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Impaired Ab production leads to Increase, Increased susceptibility to infection
Key Event Relationship Overview
AOPs Referencing Relationship
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))
Uncertainties and Inconsistencies
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.
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