Upstream eventImpaired Ab production
Increase, Increased susceptibility to infection
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of IL-1 signaling||adjacent||High||High|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
Life Stage Applicability
|Not Otherwise Specified||High|
Key Event Relationship Description
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 Supporting this KER
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))
Dexamethasone is one of the representatives that significantly suppress IL-1β production from monocytes (Auphan et al., 1995).There were several reports that described that administration of IL-1R antagonist or neutralizing antibody such as IL-1Ra (generic anakinra), canakinumab (anti-IL-1β antibody) and rilonacept (soluble IL-1R) led to the suppression of downstream phenomena, which included internalization of IL-1 (Dripps et al., 1991), production of PGE2 (Hannum et al., 1990)(Seckinger et al., 1990), IL-6 (Goh et al., 2014), and T cell proliferation (Seckinger et al., 1990).
Since these inhibitors became available to treat some of autoinflammatory syndromes, it became clear that these inhibitors increased the frequency of serious bacterial infection (De Benedetti et al., 2018; Genovese et al., 2004; Imagawa et al., 2013; Kullenberg et al., 2016; Lachmann et al., 2009; Lequerre et al., 2008; Migkos et al., 2015; Schlesinger et al., 2012; Yokota et al., 2017). Beside the blocking of IL-1 binding to its receptor, several drugs also suppress the production of IL-1. Dexamethasone is one of the representatives that significantly suppress IL-1β production from monocytes (Auphan et al., 1995). Although the effects of dexamethasone are pleiotropic, it is well known to increase the susceptibility to bacterial, fungal, or viral infection (Chatham, 2019). Similarly, 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).
Uncertainties and Inconsistencies
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
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 (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849).
These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.
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.