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Event: 1708

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Th17 cell migration and inflammation induction

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Th17 cell migration and inflammation induction

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization
Cellular

Cell term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Cell term
dendritic cell

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help
Organ term
immune system

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Skin disease by stimulation of TLR7/8 KeyEvent Hiroyuki Komatsu (send email) Under development: Not open for comment. Do not cite Under Development

Stressors

This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Psoriasis is known to play a major role in the etiology of T cell dysfunction, especially in over activation of the Th17 pathway, which Th17 cells were associated with Th1 and Th2 (Lisa C. et al. 2007) Th17 cell was identified as a cell population that produces different IL17. Abnormal activation of Toll-like receptors (TLR7, 8 and 9) is also involved in the initiation and maintenance of psoriasis. IMO-3100 (an antagonist of TLR7 and 9) and IMO-8400 (an antagonist of TLR7, 8 and 9) has been shown to reduce psoriasis-like skin lesions induced by intradermal administration of IL-23 on the back of mice (Mayte S-F et al. 2013). Immune cell infiltration in psoriasis lesions is composed of CD3 + Th1cell, Th17 cells and CD11c + dendritic cells (DC) (Chamian F et al 2005).

Cytokines such as TNF-α, IFN-γ, IL-17, IL-22, IL-23, IL-12, and IL-1β produced from these cells cause an inflammatory cascade. In particular, the IL-23 / Th17 axis plays an important role, and IL-23h is produce in DC, promotes the differentiation of naive CD4 + T cell progenitor cells into the Th17 phenotype, and stimulates the survival and expansion of the Th17 population  (Harrington LE et al. 2005) (Veldhoen M et al. 2006). IL-17 produced from Th17 cells regulates the expression of defensin, S100 family protein and LL-37. These are innate immune responses in the skin and show higher expression of IL-23 in keratinocytes and dermal tissues of psoriatic lesions than in non-lesions (Liang SC et al. 2006).

Overproduction of Th1 and TH17 cytokines is a major cause of psoriasis, and glucocorticoid (GC) regulates epidermal differentiation and acts as a potent anti-inflammatory compound to suppress the pathology of psoriasis. Synthetic glucocorticoids are uses to suppress inflammatory disease  including psoriasis, and induce the glucocorticoid-induced leucine zipper (GILZ), a protein that inhibits major immune cell signaling pathways. CILZ is deficient in lesioned skin of psoriasis patients and shows a negative correlation with the expression of pro-inflammatory cytokines IL-1, IL-23, IL-22, and STAT3. Lisa et al. was identified a T cell-specific role of CILZ that limits Th17 cell formation in vitro in response to the Th17-promoting cytokines IL-1β and IL-23 (Lisa M et al.2019). CILZ has the clinical significance of psoriasis as well as the non-redundant function of controlling pathogenic Th17 responses (Lisa M et al.2019).

One of the causes of psoriasis is an increase in pathogenic Th17 cells in people with a genetic predisposition stimulated by the production of Th17 polarized cytokines by bone marrow cells. The antibacterial peptide LL37, which forms a complex with nucleic acids released from cells, is an autoantigen that promotes the activation of cutaneous plasmacytoid dendritic cells and myeloid DCs, and Th17 cells are effector cytokines such as IL-17A. It activates keratinocytes directly through release. Activated keratinocytes proliferate abnormally and release inflammatory mediators and chemokines to amplify the inflammatory response (Boehncke WH et al.2015).

 

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?

IL17 + cell count measurement                                                                                                 

Flow cytometric analysis of psoriasis skin biopsy showed increased IL-17 + and IL-22 + CD4 + T cells,

Measurement of IL17 protein levels (in skin and serum)                                                               

Increased frequency of IL-17 +, CCR6 +, and CCR4 + T cells. IL-22-producing cells (Th-22 cells) that do not produce IL-17 or IFNγ also increased (Benham et al. 2013).

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Ras homolog gene family H (RhoH) is a membrane-bound adapter protein involved in proximal T cell receptor signaling, and spontaneously develops chronic dermatitis that closely resembles human psoriasis in RhoH gene-deficient mice. Ubiquitin protein ligase E3 component N recognition 5 (Ubr5) and nuclear receptor subfamily 2 group F member 6 (Nr2f6) expression levels are decreased at the lesion site, and protein levels and DNA binding activity of retinoic acid-related orphan receptors are increased is doing. As a result, T cells differentiated into Th17 cells due to increased production of IL-17 and IL-22. These results indicate that RhoH suppresses the differentiation of naive T cells into effector Th17 cells. RhoH is a gene expressed in blood cells, and when RhoH expression decreases in T cells, Th17 cells increase, IL-22 is produced in large quantities, and the epidermis thickens, leading to the formation of psoriasis pathology. Humans with low RhoH expression may become more severe if they suffer from psoriasis.(Journal of Allergy and Clinical Immunology)

The effect of the unique gut flora in psoriasis on the development and reactivity of inflammatory cells on the IL-23 / Th17 axis was analyzed in imiquimod-induced psoriasis model mice. Th17, γδ TCR-bearing lymphocytes in the spleen were measured from sterile (GF) mice, broad-spectrum antibiotic mixture-administered (ATB) mice, and conventional (CV) mice. GF mice and ATB-treated mice had fewer Th17 cells and γδTCR + cells than CV mice. This is thought to be due to the symbiotic bacteria that lack microbiota or changes due to ATB treatment reduce pro-inflammatory T cell response and regulate T cell development. In other words, it is proof that the interaction between the microorganisms of Clostridiales and Elysiperotricales and the host affects the reactivity of Th17 cells and is involved in the etiology of imiquimod-induced skin inflammation. The positive effect of antibiotic regulation of the gut flora on skin severity suggests the involvement of the gut and skin axes and is part of the management of psoriasis patients. (Zizana Z et al. 2016) * Wide-area antibiotic mixture (ATB): A mixture of metronidazole, colistin, streptomycin, and vancomycin.

References

List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide (https://www.oecd.org/about/publishing/OECD-Style-Guide-Third-Edition.pdf) (OECD, 2015). More help

・Lisa C. Zaba, Irma Cardinale, Patricia Gilleaudeau, Mary Sullivan-Whalen, Mayte Suárez-Fariñas, Judilyn Fuentes-Duculan, Inna Novitskaya, Artemis Khatcherian, Mark J. Bluth, Michelle A. Lowes, James G. Krueger. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J. Exp. Med. 2007, 204, 3183-3194.

・Mayte Suarez-Farinas, Robert Arbert, Weiwen Jiang, Francesca S. Ortenzio, Tim Sullivan, James G, Krueger.Suppression of Molecular Inflammatory Pathways by Toll-Like Receptor7,8 and 9 Antagonists in a Model of IL-23-Induced Skin Inflammmation. PLOS ONE, December 2013/Vol 8/Issue 12/e84634

・Chamian F, Lowes MA, Lin SL, Lee E, Kikuchi T et al. (2005)Alefacept reduces infiltrating T cells, activated dendritic cells, and inflammatory genes in psoriasis vulgaris. Proc Natl Acad Sci U S A 102: 2075-2080.

・Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy  TL et al. (2005) Interleukin 17-producing  CD4+ effector  T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 6:1123-1132.

・Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B(2006) novo differentiation of IL-17-producing  T cells. Immunity 24:179-189.

・Liang SC, Tan XY, Luxenberg DP, Karim R, Dunussi-Joannopoulos K et al. (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203:2271-2279.  

・Lisa M. Paloma Perez. Glucocorticoids and Glucocorticoid-Induced-Leucine-Zipper (GILZ) in Psoriasis:Published online 2019 Sep 13.

・Boehncke WH, Schon MP. Psoriasis. Lancet (2015)386(9997);983-94.10.1016/S0140-6736(14)61909-7

・Helen Benham, Jane C Goodall, Mihir D Wechalekar, and Dliver Fitzgerald. Th17 and Th22 cells in psoriatic arthritis and psoriasis. Arthritis research & therapy September 2013.

・Journal of Allergy and Clinical Immunology

・Zuzana Zakostelska, Jana Malkova, Kiara Klimesova, Pavel Rossmann, Michaela Hornova, Iva Novosadova, Zuzana Stehlikova, Martin Kostovcik, Tomas Hudcovic, Ranata Stepankova, Katerina Juzlova, Jana Hercogova, Helena Tlaskalova-Hogenova, Miloslav Kverka. Intestinal MicrobiotaPromotes Psoriasis-Like Skin Inflammation by Enhancing Th17 Response. PLOS ONE. 2016;Jul 19.