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Key Event Title
Exacerbation of systemic lupus erythematosus (SLE)
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
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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).
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).
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- OECD Series on Testing and Assessment [Revised Guidance Document 150 on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption. 2019].