of ERα appears to have increased/accelerated development of autoimmune disease. This finding appears in contrast to two recent reports where the ERα KO genotype was bred onto three different murine lupus prone strains, NZB/NZW f1, MRL/ lpr and NZM2410 [84,85]. In each of these three strains, the lack of ERα significantly attenuated disease and Fig.…”

Section: Effect Of Er On Murine Models Of Autoimmunitycontrasting

confidence: 98%

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Estrogen Receptors in Immunity and Autoimmunity

Cunningham

Gilkeson

2010

Clinic Rev Allerg Immunol

250

164

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Due to the female predominance of autoimmune diseases, the role of gender and sex hormones in the immune system is of long-term interest. Estrogen's primary effects are mediated via estrogen receptors alpha and beta (ER α/β) that are expressed on most immune cells. ERs are nuclear hormone receptors that can either directly bind to estrogen response elements in gene promoters or serve as cofactors with other transcription factors (i.e., NFkB/AP1). Cytoplasmic ER and membrane associated ER impact specific kinase signaling pathways. ERs have prominent effects on immune function in both the innate and adaptive immune responses. Genetic deficiency of ERα in murine models of lupus resulted in significantly decreased disease and prolonged survival, while ERβ deficiency had minimal to no effect in autoimmune models. The protective effect of ERα in lupus is multifactoral. In arthritis models, ERα agonists appears to mediate a protective effect. The modulation of ERα function appears to be a potential target for therapy in autoimmunity.

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Section: Effect Of Er On Murine Models Of Autoimmunitycontrasting

confidence: 98%

“…In Fig. 1, the renal pathology scores are presented of NZM2410 mice of different ERα genotypes at 32 weeks of age demonstrating significant protection from disease [85]. ERβ had no effect on disease expression.…”

Section: Effect Of Er On Murine Models Of Autoimmunitymentioning

confidence: 96%

Estrogen Receptors in Immunity and Autoimmunity

Cunningham

Gilkeson

2010

Clinic Rev Allerg Immunol

250

164

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“…Polymorphisms in ERα have been associated with SLE in studies of a small number of both Japanese and Swedish patients (31,32). Recently, it was shown that deletion of ERα in lupus-prone mice leads to reduced disease; the effect seems to be both a reduction in autoantibody production and an independent decrease in inflammation within the kidney itself (33,34). Our interest has been the effect of E2 on B-cell maturation and selection.…”

Section: Introductionmentioning

confidence: 99%

Differential Roles of Estrogen Receptors α and β in Control of B-Cell Maturation and Selection

Hill

Jeganathan

Chinnasamy

et al. 2010

Mol Med

115

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It is clear that estrogen can accelerate and exacerbate disease in some lupus-prone mouse strains. It also appears that estrogen can contribute to disease onset or flare in a subset of patients with lupus. We have previously shown estrogen alters B-cell development to decrease lymphopoiesis and increase the frequency of marginal zone B cells. Furthermore, estrogen diminishes Bcell receptor signaling and allows for the increased survival of high-affinity DNA-reactive B cells. Here, we analyze the contribution of estrogen receptor α or β engagement to the altered B-cell maturation and selection mediated by increased exposure to estrogen. We demonstrate that engagement of either estrogen receptor α or β can alter B-cell maturation, but only engagement of estrogen receptor α is a trigger for autoimmunity. Thus, maturation and selection are regulated differentially by estrogen. These observations have therapeutic implications.

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“…These data imply that ERα has a predominant role in the immunomodulation of lupus in (NZB×NZW) F 1 mice. However, ERα-deficient MRL/lpr female mice have lower proteinuria and renal pathology scores, but no changes in autoantibody levels [17]. Despite the discrepancies in these results, which could be due to the different mouse genetic backgrounds, these data implicate the role of estrogen and ERα in the onset of lupus-like disease.…”

Section: Introductionmentioning

confidence: 73%

“…In NZM female mice, ERα inactivation markedly prolonged life-span, lowered proteinuria, and ameliorated glomerulonephritis, but resulted in higher serum anti-dsDNA antibody levels [17]. In another study, ERα deficiency in (NZB× NZW) F 1 female mice downregulate levels of anti-dsDNA IgG antibodies.…”

Section: Introductionmentioning

confidence: 93%

The Multi-faceted Influences of Estrogen on Lymphocytes: Toward Novel Immuno-interventions Strategies for Autoimmunity Management

Karpuzoglu

Zouali

2009

Clinic Rev Allerg Immunol

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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, interferon-gamma 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 high-affinity 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.

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Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse

Cited by 85 publications

References 24 publications

Estrogen Receptors in Immunity and Autoimmunity

Estrogen Receptors in Immunity and Autoimmunity

Differential Roles of Estrogen Receptors α and β in Control of B-Cell Maturation and Selection

The Multi-faceted Influences of Estrogen on Lymphocytes: Toward Novel Immuno-interventions Strategies for Autoimmunity Management

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