Upstream eventOverproduction of IL-4
Increase of autoantibody production
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
The receptor for IL-4 is IL-4Rα, which expresses in B cells. Th2 cells secrete cytokines IL-4 that upregulate antibody formation via B cells. Naive B cells that have not yet encountered antigen express immunoglobulin M and immunoglobulin D on their surface. During an immune response, B cells can express different immunoglobulin heavy chain isotypes sharing the same variable–diversity–joining (VDJ) region. This isotype-switching recombination allows a B-cell clone to produce antibodies with the same specificity for antigens but with different effector functions. To switch to a particular isotype, a B cell needs two signals, one cytokine-dependent and the other CD40-dependent. In B cells, estrogen-mediated events could occur through the CD40/CD40L costimulatory pathway. Estrogen can also enhance differentiation of immature DCs into mature functional DCs and regulate the expression of cytokines and chemokines such as IL-6, IL-10, CXCL8, and CCL2 (Liu Y. 2009, Guo H. 2010). This increase the number of B cells producing autoantibodies.
Evidence Supporting this KER
Lack of ERα, in either male or female mice, did not increase B cell precursors (Smithson G. 1998).
Estrogen upregulates CD40L on B and T cells from SLE patients (Desai-Mehta A. 1996, Li X. 2006), and CD40L expression on B cells is increased two-fold in SLE patients (Díaz-Alderete A. 2004). Whereas anti-CD40L antibodies downregulate CD86 expression on normal and SLE B lymphocytes, blockade of CD86 only diminishes anti-DNA antibody production by SLE B cells (Nagafuchi H. 2003). Moreover, mice overexpressing CD40L develop a lupus-like disease with high levels of antibodies to nuclear antigens, DNA, and histones, as well as glomerulonephritis (Higuchi T. 2002). It is possible that this estrogen modulated elevation in CD40/CD40L crosstalk as well as stimulation via CD86 synergizes in the exacerbation of SLE by promoting autoantibody secretion as well as activation of T cells (Karpuzoglu E. 2011). In a murine model of SLE, BPA increased the number of B cells producing autoantibodies, and IgM antibody secretion by B1 cells was augmented (Yurino et al. 2004).
Direct exposure of PBMCs from SLE patients to 17β-estradiol induces secretion of anti-dsDNA antibodies and enhances the secretion of Igs, in particular IgG (Kanda et al. 1999).
CD23 on M12.4.1 cells, transfected with the luciferase reporter gene by inserting three copies of human STAT6 binding site oligonucleotide, is up-regulated with treatment1 μM 4HT for 16 hr (Kamogawa et al. 1998).
The production of IgA and IgG2a was increased in B cells from mice fed BPA (Goto et al. 2007). Similarly, in mice exposed prenatally to BPA and then immunized in adulthood with hen egg lysozyme (HEL), the anti-HEL IgG2a measured three weeks later was elevated (Yoshino et al. 2004). These Ig can be measured by ELISA. The administration of the estrogen antagonist tamoxifen diminishes anti-DNA antibody levels by ELISA as well as decreases percentages of total B cells and CD5+ B cells by FCM (Wu et al. 2000). Tamoxifen Blocks Estrogen-Induced B Cell Maturation but not survival (Peeva et al. 2005). ERα deficiency in (NZB×NZW) F1 female mice downregulated levels of anti-dsDNA IgG antibodies, and the absence of ERα In (NZB×NZW) F1 males resulted in decreased anti-dsDNA antibodies (Bynote et al. 2008).
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).
The Th1/Th2 shift is one of the most important immunologic changes during gestation. 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 et al. 2006).
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- Liu Y, Shi J, Ding B. Activation of peroxisome proliferator-activated receptor-gamma potentiates pro-inflammatory cytokine production, and adrenal and somatotropic changes of weaned pigs after Escherichia coli lipopolysaccharide challenge. Innate Immun. 2009;15(3):169-78.
- 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.
- Smithson G, Couse JF, Lubahn DB, Korach KS, Kincade PW. The role of estrogen receptors and androgen receptors in sex steroid regulation of B lymphopoiesis. J Immunol. 1998;161(1):27-34.
- Desai-Mehta A, Lu L, Ramsey-Goldman R, Datta SK. Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest. 1996. 1;97(9):2063-73.
- Li X, Rider V, Kimler BF, Abdou NI. Estrogen does not regulate CD154 mRNA stability in systemic lupus erythematosus T cells. Lupus. 2006;15(12):852-7.
- Díaz-Alderete A, Crispin JC, Vargas-Rojas MI, Alcocer-Varela J. IL-10 production in B cells is confined to CD154+ cells in patients with systemic lupus erythematosus. J Autoimmun. 2004;23(4):379-83.
- Nagafuchi H, Shimoyama Y, Suzuki N, et al. Preferential expression of B7.2 (CD86), but not B7.1 (CD80), on B cells induced by CD40/CD40L interaction is essential for anti-DNA autoantibody production in patients with systemic lupus erythematosus. Clin Exp Rheumatol. 2003;21(1):71-7.
- Higuchi T, Aiba Y, Tsubata T. Cutting Edge: ectopic expression of CD40 ligand on B cells induces lupus-like autoimmune disease. J Immunol. 2002. 1;168(1):9-12.
- Karpuzoglu E, Zouali M. The Multi-faceted Influences of Estrogen on Lymphocytes: Toward Novel Immuno-interventions Strategies for Autoimmunity Management. Clin Rev Allergy Immunol. 2011;40(1):16-26.
- Wu WM., 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.
- Peeva, E., Venkatesh, J. and Diamond, B. (2005). Tamoxifen Blocks Estrogen-Induced B Cell Maturation but Not Survival. The Journal of Immunology 175: 1415-1423.
- Bynote, K. K., Hackenberg, J. M., 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.
- Kanda N. and Tamaki, K. (1999). Estrogen enhances immunoglobulin production by human PBMCs. The Journal of Allergy and Clinical Immunology 103(2): 282-288.
- 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.
- Goto, M., Takano-Ishikawa, Y., Ono, H., Yoshida, M., Yamaki, K. and Shinmoto, H. (2007). Orally Administered Bisphenol A Disturbed Antigen Specific Immunoresponses in the Naive Condition. Bioscience, Biotechnology, and Biochemistry 71(9): 2136–2143.
- Yoshino S., Yamaki, K., Li, X., Sai, T., Yanagisawa, R., Takano, H., Taneda, S., Hayashi, H. and Mori, Y. (2004). Prenatal exposure to bisphenol A up-regulates immune responses, including T helper 1 and T helper 2 responses, in mice. Immunology 112: 489–495.
- Melissa, C. and Gary, G (2011). Estrogen Receptors in Immunity and Autoimmunity. Clinical Reviews in Allergy & Immunology 40: 66–7
- 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.
- 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
- Kamogawa, Y., Lee, H.J., Johnston, J.A., McMahon, M., O’Garra, A., and Arai, N. (1998). Cutting Edge: A conditionally active form of STAT6 can mimic certain effects of IL-4. J. Immunol. 161, 1074–1077.