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Relationship: 2023

Title

The title of the KER should clearly define the two KEs being considered and the sequential relationship between them (i.e., which is upstream and which is downstream). Consequently all KER titles take the form “upstream KE leads to downstream KE”.  More help

Increase of autoantibody production leads to Exacerbation of SLE

Upstream event
Upstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help
Downstream event
Downstream event in the Key Event Relationship. On the KER page, clicking on the Event name under Upstream Relationship will bring the user to that individual KE page. More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

This table is automatically generated upon addition of a KER to an AOP. All of the AOPs that are linked to this KER will automatically be listed in this subsection. Clicking on the name of the AOP in the table will bring you to the individual page for that AOP. More help
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 Do not cite Under Development

Taxonomic Applicability

Select one or more structured terms that help to define the biological applicability domain of the KER. In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER. Authors can indicate the relevant taxa for this KER in this subsection. The process is similar to what is described for KEs (see pages 30-31 and 37-38 of User Handbook) More help

Sex Applicability

Authors can indicate the relevant sex for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of the User Handbook). More help

Life Stage Applicability

Authors can indicate the relevant life stage for this KER in this subsection. The process is similar to what is described for KEs (see pages 31-32 of User Handbook). More help

Key Event Relationship Description

Provide a brief, descriptive summation of the KER. While the title itself is fairly descriptive, this section can provide details that aren’t inherent in the description of the KEs themselves (see page 39 of the User Handbook). This description section can be viewed as providing the increased specificity in the nature of upstream perturbation (KEupstream) that leads to a particular downstream perturbation (KEdownstream), while allowing the KE descriptions to remain generalised so they can be linked to different AOPs. The description is also intended to provide a concise overview for readers who may want a brief summation, without needing to read through the detailed support for the relationship (covered below). Careful attention should be taken to avoid reference to other KEs that are not part of this KER, other KERs or other AOPs. This will ensure that the KER is modular and can be used by other AOPs. More help

The presence of many autoantibodies is a hallmark of SLE. In particular, autoantibodies directed to double-stranded DNA (dsDNA) are characteristic (Isenberg DA. 2007).  SLE patients appear to produce significant amounts of the anti-dsDNA autoantibodies that cause the disease.  Anti-dsDNA antibody exists even in healthy people, but in SLE patients, an increase in anti-dsDNA antibody has been observed and is also used for definitive diagnosis of SLE.  Activation of autoantibody-producing B cells only serves to exacerbate that condition.

Evidence Supporting this KER

Assembly and description of the scientific evidence supporting KERs in an AOP is an important step in the AOP development process that sets the stage for overall assessment of the AOP (see pages 49-56 of the User Handbook). To do this, biological plausibility, empirical support, and the current quantitative understanding of the KER are evaluated with regard to the predictive relationships/associations between defined pairs of KEs as a basis for considering WoE (page 55 of User Handbook). In addition, uncertainties and inconsistencies are considered. More help
Biological Plausibility
Define, in free text, the biological rationale for a connection between KEupstream and KEdownstream. What are the structural or functional relationships between the KEs? For example, there is a functional relationship between an enzyme’s activity and the product of a reaction it catalyses. Supporting references should be included. However, it is recognised that there may be cases where the biological relationship between two KEs is very well established, to the extent that it is widely accepted and consistently supported by so much literature that it is unnecessary and impractical to cite the relevant primary literature. Citation of review articles or other secondary sources, like text books, may be reasonable in such cases. The primary intent is to provide scientifically credible support for the structural and/or functional relationship between the pair of KEs if one is known. The description of biological plausibility can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured (see page 40 of the User Handbook for further information).   More help

SLE has been seen to flare up during pregnancy (Petri M. 1991).  The aberrant T cell dysfunction in SLE is also associated with high levels of autoantibodies (Crispin JC. 2010).

Premenopausal women receiving low estrogen containing birth control pills did not have an increased flare rate compared to women receiving placebo suggesting that adding estrogen to an already high estrogen state had no effect on disease (Buyon JP. 1996).

Uncertainties and Inconsistencies
In addition to outlining the evidence supporting a particular linkage, it is also important to identify inconsistencies or uncertainties in the relationship. Additionally, while there are expected patterns of concordance that support a causal linkage between the KEs in the pair, it is also helpful to identify experimental details that may explain apparent deviations from the expected patterns of concordance. Identification of uncertainties and inconsistencies contribute to evaluation of the overall WoE supporting the AOPs that contain a given KER and to the identification of research gaps that warrant investigation (seep pages 41-42 of the User Handbook).Given that AOPs are intended to support regulatory applications, AOP developers should focus on those inconsistencies or gaps that would have a direct bearing or impact on the confidence in the KER and its use as a basis for inference or extrapolation in a regulatory setting. Uncertainties that may be of academic interest but would have little impact on regulatory application don’t need to be described. In general, this section details evidence that may raise questions regarding the overall validity and predictive utility of the KER (including consideration of both biological plausibility and empirical support). It also contributes along with several other elements to the overall evaluation of the WoE for the KER (see Section 4 of the User Handbook).  More help

Stat6-deficient New Zealand Mixed (NZM) 2328 mice display a significant reduction in incidence of kidney disease, with a dramatic increase in survival, despite the presence of high levels of anti-dsDNA Abs same like the wild-type NZM 2328 animals (Chaim O. 2003).  In NZM 2410 mice, STAT6 deficiency or anti-IL-4 Ab treatment decreases type 2 cytokine responses and ameliorates kidney disease, particularly glomerulosclerosis, despite the presence of high levels of IgG anti-dsDNA Abs same like the wild-type littermates or PBS-treated controls (Ram RS. 2003).  Anti-dsDNA antibodies are not what we think they are, as they may be antibodies operational in quite different biological contexts, although they bind dsDNA by chance.  This may not mean that these antibodies are not pathogenic but they do not inform how they are so (Ole PR. 2019).  In other words, might be that the high levels of anti-dsDNA Abs does not always exacerbate SLE.

Response-response Relationship
This subsection should be used to define sources of data that define the response-response relationships between the KEs. In particular, information regarding the general form of the relationship (e.g., linear, exponential, sigmoidal, threshold, etc.) should be captured if possible. If there are specific mathematical functions or computational models relevant to the KER in question that have been defined, those should also be cited and/or described where possible, along with information concerning the approximate range of certainty with which the state of the KEdownstream can be predicted based on the measured state of the KEupstream (i.e., can it be predicted within a factor of two, or within three orders of magnitude?). For example, a regression equation may reasonably describe the response-response relationship between the two KERs, but that relationship may have only been validated/tested in a single species under steady state exposure conditions. Those types of details would be useful to capture.  More help

The effects of estrogen receptor signaling on T cells also appear to be dose dependent (Cunningham M. 2011).  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 diseases (multiple sclerosis; MS, rheumatoid arthritis; RA, and experimental autoimmune encephalomyelitis; EAE, etc.) caused by Th1 rather than SLE.  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 A. 2003).  Treatment with low doses of estrogen (25 pg/ml or 0.1 nM) ameliorated autoimmune diseases caused by Th1, 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 BF. 2001, Korn-Lubetzki I. 1984).

Time-scale
This sub-section should be used to provide information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). This can be useful information both in terms of modelling the KER, as well as for analyzing the critical or dominant paths through an AOP network (e.g., identification of an AO that could kill an organism in a matter of hours will generally be of higher priority than other potential AOs that take weeks or months to develop). Identification of time-scale can also aid the assessment of temporal concordance. For example, for a KER that operates on a time-scale of days, measurement of both KEs after just hours of exposure in a short-term experiment could lead to incorrect conclusions regarding dose-response or temporal concordance if the time-scale of the upstream to downstream transition was not considered. More help

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Known modulating factors
This sub-section presents information regarding modulating factors/variables known to alter the shape of the response-response function that describes the quantitative relationship between the two KEs (for example, an iodine deficient diet causes a significant increase in the slope of the relationship; a particular genotype doubles the sensitivity of KEdownstream to changes in KEupstream). Information on these known modulating factors should be listed in this subsection, along with relevant information regarding the manner in which the modulating factor can be expected to alter the relationship (if known). Note, this section should focus on those modulating factors for which solid evidence supported by relevant data and literature is available. It should NOT list all possible/plausible modulating factors. In this regard, it is useful to bear in mind that many risk assessments conducted through conventional apical guideline testing-based approaches generally consider few if any modulating factors. More help

The Th1/Th2 shift is one of the most important immunologic changes during the menstrual cycle and gestation.  Immune activity shifts across the menstrual cycle, with higher follicular-phase Th1 cell activity and higher luteal-phase Th2 cell activity (Tierney KL. 2015).  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 A. 2006).  Incidence of flare in patients with SLE is increased during pregnancy and within the 3-months postpartum (Amanda E. 2018). 

Known Feedforward/Feedback loops influencing this KER
This subsection should define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits? In some cases where feedback processes are measurable and causally linked to the outcome, they should be represented as KEs. However, in most cases these features are expected to predominantly influence the shape of the response-response, time-course, behaviours between selected KEs. For example, if a feedback loop acts as compensatory mechanism that aims to restore homeostasis following initial perturbation of a KE, the feedback loop will directly shape the response-response relationship between the KERs. Given interest in formally identifying these positive or negative feedback, it is recommended that a graphical annotation (page 44) indicating a positive or negative feedback loop is involved in a particular upstream to downstream KE transition (KER) be added to the graphical representation, and that details be provided in this subsection of the KER description (see pages 44-45 of the User Handbook).  More help

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Domain of Applicability

As for the KEs, there is also a free-text section of the KER description that the developer can use to explain his/her rationale for the structured terms selected with regard to taxonomic, life stage, or sex applicability, or provide a more generalizable or nuanced description of the applicability domain than may be feasible using standardized terms. More help

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References

List of the literature that was cited for this KER description using the appropriate format. Ideally, the list of references should conform, to the extent possible, with the OECD Style Guide (OECD, 2015). More help
  1. 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.
  2. Petri, M. Howard, D. and Repke, J. (1991). Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience. Arthritis & Rheumatology. 34(12): 1538-1545.
  3. Crispin, JC. Liossis, SN. (2010). Pathogenesis of human systemic lupus erythematosus: recent advances. Trends in Molecular Medicine. 16: 47-57.
  4. Buyon JP. Oral contraceptives in women with systemic lupus erythematosus. Ann Med Interne (Paris) (1996) 147(4):259-264.
  5. Xuemei, Z., Stanley, L., et al. (2009). A Novel Subpopulation of B-1 Cells Is Enriched with Autoreactivity in Normal and Lupus-Prone Mice. Arthritis & Rheumatology 60 (12):3734-3743.
  6. Chaim O. Jacob, Song Zang, Lily Li, Voicu Ciobanu, Frank Quismorio, Akiei Mizutani, Minoru Satoh and Michael Koss (2003). Pivotal Role of Stat4 and Stat6 in the Pathogenesis of the Lupus-Like Disease in the New Zealand Mixed 2328 Mice. J Immunol. 171 (3): 1564-1571.
  7. Ram Raj Singh, Vijay Saxena, Song Zang, Lily Li, Fred D. Finkelman, David P. Witte and Chaim O. Jacob (2003). Differential Contribution of IL-4 and STAT6 vs STAT4 to the Development of Lupus Nephritis. J Immunol, 170 (9): 4818-4825
  8. Ole Petter Rekvig (2019), The dsDNA, Anti-dsDNA Antibody, and Lupus Nephritis: What We Agree on, What Must Be Done, and What the Best Strategy Forward Could Be, Front. Immunol. 10: 1-17.
  9. Cunningham, M., Gilkeson, G., 2011. Estrogen receptors in immunity and autoimmunity. Clinical Reviews in Allergy and Immunology 40, 66-73.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. Tierney, K. L., Julia, R. H. and Gregory, E. D. (2015). Sexual activity modulates shifts in Th1/Th2 cytokine profile across the menstrual cycle: An observational study. Fertility and Sterility 104 (6): 1513-1521.
  17. Amanda E, Anna Maria SR, Michelle P, et al. Effect of pregnancy on disease flares in patients with systemic lupus erythematosus. Ann Rheum Dis. 2018; 77(6): 855-860.