API

Event: 1713

Key Event Title

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Increase of anti-DNA antibody from autoreactive B cell

Short name

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Increase of autoantibody production

Biological Context

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Level of Biological Organization
Cellular

Cell term

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Cell term
B cell


Organ term

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Organ term
immune system


Key Event Components

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Binding to ER-α leading to exacerbation of SLE KeyEvent

Stressors

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Taxonomic Applicability

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Life Stages

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Life stage Evidence
All life stages

Sex Applicability

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Term Evidence
Mixed

Key Event Description

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The receptor for IL-4 is IL-4Rα, which expresses in B cells.  IL-4 produced by Th2 stimulates B-cells to proliferate, to switch immunoglobulin classes, and to differentiate into plasma and memory cells.  Anti-DNA antibodies are produced from autoreactive B cell.  In murine models, addition of estrogen or prolactin can lead to an autoimmune phenotype with an increase in mature high-affinity autoreactive B cells (Daniel P. 2011).


How It Is Measured or Detected

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[in vivo assay]

NZB/W F1 mice are used as model of SLE (Wu WM. 2000).  BALB/c R4Ag-gamma 2b transgenic mice are used for evaluation of autoreactive B cells (Peeva E. 2005).  These mice are administrated of the estrogen antagonist tamoxifen.  Disruption of ERα (Bynote KK. 2008, Isenberg DA. 2007) and ovariectomy of NZB/W F1 mice are used as model of estrogen dysfunction (Daniel P. 2011).  Survival and glomerulonephritis of these animals were evaluated.

Using female NZB/WF1 mice, silastic implants containing the powdered form of endocrine disruptors were placed subcutaneously on the back of ovariectomized mice. The implants were left in situ for 3 to 4 months and blood samples were collected periodically, and anti-DNA antibody was measured in ELISA using dsDNA (Yurino H. 2004).

 

[in vitro assay]

The amounts of anti-dsDNA, anti-glomerular antigens (GA), total IgG and IgM in the culture supernatants were measured by ELISA (Kanda N. 1999, Wu WM. 2000, Yurino H. 2004, Gabriela T. 2019, John LS. 2008, Wang Y.1996).  Proliferative responses PBMCs or B cells were measured by [3H]-thymidine uptake, and the cell viability was assessed by a trypan blue exclusion test (Kanda N. 1999).  Fluorescence activated cell sorting (FACScan) was used for the quantitated of total B cells and CD5+B cells expression in spleen and in peritoneal exudates or B cell subset analysis (Wu WM. 2000, Peeva E. 2005).  Plaque forming cell (PFC) assay using autologous bromelain-treated erythrocytes (Br-RBC) was conducted to examine the effect of EDs on autoantibody production by B1 cells (Yurino H. 2004).

Enzyme-linked immunospot (ELISPOT) analysis confirmed a significant increase in the number of high-affinity anti-DNA antibody-secreting B cells in the spleens of E2-treated mice (Bynoe MS. 2000).


Domain of Applicability

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Antibody production from B cells is common in humans, rodents, and other mammalian species.  Since almost experiment are performed in female, it is considered that this event in SLE are noted more frequently in females.


Evidence for Perturbation by Stressor



17beta-Estradiol

BPA as well as E2 and diethylstilbestrol (DES) enhanced anti-Br-RBC autoantibody production by B1 cells in vivo.  IgM production by B1 cells in the presence of ED was more prominent on aged BWF1 mice developing lupus nephritis. (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 (Yurino H. 2004). 

Direct exposure of PBMCs from SLE patients to E2 induces secretion of anti-dsDNA antibodies and enhances the secretion of Igs, in particular IgG (Kanda N. 1999).

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).

Hybridomas generated from E2-treated mice express high-affinity, unmutated anti-DNA antibodies, indicating that naı¨ve B cells that are normally deleted or anergized are rescued from tolerance induction (Bynoe MS. 2000).  E2 treatment resulted in a rise in anti-DNA serum titers and in Ig deposition in renal glomeruli (Bynoe MS. 2000).


Bisphenol A

BPA as well as E2 and diethylstilbestrol (DES) enhanced anti-Br-RBC autoantibody production by B1 cells in vivo.  IgM production by B1 cells in the presence of ED was more prominent on aged BWF1 mice developing lupus nephritis. (Yurino H. 2004). 

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 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 (Yurino H. 2004). 


Diethylstilbestrol

BPA as well as E2 and diethylstilbestrol (DES) enhanced anti-Br-RBC autoantibody production by B1 cells in vivo.  IgM production by B1 cells in the presence of ED was more prominent on aged BWF1 mice developing lupus nephritis. (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 (Yurino H. 2004). 

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).


References

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  1. 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
  2. Wu WM., Lin, B.-F., Su, Y.-C., Suen, J.-L. 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.
  3. 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.
  4. Bynote, KK., 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.
  5. Isenberg, DA., Manson, JJ., Ehrenstein, MR. and Rahman, A. (2007). Fifty years of anti-ds DNA antibodies: are we approaching journey’s end? Rheumatology 46:1052-6.
  6. 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.
  7. Kanda N. and Tamaki, K. (1999). Estrogen enhances immunoglobulin production by human PBMCs. The Journal of Allergy and Clinical Immunology 103(2): 282-288.
  8. 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.
  9. Peeva E, Grimaldi C, Spatz L, Diamond B. Bromocriptine restores tolerance in estrogen-treated mice. J Clin Invest. 2000;106(11):1373-9.
  10. Gabriela, T., Yessia, H., Maria, R. B. and Mario, R. (2019), A Spontaneous Mouse Model of Lupus: Physiology and Therapy. IntechOpen Limited: 1-24.
  11. 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.
  12. 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.
  13. Bynoe MS, Grimaldi CM, Diamond B. Estrogen up-regulates Bcl-2 and blocks tolerance induction of naı¨ve B cells. PNAS 2000; 97(6):2703-8.