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Event: 1713

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase of anti-DNA antibody from autoreactive B cell

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Increase of autoantibody production
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
B cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
immune system

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Binding to ER-α leading to exacerbation of SLE KeyEvent Yasuharu Otsubo (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
All life stages

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Mixed

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

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

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

[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

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

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.

References

List of the literature that was cited for this KE description. More help
  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.