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||KeyEvent|
Key Event Description
In the development of T-cell dependent antibody producing cells, the interaction between IL-4 and its receptor delivers the first signal for switching to IgE. IL-4 produced by Th2 stimulates B-cells to proliferate, to switch immunoglobulin classes, and to differentiate into plasma and memory cells. The engagement of CD40 on B cells by CD154 (CD40L) expressed on T cells and DC provides the second signal required for switching to IgE.
In a study to investigate a novel subpopulation of B-1 cells and its roles in murine lupus, anti-double-stranded DNA (anti-dsDNA) autoantibodies were preferentially secreted by a subpopulation of CD5+ B-1 cells that expressed programmed death ligand 2 (L2pB1 cells) (Xuemei et al. 2009). A substantial proportion of hybridoma clones generated from L2pB1 cells reacted to dsDNA. L2pB1 cells are potent antigen-presenting cells and a dramatic increase of circulating L2pB1 cells in lupus-prone BXSB mice correlates with elevated serum titers of anti-dsDNA antibodies (Xuemei et al. 2009).
Bisphenol-A (BPA) as well as E2 and DES enhanced anti-Br-RBC autoantibody production by B1 cells in vivo. IgM production by B1 cells in the presence of EDs was more prominent on aged BWF1 mice developing lupus nephritis. B1 cells from aged mice exhibited increased expression of ERα mRNA compared to young mice (Yurino H. 2004).
How It Is Measured or Detected
For the detection of anti-DNA antibodies in serum of female NZB/W F1 mice administrated of the estrogen antagonist tamoxifen, enzyme-linked immunosorbent assay (ELISA) was carried out. For the quantitated of total B cells and CD5+B cells expression in spleen and in peritoneal exudates were analyzed with fluorescence activated cell sorting (FACScan) (Wu et al. 2000). For the B cell subset analysis (including immature (transitional T1 and T2) and mature (MZ and follicular)) in BALB/c R4Ag-gamma 2b transgenic mice administrated the tamoxifen were performed with FACScan (Peeva et al. 2005).
In another study, used ERα deficiency in NZB/W F1 mice, autoantibody (anti-dsDNA antibodies) development and concentration was assessed by ELISA using serum isolated from blood collected monthlyvia (Bynote et al. 2008).
Using female NZB/WF1 mice, silastic implants containing the powdered form of endocrine disruptors were placed subcutaneously on the back of ovariectomized mice, and 3 to 4 months blood samples were collected peritoneal. 4 months after implantation, peritoneal lavage cells and splenic cells were obtained from mice. Anti-DNA antibody was measured in ELISA using ssDNA for the culture supernatant of and dsDNA for the serum. To examine the effect of EDs on autoantibody production by B1 cells, a PFC assay using autologous bromelain-treated erythrocytes (Br-RBC) was conducted. To evaluate autoantibody (IgG) production including plaque forming cell (PFC) assay for anti-RBC Ab. It has been reported
that B1 cells produce autoantibody against phosphatidylcholine expressed on bromelain-treated red blood cells (Br-RBC) using PFC assay (Yurino H. 2004).
To examine a direct effect of endocrine disruptors on IgM antibody production by B1 or B2 cells, B1 cells were prepared from peritoneal cells and B2 cells from spleen, B1 or B2 cells were cultured in the presence of endocrine disruptors (E2: 100 nM, DES: 100 nM, BPA: 1 μM) for 4 days. The amount of total IgM and IgM anti-DNA Ab in the culture supernatant was measured by ELISA. Expression level of ERα and ERβ genes in B cells was examined by RT-PCR and quantitative real-time PCR analysis (Yurino H. 2004).
For the investigate the in vitro effects of 17β-estradiol (E2) on spontaneous immunoglobulin production by human PBMCs, PBMCs from healthy human volunteers were cultured with E2. Levels of IgG and IgM and cytokine activity were measured by ELISA. Proliferation was determined by [3H]-thymidine uptake. The cell viability was assessed by a trypan blue exclusion test (Kanda et al. 1999).
Domain of Applicability
- Xuemei, Z., Stanley, L., Chunyan, B., Nicolas, D., Nichol, E. H., Scott, J. S., Joseph, T., Wenda, G. and Thomas, L. R. (2009). A Novel Subpopulation of B-1 Cells Is Enriched with Autoreactivity in Normal and Lupus-Prone Mice. Arthritis & Rheumatology 60 (12):3734-3743
- 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.
- 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.