Aop: 314

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Binding to estrogen receptor (ER)-α in immune cells leading to exacerbation of systemic lupus erythematosus (SLE)

Short name
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Binding to ER-α leading to exacerbation of SLE

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

The names and affiliations of the individual(s)/organisation(s) that created/developed the AOP. More help

Yasuharu Otsubo (1) Takao Ashikaga (1) Tomoki Fukuyama (1) Ken Goto (1) Shinko Hata (1) Shigeru Hisada (1) Shiho Ito (1) Hiroyuki Komatsu (1) Sumie Konishi (1) Tadashi Kosaka (1) Kiyoshi Kushima (1) Shogo Matsumura (1) Takumi Ohishi (1) Junichiro Sugimoto (1) Yasuhiro Yoshida (1)

(1) AOP Working Group, Testing Methodology Committee, The Japanese Society of Immunotoxicology

Corresponding author: Yasuharu Otsubo (otsubo-yasuharu@snbl.co.jp)

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Yasuharu Otsubo   (email point of contact)

Contributors

Users with write access to the AOP page.  Entries in this field are controlled by the Point of Contact. More help
  • Takumi Ohishi
  • Yasuharu Otsubo

Status

Provides users with information concerning how actively the AOP page is being developed, what type of use or input the authors feel comfortable with given the current level of development, and whether it is part of the OECD AOP Development Workplan and has been reviewed and/or endorsed. OECD Status - Tracks the level of review/endorsement the AOP has been subjected to. OECD Project Number - Project number is designated and updated by the OECD. SAAOP Status - Status managed and updated by SAAOP curators. More help
Author status OECD status OECD project SAAOP status
Under development: Not open for comment. Do not cite Under Development 1.73 Included in OECD Work Plan
This AOP was last modified on June 04, 2021 16:36

Revision dates for related pages

Page Revision Date/Time
Binding to estrogen receptor (ER)-α in immune cells August 14, 2020 20:59
Induction of GATA3 expression August 14, 2020 21:16
Increase of Th2 cells producing IL-4 August 14, 2020 21:26
Increase of anti-DNA antibody from autoreactive B cell August 14, 2020 21:57
Exacerbation of systemic lupus erythematosus (SLE) August 14, 2020 22:11
Binding to estrogen receptor (ER)-α leads to Induction of GATA3 expression August 14, 2020 22:17
Induction of GATA3 expression leads to Increase of Th2 cells producing IL-4 August 14, 2020 22:22
Increase of Th2 cells producing IL-4 leads to Increase of autoantibody production August 14, 2020 22:29
Increase of autoantibody production leads to Exacerbation of SLE August 14, 2020 22:35
Bisphenol A December 29, 2019 18:38
17beta-Estradiol November 29, 2016 18:42

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

This AOP describes the linkage between the binding to estrogen receptor (ER) α in immune cells with the exacerbation of the autoimmune disease systemic lupus erythematosus (SLE).

Estrogen receptors (ERs), ERα and ERβ, are a group of proteins that are activated by the steroid hormone estrogen and are widely expressed in most tissue types, including most immune cells.  ERα can be activated with exogenous and endogenous estrogens.  Also, there are numerous xenoestrogens that exist in the environment and imitate estrogen.  Bisphenol A (BPA) is an example of a xenoestrogen that is considered an endocrine disrupting (ED) compound.  SLE is an autoimmune disease characterized by overproduction of a variety of anti-cell nuclear and other pathogenic autoantibodies.  It is characterized by B-cell hyperactivity, polyclonal hypergammaglobulinemia, and immune complex deposition.

Binding to ERα in immune cells by a xenoestrogen or endogenous estrogen marks the molecular initiating event (MIE), which results in induction of GATA3 expression (KE1).  One theory of immune regulation involves homeostasis between T-helper 1 (Th1) and T-helper2 (Th2) activity, however GATA3 expression induce increase of Th2 cells producing cytokine interleukin-4 (IL-4) (KE2), which results in increase of anti-DNA antibody from autoreactive B cell (KE3).  This sequence of pathway means that the immune system skew from a Th1 to a Th2 profile, which results in the adverse outcome (AO) of exacerbated SLE.

We have identified a number of key events along this pathway and determined the key event relationships, based on which we have created an AOP for binding to ERα in immune cells leading to exacerbated SLE.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

It is well recognized that allergic diseases and autoimmune diseases are markedly increased the last several decades.  About the same time, increasing scientific and social attention had been paid to environmentally dispersed chemicals that can enter the body by ingestion or adsorption and that mimic the actions of estrogens.  These chemicals are termed endocrine disruptors (EDs) or environmental estrogens and are found in plastics (bisphenol-A, phthalates), pesticides (DDT, hexachlorobenzene, and dieldrin) and the like.  Some of these estrogenic chemicals have also been shown to influence the immune system.  Endocrine disruptors mimic hormones, block or alter hormone binding to receptors, or alter the metabolism of natural estrogens.  It has been widely noted that females have stronger immune capabilities than males, as evidenced by their better immune responses to a variety of self-antigens and non-self-antigens, or vaccination.  Paradoxically, the stronger immune response comes at a steep price, which is the high incidence of autoimmune diseases in females.  This phenomenon of gender-based immune capability is largely attributed to the effects of sex hormones.  Estrogens regulate the level of serum and uterine IgM, IgA, and IgG, and they augment antibody production to several nonself- antigens and self-antigens. It is possible that endocrine disruptors that mimic estrogenic activity may be involved in the increased incidence of autoimmune diseases such as SLE (Yurino H. 2004, Vaishali RM. 2018).

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

Summary of the AOP

This section is for information that describes the overall AOP. The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
MIE 1710 Binding to estrogen receptor (ER)-α in immune cells Binding to estrogen receptor (ER)-α
KE 1711 Induction of GATA3 expression Induction of GATA3 expression
KE 1712 Increase of Th2 cells producing IL-4 Increase of Th2 cells producing IL-4
KE 1713 Increase of anti-DNA antibody from autoreactive B cell Increase of autoantibody production

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
All life stages Moderate

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens Moderate NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

It has long been appreciated that most autoimmune disorders are characterized by increased prevalence in females, suggesting a potential role for sex hormones (estrogen) in the etiology of autoimmunity.  Females generally exhibit a stronger response to a variety of antigens including ERα ligands than males, which is perhaps one reason that they are more prone to develop autoimmune and allergic diseases such as SLE in greater severity than males.  Therefore, this AOP is applicable to females and is dependent on the levels of estrogen, which means it varies with life stage, and age.

SLE frequently develop and progress in setting in which sympathoadrenomedullary and gonadal hormone levels are changing, e.g., during pregnancy, the postpartum period, or estrogen administration in menopause (Wilder RL. 1999).  Women using oral contraceptives that contain estrogen or undergoing hormone replacement therapy are susceptible to major flare ups and exacerbation of the disease (Whitelaw DA. 2007).

The mechanisms described in this AOP are applicable to rodents and humans, and then the findings of this AOP are not found in any other species.  However, Th2 dominant conditions induced by binding to ERα is considered likely to occur in a variety of mammalian species since ERα are expressed in all vertebrates (Eick GN. 2011).

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

Stressor , MIE and later events:

The NZB/W F1 mouse is the oldest classical model of lupus generated by the F1 hybrid between the NZB and NZW strains.  The administration of the estrogen antagonist tamoxifen diminishes immune complex deposition in the kidneys and increases survival in NZB/W F1 strain.  Renal disease was evaluated by the development of albuminuria and histological changes in the kidney (Wu WM. 2000).  In females of the NZB/NZW F1 strain, disruption of ERα attenuated glomerulonephritis and increased survival and reduced anti-dsDNA antibodies (Bynote KK. 2008, Isenberg DA. 2007) and ovariectomy of NZB/W F1 mice not only delayed onset of the disease but also decreased autoantibody titer  Meanwhile, restoration of estradiol in ovariectomized NZB/W F1 mice reestablished high numbers of autoantibody-producing (DNA-specific) B cells, and thereby suggests a pathogenic role of estrogen in lupus (Daniel P. 2011). Both NZB and NZW display limited autoimmunity, while NZB/W F1 hybrids develop severe lupus-like phenotypes comparable to that of lupus patients.  In NZM female mice, ERα inactivation markedly prolonged life-span, lowered proteinuria, and ameliorated glomerulonephritis but resulted in higher serum anti-dsDNA antibody levels (Svenson JL. 2008).

KE1 and later events:

GATA3 mRNA expression has potential to induced IL-4 production in CD4+T cell (Lambert KC. 2005).  The differentiation of activated CD4+T cells into the T helper type 1 (Th1) or Th2 fate is regulated by cytokines and the transcription factors T-bet and GATA-3.  Early GATA-3 expression, required for Th2 differentiation, was induced by T cell factor 1 (TCF-1) and its cofactor β-catenin, mainly from the proximal Gata3 promoter upstream of exon 1b.  TCF-1 blocked Th1 fate by negatively regulating interferon-γ (IFN-γ) expression independently of β-catenin.  Thus, TCF-1 initiates Th2 differentiation of activated CD4+T cells by promoting GATA-3 expression and suppressing IFN-γ expression.  Higher GATA-3 expression promotes IL-4 production and initiates Th2 differentiation (Qing Y. 2009).  GATA-3 mRNA expression also increased in patients with SLE, compared with the healthy control groups (Zheng H. 2015, Sonia GR. 2012).

KE2 and later events:

Administration of mAb against IL-4 before the onset of lupus was effective in preventing the onset of lupus nephritis (Nakajima A. 1997).

KE3 and later events:

In a study to investigate a novel subpopulation of B-1 cells and its roles in murine lupus, anti-double-stranded DNA (anti-dsDNA) autoantibodies were preferentially secreted by a subpopulation of CD5+ B-1 cells that expressed programmed death ligand 2 (L2pB1 cells) (Xuemei Z. 2009).  A substantial proportion of hybridoma clones generated from L2pB1 cells reacted to dsDNA.  L2pB1 cells are potent antigen-presenting cells and a dramatic increase of circulating L2pB1 cells in lupus-prone BXSB mice correlates with elevated serum titers of anti-dsDNA antibodies (Xuemei Z. 2009).

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

Biological Plausibility

KER KEup-KEdown Plausibility Rationales supported by literatures
KER 1 Binding, Estrogen receptor α in immune cells - Induction, GATA3 expression Weak In immune cells, this event is confirmed indirectly; using artificial STAT6-ER fusion protein.
KER 2 Induction, GATA3 expression - Increase, Th2 cells producing IL-4 Strong XXXX
KER 3 Increase, Th2 cells producing IL-4 - Increase, anti-DNA antibody production from autoreactive B cell Weak XXXX
KER 4 Increase, anti-DNA antibody production from autoreactive B cell - Strong XXXX

Empirical Support

KER Empirical support of KERs
MIE=>KE 1:Binding, Estrogen receptor α in immune cells leads to Induction, GATA3 expression

Empirical support of the MIE => KE1 is weak.

Rationale:

MIE: XXX

KE XX: XXXX
KE 1=> KE 2: Induction, GATA3 expression leads to Increase, Th2 cells producing IL-4

Empirical support of the KE 1=> KE 2 is strong.

Rationale:

KE XX: XXXX

AO: XXXX
KE 2=> KE 3: Increase, Th2 cells producing IL-4 leads to Increase, anti-DNA antibody production from autoreactive B cell

Empirical support of the KE 2=> KE 3 is weak.

Rationale:

KE XX: XXXX

AO: XXXX
KE 3=>AO:  Increase, antibody production from anti-DNA antibody production from autoreactive B cell leads to Exacerbation, systemic lupus erythematosus (SLE)

Empirical support of the KE 3 => AO is strong.

Rationale:

KE XX: XXXX

AO: XXXX

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

KER1:

CD4+T cell expressed GATA3 mRNA cultured with 10-9 M (272.4 pg/mL) concentrations of 17β-estradiol for 12-16 hr (Lambert KC. 2005).  

BPA (0.1 mM) also indirectly induced GATA3 expression of Th cells, and this effect is mediated by dendritic cells exposed to BPA for 24 hr (Guo H. 2010).  Naïve Th cells increased GATA3 expression cultured with dendritic cells exposure of BPA (0.1 mM) for 7 days.

KER2:

Pre-stimulation 16 hr of 17β-estradiol (the concentration 10-9 M = 272.4 pg/mL) increased IL-4 secretion from CD4+T cell (Lambert KC. 2005). 

KER3:

PBMCs or B cells were cultured for 7 days with 17β-estradiol (10–8 mol/L)  and then, IgG and IgM production were increased up to about 150% (PBMC) and 200% (B cells) (Kanda N. 1999).

KER4:

XXXX

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

References

List of the literature that was cited for this AOP. More help
  1. Yurino, H., Ishikawa, S., Sato, T., Akadegawa, K., Ito, T., Ueha, S., Inadera, H. and Matsushima, K. (2004). Endocrine disruptors (environmental estrogens) enhance autoantibody production by B1 cells. Toxicological Sciences 81(1): 139-147.
  2. Vaishali RM. Sex Hormones in Acquired Immunity and Autoimmune Disease. Frontiers in Immunology 2018. 9: 2279; 1-21.
  3. Wilder RL, Elenkov IJ, Hormonal regulation of tumor necrosis factor-alpha, interleukin-12 and interleukin-10 production by activated macrophages. A disease-modifying mechanism in rheumatoid arthritis and systemic lupus erythematosus? Ann N Y Acad Sci. 1999. 22; 876:14-31.
  4. Whitelaw DA, Jessop SJ. Major flares in women with SLE on combined oral contraception. Clin Rheumatol. 2007; 26(12):2163-2165.
  5. Eick GN, Thornton JW. Evolution of steroid receptors from an estrogen-sensitive ancestral receptor. Molecular and cellular endocrinology. 2011; 334: 31-38.
  6. Wu WM, Lin BF, Su YC, et al. (2000). Tamoxifen decreases renal inflammation and alleviates disease severity in autoimmune NZB/W F1 mice. Scandinavian Journal of Immunology 52(4): 393-400.
  7. Bynote, KK, Hackenberg, JM., Korach, K.S., Lubahn, D. B., Lane, P. H. and Gould, K. A. (2008). Estrogen receptor-alpha deficiency attenuates autoimmune disease in (NZB xNZW) F1 mice. Genes and Immunity. 9: 137-152.
  8. Isenberg, DA., Manson, JJ., Ehrenstein, MR. and Rahman, A. (2007). Fifty years of anti-ds DNA antibodies: are we approaching journey’s end? Rheumatology 46:1052-6.
  9. Daniel, P., Allison, S., Yiming, Y., Ying-Yi, Z. and Laurence, M. Murine Models of Systemic Lupus erythematosus. Journal of Biomedicine and Biotechnology 2011: ArticleID 271694
  10. Svenson JL, EuDaly J, Ruiz P, Korach KS, Gilkeson GS. Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse. Clin Immunol. 2008;128(2):259-68.
  11. Lambert KC, Curran EM, et al. Estrogen receptor alpha (ERalpha) deficiency in macrophages results in increased stimulation of CD4+ T cells while 17beta-estradiol acts through ERalpha to increase IL-4 and GATA-3 expression in CD4+ T cells independent of antigen presentation. J Immunol. 2005; 175(9): 5716-23.
  12. Qing Y., Archna S., Sun Y. O., Hyung-Geun M., M Zulfiquer H., Theresa M. S., Karen E. L., Hansen D., Beibei W., Marian L. W., Zhou Z. and Jyoti M. S., T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-γ. Nat Immunol. 2009; 10(9): 992–999.
  13. Zheng H, Guo X, Zhu Y, et al., Distinct role of Tim-3 in systemic lupus erythematosus and clear cell renal cell carcinoma. Int J Clin Exp Med 2015;8(5):7029-7038.
  14. Sonia GR, et al. Altered AKT1 and MAPK1 Gene Expression on Peripheral Blood Mononuclear Cells and Correlation with T-Helper-Transcription Factors in Systemic Lupus Erythematosus Patients. Mediators of Inflammation 2012, Article ID 495934
  15. Nakajima A, Hirose S, Yagita H and Okumura K, Roles of IL-4 and IL-12 in the development of lupus in NZB/W F1 mice. J Immunol 1997; 158 (3) 1466-1472.
  16. Xuemei, Z., Stanley, L., et al. (2009). A Novel Subpopulation of B-1 Cells Is Enriched with Autoreactivity in Normal and Lupus-Prone Mice. Arthritis & Rheumatology 60 (12):3734-3743.
  17. Guo H, Liu T, Ling F, et al. Bisphenol A in combination with TNF-alpha selectively induces Th2 cell-promoting dendritic cells in vitro with an estrogen-like activity. Cell Mol Immunol. 2010;7(3):227-34.
  18. Kanda N. and Tamaki, K. (1999). Estrogen enhances immunoglobulin production by human PBMCs. The Journal of Allergy and Clinical Immunology 103(2): 282-288.