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Relationship: 2004


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

Suppression of T cell activation leads to Increase, Increased susceptibility to infection

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
Impaired IL-1R1 signaling leading to increased susceptibility to infection adjacent High High Yutaka Kimura (send email) Open for citation & comment EAGMST Under Review

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
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

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
Sex Evidence
Unspecific High

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
Term Evidence
All life stages High

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

Normal T cell and B cell function is indispensable for host defense mechanism.

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

The experiments using knockout mice revealed that the lack of IL-1 signaling led to bacterial, tuberculosis or viral infection (Guler et al., 2011; Horino et al., 2009; Juffermans et al., 2000; Tian et al., 2017; Yamada et al., 2000).

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

The activation of NF-κB plays a principal role in the immunological function of IL-1R signalling. NF-κB plays a crucial role in the activation of dendritic cells as well as T cells. In dendritic cells, the activation of the canonical NF-κB pathway in response to pro-inflammatory stimuli, such as cytokines including IL-1a or IL-1b and TLR ligands, stimulate the maturation of dendritic cells with enhanced antigen presenting function. The inhibition of NF-κB suppress antigen presenting function of dendritic cells, resulting in suppression of T cell activation (reviewed by Reinhard et al (Reinhard et al., 2012) and van Delft et al (van Delft, Huitema and Tas, 2015).

In T cells, NF-kB can be activated by several pathways of signal transduction. Although the engagement of the TCR by major histocompatibility complex (MHC) plus antigen is a main stream of NF-kB activation in T cells, the stimulation of T cells by IL-1 activates NF-kB as already described before. Once in the nucleus, NF-kB governs the transcription of numerous genes involved in T cell survival, proliferation, and effector functions (Paul and Schaefer, 2013). Although CD4 T cells are able to commit to Th1, Th2 and Th17 lineages in the absence of IL-1R signaling at steady state, these committed CD4 T cells are unable to effectively secrete their cytokines upon TCR ligation. Namely, IL-1 is indispensable for CD4 T cell effector function (Lin et al., 2015).

To protect the infection from different pathogens, different types of immune response depending on the pathogens are required (reviewed by Soares et al. (Soares et al., 2017)). 

1). Type 1 immunity drives resistance to viruses and intracellular bacteria, such as Listeria monocytogenesSalmonella sppand 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 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 CD8cytotoxic 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. 

2) Resistance to extracellular metazoan parasites and other large parasites is mediated and/or involves type 2 immunit. 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 epithelia. 

3) TH17 immunity confers resistance to extracellular bacteria such as Klebsiella pneumoniaeEscherichia coli, Citrobacter rodentium, Bordetella pertussis, Porphyromonas gingivalis and Streptococcus pneumoniae, and also to fungi such as Candida albicans, Coccidioides posadasiiHistoplasma capsulatum and Blastomyces dermatitidis. 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.

Based on these evidences, the insufficient T cell or B cell function causes impaired resistance to infection. 

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
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

Luster et al  (1993) demonstrated that Concanavalin A response of splenocytes showed the linear dose-response relationship with the host resistnace to Listeria monocytogenes or Streptococcus pneumoniae.

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
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
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

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


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

Bohrer, A.C., Tocheny, C., Assmann, M., et al. (2018), Cutting Edge: IL-1R1 Mediates Host Resistance to Mycobacterium tuberculosis by Trans-Protection of Infected Cells. J Immunol 201: 1645-1650, 10.4049/jimmunol.1800438

De Benedetti, F., Gattorno, M., Anton, J., et al. (2018), Canakinumab for the Treatment of Autoinflammatory Recurrent Fever Syndromes. N Engl J Med 378: 1908-1919, 10.1056/NEJMoa1706314

Dripps, D.J., Brandhuber, B.J., Thompson, R.C., et al. (1991), Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem 266: 10331-10336,

Fleischmann, R.M., Schechtman, J., Bennett, R., et al. (2003), Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: A large, international, multicenter, placebo-controlled trial. Arthritis Rheum 48: 927-934, 10.1002/art.10870

Genovese, M.C., Cohen, S., Moreland, L., et al. (2004), Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate. Arthritis Rheum 50: 1412-1419, 10.1002/art.20221

Goh, A.X., Bertin-Maghit, S., Ping Yeo, S., et al. (2014), A novel human anti-interleukin-1beta neutralizing monoclonal antibody showing in vivo efficacy. MAbs 6: 765-773, 10.4161/mabs.28614

Guler, R., Parihar, S.P., Spohn, G., et al. (2011), Blocking IL-1alpha but not IL-1beta increases susceptibility to chronic Mycobacterium tuberculosis infection in mice. Vaccine 29: 1339-1346, 10.1016/j.vaccine.2010.10.045

Hannum, C.H., Wilcox, C.J., Arend, W.P., et al. (1990), Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature 343: 336-340, 10.1038/343336a0

Horino, T., Matsumoto, T., Ishikawa, H., et al. (2009), Interleukin-1 deficiency in combination with macrophage depletion increases susceptibility to Pseudomonas aeruginosa bacteremia. Microbiol Immunol 53: 502-511, 10.1111/j.1348-0421.2009.00143.x

Imagawa, T., Nishikomori, R., Takada, H., et al. (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). Clin Exp Rheumatol 31: 302-309,

Juffermans, N.P., Florquin, S., Camoglio, L., et al. (2000), Interleukin-1 signaling is essential for host defense during murine pulmonary tuberculosis. J Infect Dis 182: 902-908, 10.1086/315771

Kullenberg, T., Lofqvist, M., Leinonen, M., et al. (2016), Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology (Oxford) 55: 1499-1506, 10.1093/rheumatology/kew208

Labow, M., Shuster, D., Zetterstrom, M., et al. (1997), Absence of IL-1 signaling and reduced inflammatory response in IL-1 type I receptor-deficient mice. J Immunol 159: 2452-2461,

Lachmann, H.J., Kone-Paut, I., Kuemmerle-Deschner, J.B., et al. (2009), Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360: 2416-2425, 10.1056/NEJMoa0810787

Lequerre, T., Quartier, P., Rosellini, D., et al. (2008), Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France. Ann Rheum Dis 67: 302-308, 10.1136/ard.2007.076034

Lin, D., Lei, L., Zhang, Y., et al. (2015), Secreted IL-1alpha promotes T-cell activation and expansion of CD11b(+) Gr1(+) cells in carbon tetrachloride-induced liver injury in mice. Eur J Immunol 45: 2084-2098, 10.1002/eji.201445195

Luster, M.I., Portier, C., Pait, D.G., et al. (1993), Risk assessment in immunotoxicology. II. Relationships between immune and host resistance tests. Fundam Appl Toxicol 21: 71-82,

Migkos, M.P., Somarakis, G.A., Markatseli, T.E., et al. (2015), Tuberculous pyomyositis in a rheumatoid arthritis patient treated with anakinra. Clin Exp Rheumatol 33: 734-736,

Paul, S., Schaefer, B.C. (2013), A new look at T cell receptor signaling to nuclear factor-kappaB. Trends Immunol 34: 269-281, 10.1016/

Reinhard, K., Huber, M., Lohoff, M., et al. (2012), The role of NF-kappaB activation during protection against Leishmania infection. Int J Med Microbiol 302: 230-235, 10.1016/j.ijmm.2012.07.006

Schlesinger, N., Alten, R.E., Bardin, T., et al. (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. Ann Rheum Dis 71: 1839-1848, 10.1136/annrheumdis-2011-200908

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, 10.1016/s0171-2985(11)80295-0

Singh, N. (2005), Infectious complications in organ transplant recipients with the use of calcineurin-inhibitor agent-based immunosuppressive regimens. Curr Opin Infect Dis 18: 342-345, 10.1097/

Soares, M.P., Teixeira, L., Moita, L.F. (2017), Disease tolerance and immunity in host protection against infection. Nat Rev Immunol 17: 83-96, 10.1038/nri.2016.136

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, 10.4049/jimmunol.1500106

van Delft, M.A., Huitema, L.F., Tas, S.W. (2015), The contribution of NF-kappaB signalling to immune regulation and tolerance. Eur J Clin Invest 45: 529-539, 10.1111/eci.12430

Yamada, H., Mizumo, S., Horai, R., et al. (2000), Protective role of interleukin-1 in mycobacterial infection in IL-1 alpha/beta double-knockout mice. Lab Invest 80: 759-767,

Yokota, S., Imagawa, T., Nishikomori, R., et al. (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. Clin Exp Rheumatol 35 Suppl 108: 19-26,