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Relationship: 2023

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Increase of autoantibody production leads to Exacerbation of SLE

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Increase of autoantibody production
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help
Exacerbation of SLE

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

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 Do not cite Under Development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

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. 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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field 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.   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
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. 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.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  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). 

Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  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
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?). More help

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Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

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Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

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References

List of the literature that was cited for this KER description. 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.