Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Binding to ER-α leading to exacerbation of SLE||AdverseOutcome|
|All life stages|
Key Event Description
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 glomerulonephritis as immune complex deposition. Once SLE is suspected, the initial evaluation should include an antinuclear antibody (ANA) test. This is a highly sensitive test, with positive results in about 94% of patients with SLE. However, it also has low specificity, and may be positive in healthy patients. If ANA results show a 1:40 titer or higher, more specific tests should be performed, including measurement of anti–double-stranded DNA (anti-dsDNA), anti-Smith, anti-RNP, anticardiolipin, beta-2 glycoprotein antibodies and lupus anticoagulant; elevated levels of one or more of these biomarkers increase the likelihood of SLE (Nguyet-Cam VL. 2016). In the Systemic Lupus International Collaborating Clinics 2012 classification for SLE, biopsy-proven lupus nephritis plus positive ANA or anti-dsDNA is sufficient to fulfil SLE classification criteria (Bernard T. 2017). SLE is the prototypic multisystem autoimmune disorder with a broad spectrum of clinical presentations encompassing almost all organs and tissues including skin, kidney, heart, lungs, and joints. The pathogenesis of SLE includes both genetic and environmental components with female sex strongly influencing pathogenesis. These factors lead to an irreversible break in immunological tolerance manifested by immune responses against endogenous nuclear antigens (Daniel P. 2011).
It has been determined in a murine model of SLE that ERα is required for disease progression and that ERα deficiency impedes the course of the disease (Bynote KK. 2008). There is increased ERα mRNA expression in PBMCs of SLE patients (Inui A. 2007). It is considered that MIE affect later events and result in SLE.
How It Is Measured or Detected
[in vivo assay]
Murine lupus models such as New Zealand Black (NZB)×New Zealand White (NZW) F1 (NZB/W F1), NZB.H-2bm12, NZB×SWR F1 (SNF1), MRL.lpr/lpr, and BXSB mice have led to a better understanding of the pathogenic mechanisms of lupus. All of these species of mice develop anti-dsDNA antibody, which is a characteristic of lupus, and die of uremia in early life. Among these murine lupus models, the natural course of NZB/W F1 mice is closer to human lupus than MRL.lpr/lpr and BXSB mice (Zhang DH. 1997, Pai SY. 2004, Daniel P. 2011).
For the disease onset, mice can monitor by proteinuria levels, body weights, blood urea nitrogen and appearance over time. (Gabriela T. 2019, John LS. 2008, Wang Y.1996). The major cause of death in the NZB/W F1 female is chronic glomerulonephritis with heavy mesangial deposits, tubular cast formation, proliferation of glomerular cells, prominent crescent formation, and a significant periglomerular and interstitial monocytic infiltrate. Extraglomerular renal deposits of IgG2a and C3 are present in the peritubular tissue and arterioles, and increase in frequency with age. Histological alterations in the kidney were assessed by Hematoxylin Eosin (H&E) and Periodic acid-Schiff (PAS) staining, expression of IgG and C3 was detected by immunohistochemistry (Gabriela T. 2019, Brian S. 1978).
To examine the relationship between oral contraceptive (OC) use and the development of SLE, analyzed data (1976 - 1990) from the Nurses’ Health Study cohort. The questionnaire used to assemble biennially the group sought information on a variety of health conditions and exposures, such as use of OCs, use of post-menopausal hormones (PMH), current and past cigarette smoking habits and other health practices. Incidence of SLE was defined by; 1) strict American College of Rheumatology (ACR) classification criteria (> or = 4 ACR criteria), 2) > or = 4 ACR criteria and any physician's diagnosis, 3) > or = 4 ACR criteria and diagnosis by an ACR-certified rheumatologist, 4) > or = 3 ACR criteria, or 5) diagnosis by a physician even if the patient did not meet the ACR criteria. (Bertsias G. 2012, Sanchez-Guerrero J.1997).
Typical clinical symptoms include combinations of renal disease, swollen joints, skin rash, hematologic disorders, respiratory, and neurologic dysfunction.
Domain of Applicability
Exacerbation of SLE is common in humans and rodents, and is considered likely to occur in other animal species, as well. SLE is an autoimmune disease that occurs primarily in women (9:1 compared to men) (Rider V. 2001). SLE is an autoimmune disease that affects predominantly women during reproductive years, and its evolution is altered by hormonal events such as menses, menopause, and especially pregnancy (Luis JJ. 2014). The incidence of SLE is markedly increased in females of child-bearing age (Grainne M. 2013). Th1/Th2 shift is one of the most important immunologic changes during gestation. It is due to the progressive increase of estrogens, which reach peak level in the third trimester of pregnancy. At these high levels, estrogens suppress the Th1-mediated responses and stimulate Th2-mediated immunologic responses. For this reason, Th1-mediated diseases, such as rheumatoid arthritis, tend to improve, while Th2-mediated diseases, such as SLE tend to worsen during pregnancy (Doria A. 2006).
Female MRL/lpr mice that developed lymphadenopathy and a lupus-like disease also exhibited a 50% higher mortality rate than males at 5 months of age. In (NZB×NZW) F1 mice too, females develop signs of SLE several months before males, with severe autoimmune hemolytic anemia, glomerulonephritis, and autoantibodies to single-stranded DNA, doublestranded DNA, and histones (Carlsten H. 1992).
The effects of estrogen receptor signaling on T cells also appear to be dose dependent (Melissa, and Gary 2011). Low serum levels (60‑100 pg/mL or 0.26‑0.43 nM) of estradiol have been shown to increase Th1 T-cell development in vitro through an ERα mediated mechanism (Maret A. 2003). In contrast of SLE exacerbated by Th2, treatment with low doses of estrogen (25 pg/ml or 0.1 nM) ameliorated autoimmune diseases (multiple sclerosis; MS, rheumatoid arthritis; RA, and experimental autoimmune encephalomyelitis; EAE, etc.) caused by Th1, while high doses (>1000 pg/ml or 4.3 nM), which mimic pregnancy levels, prevented EAE onset polarized T-cells to a Th2 phenotype in the EAE model (Bebo BF. 2001).
Evidence for Perturbation by Stressor
The NZB/W F1 mouse is the oldest classical model of lupus generated by the F1 hybrid between the NZB and NZW strains. In both NZB/W F1 and MRL/lpr mice, estrogen treatment exacerbates the lupus disease (Grimaldi CM. 2002, Peeva E. 2000). In postmenopausal women there was an increase in number of mild flares in women receiving estrogen supplementation suggesting that the addition of estrogen to a low estrogen state enhances flare rate (Buyon JP. 1998).
Regulatory Significance of the Adverse Outcome
There are concerns about the increase in autoimmune diseases caused by estrogen-like substances, and its accurate in vitro toxicity assessment system is required in international regulations. The OECD has published a revised version of the guidance document on standardized test guidelines for evaluating ED (OECD. 2019).
- Nguyet-Cam Vu Lam, Maria V. Ghetu and Marzena L. BIENIEK. Systemic Lupus Erythematosus: Primary Care Approach to Diagnosis and Management. American Family Physician, 2016; 94 (4): 284-294.
- Bernard Thong and Nancy J. Olsen. Systemic lupus erythematosus diagnosis and management. Rheumatology 2017; 56: i3-i13.
- 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
- 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.
- Inui A, Ogasawara H, Ogawa H, et al. Estrogen receptor expression by peripheral blood mononuclear cells of patients with systemic lupus erythematosus. Clin Rheumatol. 2007;26(10):1675-8.
- Zhang DH, Cohn L, Ray P, Bottomly K, Ray A. Transcription factor GATA-3 is differentially expressed in murine Th1 and Th2 cells and controls Th2-specific expression of the interleukin-5 gene. J Biol Chem. 1997. 22;272(34):21597-603.
- Pai SY, Truitt ML, Ho IC. GATA-3 deficiency abrogates the development and maintenance of T helper type 2 cells. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):1993-8.
- Gabriela, T., Yessia, H., Maria, R. B. and Mario, R. (2019), A Spontaneous Mouse Model of Lupus: Physiology and Therapy. IntechOpen Limited: 1-24.
- John, L. S., Jackie, E., Phil, R., Kenneth, S. K. and Gary, S. G. (2008), Impact of estrogen receptor deficiency on disease expression in the NZM2410 lupus prone mouse. Clin Immunol. 128(2): 259-268.
- Wang, Y., Hu, Q., Madri, J. A., Rollins, S.A., Chodera, A, and Matis, L. A. (1996), Amelioration of lupus-like autoimmune disease in NZB/W F1 mice after treatment with a blocking monoclonal antibody specific for complement component C5. Proc Natl Acad Sci U S A. 93(16):8563-8568.
- Brian S. Andrews, Robert A. Eisenberg, Argyrios N. Theofilopoulos, S Izui, Curtis B. Wilson, Patricia J. McConahey, Edwin D. Murphy, John B. Roths and Frank J. Dixon. Spontaneous Murine Lupus-Like Syndromes. Clinical and Immunopathological Manifestations in Several Strains. J. EXP. Med. 1978; 148(5):1198-215
- Bertsias G, Ricard Cervera and Dimitrios T. Boumpas. Systemic Lupus Erythematosus: Pathogenesis and Clinical Features. 20_Eular_Fpp.indd. 2012; 476-505.
- Sanchez-Guerrero J. Karlson EW. Liang MH. Hunter DJ,. Speizer F. E, and Colditz. G. A. Past Use of Oral Contraceptives and the Risk of Developing Systemic Lupus Erythematosus. Arthritis Rheum. 1997; 40 (5): 804-808.
- Rider, V. and Abdou, N. I. (2001). Gender differences in autoimmunity: molecular basis for estrogen effects in systemic lupus erythematosus. International Immunopharmacology 1(6): 1009-1024.
- Luis, J. J., Gabriela, M., Pilar, C.-D., Carmen, N., Olga V.-L. and Miguel., A. S. (2014). Risk factors of systemic lupus erythematosus ﬂares during pregnancy. Immunologic Research 60: 184-192
- Grainne, M. and David, I. (2013). Effect of gender on clinical presentation in systemic lupus erythematosus. Rheumatology 52: 2108-2115
- Doria, A., Iaccarino, L., Sarzi-Puttini, P., Ghirardello, A., Zampieri, S., Arienti, S., Cutolo, M. and Todesco, S. (2006). Estrogens in pregnancy and systemic lupus erythematosus. Annals of the New York Academy of Sciences 1069: 247-256.
- Carlsten H, Nilsson N, Tarkowski A, et al. Estrogen accelerates immune complex glomerulonephritis but ameliorates T cell-mediated vasculitis and sialadenitis in autoimmune MRL lpr/lpr mice. Cell Immunol. 1992;144(1):190-202.
- Melissa, C and Gary, G (2011). Estrogen Receptors in Immunity and Autoimmunity. Clinical Reviews in Allergy & Immunology 40: 66-73.
- Maret, A., Coudert, J. D., Garidou, L., Foucras, G., Gourdy, P., Krust, A., Dupont, S., Chambon, P., Druet, P., Bayard, F. and Guéry, J. C. (2003). Estradiol enhances primary antigen-specific CD4 T cell responses and Th1 development in vivo. Essential role of estrogen receptor α expression in hematopoietic cells. The European Journal of Immunology 33: 512-521.
- Bebo, B. F. Jr., Fyfe-Johnson, A., Adlard, K., Beam, A. G., Vandenbark, A. A.and Offner, H. Low-Dose Estrogen Therapy Ameliorates Experimental Autoimmune Encephalomyelitis in Two Different Inbred Mouse Strains. (2001). The Journal of Immunology. 166: 2080-2089.
- Grimaldi CM, Cleary J, Dagtas AS, Moussai D, Diamond B. Estrogen alters thresholds for B cell apoptosis and activation. J Clin Invest. 2002;109(12):1625-33.
- Peeva E, Grimaldi C, Spatz L, Diamond B. Bromocriptine restores tolerance in estrogen-treated mice. J Clin Invest. 2000;106(11):1373-9.
- Buyon JP. Hormone replacement therapy in postmenopausal women with systemic lupus erythematosus. J Am Med Womens Assoc (1998) 53(1):13-17.
- OECD Series on Testing and Assessment [Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption. 2019].