Upstream eventIncrease of autoantibody production
Exacerbation of SLE
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Activation of estrogen receptor in immune cells leading to exacerbation of systemic lupus erythematosus||adjacent||Moderate||Moderate|
Life Stage Applicability
Key Event Relationship Description
SLE patients appear to produce significant amounts of the anti-double-stranded DNA (anti-dsDNA) autoantibodies that cause the disease. Activation of autoantibody-producing B cells only serves to exacerbate that condition.
Evidence Supporting this KER
SLE has been seen to flare up during pregnancy (Petri et al., 1991). 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 (Carlsten H. 1992).
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. In both (NZB×NZW) F1 and MRL/lpr mice, estrogen treatment exacerbates the lupus disease, with augmented levels of autoantibodies against dsDNA and phospholipids as well as formation of circulating immune complexes (Grimaldi CM. 2002, Peeva E. 2000).
Murine lupus models such as NZB×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 (Zhang DH. 1997, Pai SY. 2004). All of these species of mice develop immunoglobulin G (IgG) 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. The administration of the estrogen antagonist tamoxifen diminishes immune complex deposition in the kidneys and increases survival. Renal disease was evaluated by the development of albuminuria and histological changes in the kidney (Wu et al. 2000).
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).
Estrogen enhances anti-double-stranded DNA antibody and IgG, IgM production by PBMCs. PBMCs or B cells were cultured for 7 days with E2 (10–8 mol/L). Theamounts of total IgG and IgM in the supernatants were measured by ELISA. Proliferative responses PBMCs or B cells were measured by [3H]-thymidine (Kanda N. 1999).
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
When estrogen levels are low, T cell expansion shift toward a Th1 phenotype that produces IL-12, TNF-α, and IFN-γ. This response results in cellular immunity inducing inflammation and exacerbating cellular type autoimmune disease such as multiple sclerosis (MS) and EAE rather than SLE.
The effects of estrogen receptor signaling on T cells also appear to be dose dependent (Cunningham and Gilkeson, 2011). Treatment with low serum levels (60–100 pg/mL or 0.26–0.43 nM) of estradiol increased Th1 T-cell development in vitro by acting through an ERα mediated mechanism (Maret et al. 2003). Treatment with low doses of estrogen (25 pg/ml or 0.1 nM) ameliorated disease, while high dose levels (>1000 pg/ml or 4.3 nM), which mimic pregnancy levels, prevented EAE onset and polarized T-cells to a Th2 phenotype in the EAE. (Bebo et al. 2001). High levels of estrogen during pregnancy have been reported to ameliorate T cell mediated diseases such as multiple sclerosis (Korn-Lubetzki et al. 1984).
Known modulating factors
The Th1/Th2 shift is one of the most important immunologic changes during the menstrual cycle and gestation. Immune activity shifts across the menstrual cycle, with higher follicular-phase Th1 cell activity and higher luteal-phase Th2 cell activity (Tierney et al. 2015). This 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 (Doria, A., et al. 2006).
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Petri, M. Howard, D. and Repke, J. (1991). Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience. Arthritis & Rheumatology. 34(12): 1538-1545.
- Estrogen accelerates immune complex glomerulonephritis but ameliorates T cell-mediated vasculitis and sialadenitis in autoimmune MRL lpr/lpr mice Estrogen alters thresholds for B cell apoptosis and activation.
- 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.
- 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.
- 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.
- 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.
- 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.
- Kanda N. and Tamaki, K. (1999). Estrogen enhances immunoglobulin production by human PBMCs. The Journal of Allergy and Clinical Immunology 103(2): 282-288.
- 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.
- Korn-Lubetzki, I., Kahana, E., Cooper, G. and Abramsky, O. (1984). Activity of multiple sclerosis during pregnancy and puerperium. Annals of Neurology 16(2): 229-231
- Tierney, K. L., Julia, R. H. and Gregory, E. D. (2015). Sexual activity modulates shifts in Th1/Th2 cytokine profile across the menstrual cycle: An observational study. Fertility and Sterility 104 (6): 1513–1521.
- 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.