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|
|Exacerbation of SLE by activation of estrogen receptor||AdverseOutcome|
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 immune complex deposition. Epstein– Barr virus (EBV) has been identified as a possible factor in the development of lupus. Over 100 drugs have been reported to cause drug-induced lupus (DIL), including a number of the newer biologics and antiviral agents. Although the pathogenesis of DIL is not well understood, these drugs may alter gene expression in CD4+ T cells by inhibiting DNA methylation and induce over-expression of lymphocyte function-associated antigen 1, thus promoting autoreactivity. Generally, sunlight is the most obvious environmental factor that may exacerbate SLE. High estrogen levels and BPA-induced ER activation skewed T cells toward a Th2 phenotype, thereby inducing hyperactivity by B-cells, which leads to exacerbation of SLE. T cell dysfunction is a characteristic of SLE, which is also associated with high levels of autoantibodies (Crispin et al. 2010).
How It Is Measured or Detected
Most of the mouse models of lupus produce autoantibodies and develop immune complex glomerulonephritis. For the disease onset, mice can monitor by proteinuria levels, body weights, blood urea nitrogen and appearance over time. Additionally, serum levels of anti-dsDNA, anti-glomerular antigens (GA), total IgG can measure by ELISA. (Gabriela et al., 2019, Yurino et. al.,2004, John et. al.,2008, Wang et. al.1996).
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 et al., 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 et al., 2014). The incidence of SLE is markedly increased in females of child-bearing age (Grainne et al., 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 systemic lupus erythematosus (SLE) tend to worsen during pregnancy (Doria et al., 2006).
Regulatory Significance of the Adverse Outcome
- Crispín, J. C., Stamatis-Nick, C. L., Katalin Kis-Toth1, Linda A. Lieberman1, Vasileios C. Kyttaris1, Yuang-Taung Juang1, and George C. Tsokos1. (2010) Pathogenesis of human systemic lupus erythematosus: recent advance. Trends in Molecular Medicine 16(2): 47-57.
- Wu, W.-M., Lin, B.-F., Su, Y.-C., Suen, J.-L. and Chiang, B.-L. (2000). Tamoxifen decreases renal inflammation and alleviates disease severity in autoimmune NZB/W F1 mice. Scandinavian Journal of Immunology 52(4): 393-400.
- 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
- Buyon JP. Oral contraceptives in women with systemic lupus erythematosus. Ann Med Interne (Paris) (1996) 147(4):259–264.
- Buyon JP. Hormone replacement therapy in postmenopausal women with systemic lupus erythematosus. J Am Med Womens Assoc (1998) 53(1):13–17.
- Gabriela, T., Yessia, H., Maria, R. B. and Mario, R. (2019), A Spontaneous Mouse Model of Lupus: Physiology and Therapy. IntechOpen Limited: 1-24
- 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: 139–147.
- 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.
- George, B., Ricard, C. and Dimitrios, T. B. (2012). Systemic Lupus Erythematosus: Pathogenesis and Clinical Feature. EULAR Textbook on Rheumatic Diseases