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Event: 1709

Key Event Title

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Psoriatic skin disease

Short name
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Skin disease
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Biological Context

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Level of Biological Organization
Individual

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  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 signaling 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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

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AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Skin disease by stimulation of TLR7/8 AdverseOutcome Evgeniia Kazymova (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

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Life Stages

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Sex Applicability

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Key Event Description

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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

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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

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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

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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. 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.