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Event: 1709

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

Psoriatic skin disease

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
Skin disease

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

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 AdverseOutcome 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 a complex inflammatory disease caused by activation of Th1 and TH17 cells. The epidermis is composed of keratinocytes that differentiate to form a permeable barrier. Abnormal balance between proliferation and differentiation of keratinocytes affects barrier function and causes inflammatory skin lesions. Psoriasis is a complex combination of genetic and environmental risk factors, and dysregulation of Th1 and Th17 lines is due to overproduction of cytokines including IFN-α, TNF-α, IL-23, IL-17, and IL-22. Causes overgrowth and skin immunity. (Harrington LE et al. 2005)

Histopathological features of psoriasis lesions include epidermal thickening, epidermal differentiation, and epidermal protrusions (reticular ridges), with intraepithelial neutrophil moistening (manlo-like abscess) and marked immune moistening consisting of T cells and dendritic cells. See an increase in. (Boehncke WH et al. 2018) Commonly used psoriasis model mice were produced by topical application of the TLR7 agonist imiquimod, which induces the IL-23-Th17 cell axis and histopathology of human psoriasis pathology. Strictly reproduce the target and molecular features. (Wagner EF et al.2010)

Psoriasis vulgaris shows overexpression of the S100 protein family soriacin (sorazine), cobunericin (kebuneridine), and epidermal antibacterial peptide (AMP). AMP is induced by IL-17 and itself functions as a chemotactic factor and cytokine. Mobilize CD4 + T cells and neutrophils that exacerbate inflammation. (Kanagawa Psoriasis Treatment Study Group)

Serum IL-17 levels in psoriasis patients are significantly higher than in healthy individuals, and brodalumab, a neutralizing antibody against the IL-17A receptor, has been shown to be effective in the treatment of psoriasis (Gilliet et al. 2004). In addition, antibody preparations against IL-17 ixekizumab (John K. et al. 2002) and Szeimies et al. 2004 were used to treat psoriasis, and with positive results, Th17-mediated pathways are important for the etiology of psoriasis. It is believed to play a role. Immunohistological examination of biopsies of skin areas with psoriatic plaques, including surrounding normal skin, shows an increase in the number of activated dendritic cells, especially CD1a-positive Langerhans cells in the epidermis of psoriatic lesions. In CD83-positive CD1a-negative Langerhans, -negative CD11c-positive dermal dendritic cells increased in the epidermis at the border of psoriatic plaques. In normal skin, there were significantly fewer CD3-positive T lymphocytes than lesions.

CD4 and CD8 T cells infiltrate both the epidermis and dermis and show increased expression of IL17A, IL22, and IFNG in epidermal CD4 and CD8 T cells near keratinocytes, but with lower dermal T cell upregulation. IL-22, produced primarily by lesion epidermal CD4 T cells, is associated with keratinocyte activation and the formation of epidermal thickening, a prominent morphological feature of psoriasis. Lesion epithelial CD8 T cells mainly produce IL-17A and promote the production of inflammatory cytokines and chemokines by keratinocytes. IL-17A is an important mediator of psoriatic inflammation through skin recruitment and activation of leukocytes. (Cheuk et al. 2014)

In patients with psoriasis, inflammatory keratin K6 and K16-positive keratinocytes were found, even in areas of normal-appearing skin that were not affected by psoriasis lesions. In addition, the transcription factor C / EBPβ, which is normally expressed only in the stratum granulosum of the healthy epidermis, was expressed throughout the epidermis, including the epidermis of the lesion. This suggests that early inflammatory changes have already occurred in areas that have not yet shown obvious skin lesions, and that these changes are caused by dendritic cells rather than lymphocytes. (Komine et al. 2007)

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). ?

Biopsy of the skin area and surrounding normal skin of patients with psoriasis vulgaris

The dendritic cell surface marker and lymphocyte surface marker of the section were used as the primary antibody.

In the vicinity of psoriasis lesions, an increased number of activated dendritic cells was observed, with CD1a-positive Langerhans cells in the epidermis and CD83-positive CD1a-negative Langerin-negative CD11c-positive dermal dendritic cells at the epidermal border.

There were significantly fewer CD3-positive T lymphocytes than lesions in normal skin.

Inflammatory keratin K6 and K16 positive keratinocytes were found in the normal part.

The transcription factor C / EBPβ, which is normally expressed only in the granular layer of the normal epidermis, was expressed in the entire epidermis in the same manner as the lesion. (Komine et al. 2007)

Serum amyloid A: SAA measurement ... measured in 35 psoriasis patients and healthy humans

DNA microarray analysis in lesions of psoriasis patients ... SAA levels are about 5 times higher than in normal skin. The average SAA of psoriasis patients was 19.1 ug / ml, and the average SAA after treatment was 6.9 ug / ml.

There is a correlation between SAA and psoriasis severity score (PASI).

Amyloid A deposition was observed in the skin-stained area of the psoriasis lesion skin area (Tanizaki H 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

Mouse psoriasis-like dermatitis model: K14 / mIL-1F6 gene-modified mice overexpress mouse IL-1F6 (IL-36a) selectively under the keratin 14 promoter, and TPA: 12-O- tetradecanoy1phorbol-13-acetate(TPA)  was applied, skin pathological featuresfindings specific to psoriasis-such as epidermal hyperplasia, epidemal exfoliation and micro-abscess formation, and wet inflammatory cells in the dermis-were observed. Quantitative RT-PCR. Measures mRNA expression levels of Inflammatory chemokines and cytokines in skin tissues, and includes inflammatory chemokines: CCL3, CCL4, CXCL10, CXCL1 and cytokines: IL-23, IL-12, IL-1β etc. Expression was observed. (Kyowa Hakko Kirin Co., Ltd.)

Epidermal keratinocyte expression genes that were elevated in psoriatic lesions of patients with psoriasis with stage-type skin eruption: mRNA expression level of keratin6a and 16, s100A7A, S100A12, DEFB4, IL-1F6, CCL20, IL-17C, etc. was rapidly reduced by 700㎎ single intravenous dose of brodalumab and decreased to non-lesional skin level two weeks after administration.On the other hand, leukocyte expression genes with increased expression in psoriatic lesion skin: IL-17A, IL-17F, IL-23F, IL-12B, IL-22, IFN-γ and other mRNA expression levels decreased with brodalumab administration However, at 2 weeks after administration,  the level did not decrease to the level of the non-lesional skin. Since the expression of pathophysiology-related genes is reduced prior to the decrease in the expression of leukocyte expression genes and the decrease in the PASI score, brodalumab expresses pathophysiology-related genes by blocking IL-17 signaling in the epidermal keratinocytes of psoriatic lesions It is possible to improve the skin eruption promptly. (Kyowa Hakko Kirin Co., Ltd.:In-house materials)

The monoclonal antibody-mediated IL-17A (secukinumab / ixekizumab) and the receptor subunit IL-17RA (brodalumab) are effective approaches in the treatment of psoriasis. Blocking IL-17RA results in inhibition of the IL-17 family, including IL-17A, IL-17F, IL-17C, and IL-17E. Other drugs are under clinical development that target bimekizumab targeting IL-17A and IL-17F, IL-23 upstream of the IL-17 pathway, or signal transduction substances downstream. (Conrad C et al. 2018)

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

Psoriasis model mice have been developed as a tool for understanding the etiology of this disease and as a preclinical model. Five representative models are based on K14-amphiregulin, K5-Stat3C, K5-Tie2, K5-TGF-β1, and imiquimod. There were statistically significant similarities between the gene expression patterns associated with epidermal development and keratinization in these models and the gene expression patterns in human psoriasis. Direct high-level activation of keratinocytes via autoclean growth factor (amphiregulin) has the ability to induce cytokine-related genetic circuits that closely resemble human psoriasis. Through transgenes, inward mutations (CARD14), injury, and exposure to specific T cell-producing cytokines, activated keratinocytes induce and lead to a chronic inflammatory response that is highly consistent with psoriasis. However, there were frequent differences in the expression of immune-related genes between the models. (Cook PW et al. 1997)

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

・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.

・Wagner EF, Schonthaler HB, Guinea-Viniegra J, Tschachler E. Psoriasis: what we have learned from mouse models. Nat Rev Rheumatol. (2010) 6:704–14. doi: 10.1038/nrrheum.2010.157

・Kanagawa Psoriasis Treatment Study Group 2013.

・Michel Gilliet,Curdin Conrad, Michael Geiges, Antonio Cozzio, Wolfgang Thürlimann, Günter Burg, Frank O. Nestle, Reinhard Dummer. Psoriasis triggered by toll-like receptor 7 agonist imiquimod in the presence of dermal plasmacytoid dendritic cell precursors.Arch.Dermatol.2004, 140, 1490-1495.

・John K. Geisse, Phoebe Rich, Amit Pandya, Kenneth Gross, Kara Andres, Angie Ginkel, Mary Owens. Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind, randomized, vehicle-controlled study. J. Am. Acad. Dermatol. 2002, 47, 390-398.

・Stanley Cheuk, Maria Wikén, Lennart Blomqvist, Susanne Nylén, Toomas Talme, Mona Ståhle and Liv Eidsmo. Epidermal Th22 and Tc17 Cells Form a Localized Disease Memory in Clinically Healed PsoriasisJ Immunol. 2014, Apr 1; 192(7): 3111-3120.

・Komene M, Karakawa M, Takekoshi T, Sakurai N, Minatani Y, Mitsui H, Tada Y, Saeki H, Asahina A, and Tamaki K. Early inflammatory changes in the “perilesional skin” of psoriatic plaques: is there interaction betweendendritic cells and keratinocytes?  J Invest Dermatol. 2007, Aug; 127(8): 1915-22. Epub 2007 Apr 19.

・Tanizaki H, Nakahigashi K, Miyachi Y, and Kabashima K. Comparison of the efficacy of fexofenadine 120 and 240 mg/day on chronic idiopathic urticarial and histamine-induced skin responses in Japanese populations. J Dermatolog Treat. 2013; Dec; 24(6): 477-80.

・Kyowa Hakko Kirin Co., Ltd. Clinical pharmacology study, internal data

・Conrad C, Gilliet M, Psoriasis: from pathogenesis to targeted therapies. Clin Rev Allergy Immunol(2018)54(1):102-13.10.1007/s12016-018-8668-1

・Cook PW, Piepkorn M, Clegg CH, Plowman GD, DeMay JM, et al. Transgenic expression of the human amphiregulin gene induces a psoriasis-like phenotype. J Clin Investig.1997;100:2286-94.