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Increase of Th2 cells producing IL-4 leads to Increase of autoantibody production
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Binding to estrogen receptor (ER)-α in immune cells leading to exacerbation of systemic lupus erythematosus (SLE)||adjacent||Moderate||Moderate||Yasuharu Otsubo (send email)||Under development: Not open for comment. Do not cite||Under Development|
Life Stage Applicability
Key Event Relationship Description
During process of B cell maturation, the autoreactive B cell which has high-affinity for DNA are normally silenced by anergy, and activated by stimulation with antigen independent CD40 ligand (CD154) or IL-4 from Th2 cells. The receptor for IL-4 is IL-4Rα, which expresses in B cells. In the development of T-cell dependent antibody producing cells, the interaction between IL-4 and its receptor stimulates B-cells to mature (proliferate, switch immunoglobulin classes). As a result, production of anti-DNA antibody from activated autoreactive B cells in increased.
Evidence Supporting this KER
Lack of ERα, in either male or female mice, did not increase B cell precursors (Smithson G. 1998). Restoration of estradiol in ovariectomized NZB/W F1 mice reestablished high numbers of autoantibody-producing (DNA-specific) B cells, and thereby suggests a pathogenic role of estrogen in lupus (Daniel P. 2011).
Anergic B cells, dsDNA-specific models, can be stimulated by IL-4 specific antibody in vitro, suggesting that they are capable of responding to T-cell-derived signals (Acevedo-Suarez CA. 2005, Noorchashm H. 1999, Mandik-Nayak L. 2000, Eris JM. 1994).
Transfer of either IL-4-stimulated splenocytes from 5-mo-old NZB/W F1 mice into NZB/W F1 mice of the same age enhanced the production of IgG anti-dsDNA Ab. Consistently, administration of mAb against IL-4 before the onset of lupus was effective in preventing the onset of lupus nephritis (Nakajima A. 1997).
Uncertainties and Inconsistencies
Estrogen upregulates CD40L (CD154) on T cells from SLE patients (Desai-Mehta A. 1996, Li X. 2006). 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). Activation of autoreactive B cell may be involved in stimulation not only IL-4, but also CD40 ligand (CD154) of Th2 cell as well as the other immune cells.
B1 cells from aged mice exhibited increased expression of ERα mRNA compared to young mice (Yurino H. 2004). Since the ER of B cell is also expressed, there may be a direct route that does not go through Th2.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
- 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.
- 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
- Acevedo-Suarez CA, Hulbert C, Woodward EJ, Thomas JW. Uncoupling of anergy from developmental arrest in anti-insulin B cells supports the development of autoimmune diabetes. J. Immunol. 2005; 174:827-833.
- Noorchashm H, et al. Characterization of anergic anti-DNA B cells: B cell anergy is a T cellindependent and potentially reversible process. Int. Immunol. 1999; 11:765-776.
- Mandik-Nayak L, et al. Functional consequences of the developmental arrest and follicular exclusion of anti-double-stranded DNA B cells. J. Immunol. 2000; 164:1161-1168.
- Eris JM, et al. Anergic self-reactive B cells present self-antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions. Proc. Natl Acad. Sci. USA. 1994; 91:4392-4396.
- Nakajima A, Hirose S, Yagita H and Okumura K, Roles of IL-4 and IL-12 in the development of lupus in NZB/W F1 mice. J Immunol 1997; 158 (3) 1466-1472.
- 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, KK. Hackenberg, JM., Korach, KS, Lubahn, DB., Lane, PH.and Gould, KA. (2008). Estrogen receptor-alpha deficiency attenuates autoimmune disease in (NZB xNZW) F1 mice. Genes and Immunity. 9: 137-152.
- 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.
- 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.
- 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.