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Relationship: 1923


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

Impaired Ab production leads to Impairment, Impairment of TDAR

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). 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

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
Term Scientific Term Evidence Link
Homo sapiens Homo sapiens High NCBI
Mus musculus Mus musculus High NCBI
Rattus norvegicus Rattus norvegicus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Not Otherwise Specified High

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

Normal T cell and B cell function is indispensable for host defense mechanism and dysfunction of either T cell or B cell function leads to increased susceptibility to infection

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

Different pathogens induce different types of immune response. 1). Type 1 immunity drives resistance to viruses and intracellular bacteria, such as Listeria monocytogenes, Salmonella spp. and Mycobacteria spp., as well as to intracellular protozoan parasites such as Leishmania spp. The T helper 1 (TH1) signature cytokine interferon-γ (IFNγ) has a central role in triggering cytotoxic mechanisms that, although directed against intracellular pathogens, can lead to tissue damage through various means, including macrophage polarization towards an antimicrobial response associated with the production of high levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS), activation of CD8+ cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells to kill infected cells via the perforin and/or granzyme B-dependent lytic pathway or via the ligation of surface death receptors; and B cell activation towards the production of cytolytic antibodies that target infected cells for complement and Fc receptor-mediated cellular cytotoxicity. Tissue damage control mechanisms counteracting type 1 immunopathology rely on cellular regeneration and tissue repair to restore homeostasis. The mechanisms by which type 1 immunity contributes to this tissue damage control response are not clear but probably involve the production of epidermal growth factors (EGFs), transforming growth factor-β (TGFβ) and platelet-derived growth factor (PDGF), which drive the proliferation and differentiation of stem cells into functional parenchymal cells, restoring tissue integrity and function. 2) Resistance to extracellular metazoan parasites and other large parasites is mediated and/or involves type 2 immunity. Pathogen neutralization is achieved via different mechanisms controlled by TH2 signature cytokines, including interleukin-4 (IL-4), IL-5 and IL-13, and by additional type 2 cytokines such as thymic stromal lymphopoietin (TSLP), IL-25 or IL-33, secreted by damaged cell. TH2 signature cytokines drive B cell activation towards the production of high-affinity pathogen-specific IgG1 and IgE antibodies that function via Fc-dependent mechanisms to trigger the activation of eosinophils, mast cells and basophils, expelling pathogens across epithelia102. Some of these parasites, for example, helminths, are damaging to parenchymal cells and type 2 immunity encompasses tissue damage control mechanisms that confer disease tolerance to infection by these parasites. These mechanisms involve the production of EGFs, vascular endothelial growth factor (VEGF), TGFβ, resistin-like molecule-α (RELMα) and RELMβ. 3) TH17 immunity confers resistance to extracellular bacteria such as Klebsiella pneumoniae, Escherichia coli, Citrobacter rodentium, Bordetella pertussis, Porphyromonas gingivalis and Streptococcus pneumoniae, and also to fungi such as Candida albicans,  Coccidioides posadasii, Histoplasma capsulatum and Blastomyces dermatitidis1. Activation of TH17 cells by cognate T cell receptor (TCR–MHC class II interactions and activation of group 3 innate lymphoid cells (ILC3s) via engagement of IL-1 receptor (IL-1R) by IL-1β secreted from damaged cells lead to the recruitment and activation of neutrophils. TH17 immunopathology is driven to a large extent by products of neutrophil activation, such as ROS and elastase. This is countered by tissue damage control mechanisms regulated directly or indirectly by IL-22, originating from TH17 cells, TH22 cells (not shown) or ILC3s, and promoting tissue damage control. Other cytokines produced by TH17 cells, including IL-17, can amplify this protective response, working together with fibroblast growth factor 2 (FGF2) produced by regulatory T (Treg) cells to promote tissue damage control at epithelial barriers. Based on these scheme, the insufficient T cell or B cell function causes impaired resistance to infection. DC, dendritic cell; EGFR, EGF receptor; FGF2R, FGF2 receptor; IFNγR, IFNγ receptor; ILR, interleukin receptor; PCD, programmed cell death; PRR, pattern recognition receptor (reviewed by Soares et al. (Soares et al., 2017))

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

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

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

Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent.  Again, age-dependent difference in IL-1 signaling is not known. 

The IL1B gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (, and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (

These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.


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

Auphan, N., DiDonato, J.A., Rosette, C., Helmberg, A., Karin, M., 1995. Immunosuppression by glucocorticoids: inhibition of NF-kappa B activity through induction of I kappa B synthesis. Science (New York, N.Y.) 270, 286-290.

Chatham, W.W., 2019. Glucocorticoid effects on the immune system.

De Benedetti, F., Gattorno, M., Anton, J., Ben-Chetrit, E., Frenkel, J., Hoffman, H.M., Kone-Paut, I., Lachmann, H.J., Ozen, S., Simon, A., Zeft, A., Calvo Penades, I., Moutschen, M., Quartier, P., Kasapcopur, O., Shcherbina, A., Hofer, M., Hashkes, P.J., Van der Hilst, J., Hara, R., Bujan-Rivas, S., Constantin, T., Gul, A., Livneh, A., Brogan, P., Cattalini, M., Obici, L., Lheritier, K., Speziale, A., Junge, G., 2018. Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. The New England journal of medicine 378, 1908-1919.

Dripps, D.J., Brandhuber, B.J., Thompson, R.C., Eisenberg, S.P., 1991. Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. The Journal of biological chemistry 266, 10331-10336.

Genovese, M.C., Cohen, S., Moreland, L., Lium, D., Robbins, S., Newmark, R., Bekker, P., 2004. Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis and rheumatism 50, 1412-1419.

Goh, A.X., Bertin-Maghit, S., Ping Yeo, S., Ho, A.W., Derks, H., Mortellaro, A., Wang, C.I., 2014. A novel human anti-interleukin-1beta neutralizing monoclonal antibody showing in vivo efficacy. mAbs 6, 765-773.

Guler, R., Parihar, S.P., Spohn, G., Johansen, P., Brombacher, F., Bachmann, M.F., 2011. Blocking IL-1alpha but not IL-1beta increases susceptibility to chronic Mycobacterium tuberculosis infection in mice. Vaccine 29, 1339-1346.

Hannum, C.H., Wilcox, C.J., Arend, W.P., Joslin, F.G., Dripps, D.J., Heimdal, P.L., Armes, L.G., Sommer, A., Eisenberg, S.P., Thompson, R.C., 1990. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343, 336-340.

Horino, T., Matsumoto, T., Ishikawa, H., Kimura, S., Uramatsu, M., Tanabe, M., Tateda, K., Miyazaki, S., Aramaki, Y., Iwakura, Y., Yoshida, M., Onodera, S., Yamaguchi, K., 2009. Interleukin-1 deficiency in combination with macrophage depletion increases susceptibility to Pseudomonas aeruginosa bacteremia. Microbiology and immunology 53, 502-511.

Imagawa, T., Nishikomori, R., Takada, H., Takeshita, S., Patel, N., Kim, D., Lheritier, K., Heike, T., Hara, T., Yokota, S., 2013. Safety and efficacy of canakinumab in Japanese patients with phenotypes of cryopyrin-associated periodic syndrome as established in the first open-label, phase-3 pivotal study (24-week results). Clinical and experimental rheumatology 31, 302-309.

Juffermans, N.P., Florquin, S., Camoglio, L., Verbon, A., Kolk, A.H., Speelman, P., van Deventer, S.J., van Der Poll, T., 2000. Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. The Journal of infectious diseases 182, 902-908.

Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.

Kullenberg, T., Lofqvist, M., Leinonen, M., Goldbach-Mansky, R., Olivecrona, H., 2016. Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford, England) 55, 1499-1506.

Lachmann, H.J., Kone-Paut, I., Kuemmerle-Deschner, J.B., Leslie, K.S., Hachulla, E., Quartier, P., Gitton, X., Widmer, A., Patel, N., Hawkins, P.N., 2009. Use of canakinumab in the cryopyrin-associated periodic syndrome. The New England journal of medicine 360, 2416-2425.

Lequerre, T., Quartier, P., Rosellini, D., Alaoui, F., De Bandt, M., Mejjad, O., Kone-Paut, I., Michel, M., Dernis, E., Khellaf, M., Limal, N., Job-Deslandre, C., Fautrel, B., Le Loet, X., Sibilia, J., 2008. Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Annals of the rheumatic diseases 67, 302-308.

Migkos, M.P., Somarakis, G.A., Markatseli, T.E., Matthaiou, M., Kosta, P., Voulgari, P.V., Drosos, A.A., 2015. Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra. Clinical and experimental rheumatology 33, 734-736.

Schlesinger, N., Alten, R.E., Bardin, T., Schumacher, H.R., Bloch, M., Gimona, A., Krammer, G., Murphy, V., Richard, D., So, A.K., 2012. Canakinumab for acute gouty arthritis in patients with limited treatment options: results from two randomised, multicentre, active-controlled, double-blind trials and their initial extensions. Annals of the rheumatic diseases 71, 1839-1848.

Seckinger, P., Kaufmann, M.T., Dayer, J.M., 1990. An interleukin 1 inhibitor affects both cell-associated interleukin 1-induced T cell proliferation and PGE2/collagenase production by human dermal fibroblasts and synovial cells. Immunobiology 180, 316-327.

Soares, M.P., Teixeira, L., Moita, L.F., 2017. Disease tolerance and immunity in host protection against infection. Nature reviews. Immunology 17, 83-96.

Tian, T., Jin, M.Q., Dubin, K., 2017. IL-1R Type 1-Deficient Mice Demonstrate an Impaired Host Immune Response against Cutaneous Vaccinia Virus Infection.  198, 4341-4351.

Yamada, H., Mizumo, S., Horai, R., Iwakura, Y., Sugawara, I., 2000. Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice. Laboratory investigation; a journal of technical methods and pathology 80, 759-767.

Yokota, S., Imagawa, T., Nishikomori, R., Takada, H., Abrams, K., Lheritier, K., Heike, T., Hara, T., 2017. Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndrome: results from an open-label, phase III pivotal study in Japanese patients. Clinical and experimental rheumatology 35 Suppl 108, 19-26.