API

Event: 1709

Key Event Title

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Psoriatic skin disease

Short name

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Skin disease

Biological Context

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Level of Biological Organization
Individual



Key Event Components

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
Skin disease by stimulation of TLR7/8 AdverseOutcome

Stressors

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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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In psoriasis vulgaris, the S100 protein family psoriasin (sorazine) and koebnerisin (kebneridine) are overexpressed, and the epidermal antimicrobial peptide induced by IL-17 functions itself as a chemotactic factor and cytokine. It recruits CD4 + T cells and neutrophils to exacerbate inflammation. (Kanagawa Psoriasis Treatment Study Group)

A biopsy of the skin area of psoriasis and surrounding normal skin was performed, and immunohistological examination of the sections was performed. In psoriatic lesions, the number of activated dendritic cells was increased, and CD1a-positive Langerhans cells in the epidermis and CD83-positive CD1a-negative Langerin-negative CD11c-positive dermal dendritic cells in the epidermis boundary were observed. In normal skin, the number of wet cells was the same as in the lesion, but CD3-positive T lymphocytes were significantly less than in the lesion.

In the normal area, inflammatory keratin K6 and K16-positive keratinocytes were found, and the transcription factor C / EBPβ, which is normally expressed only in the granular layer of the normal epidermis, was expressed in the entire epidermis as in the lesion. This suggests that early inflammatory changes have already occurred in normal 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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A biopsy of the skin area and the surrounding normal skin of a patient with psoriasis vulgaris was performed, and immunohistological studies were performed using dendritic cell surface markers and lymphocyte surface markers as primary antibodies in the sections. In the vicinity of the psoriatic lesion, an increased number of activated dendritic cells was observed, and CD1a-positive Langerhans cells in the epidermis and CD83-positive CD1a-negative Langerin-negative CD11c-positive dermal dendritic cells in the epidermis boundary were observed. In normal skin, the number of wet cells was the same as in the lesion, but CD3-positive T lymphocytes were significantly less than in the lesion. In the normal area, inflammatory keratin K6 and K16-positive keratinocytes were found, and the transcription factor C / EBPβ, which is normally expressed only in the granular layer of the normal epidermis, was expressed in the entire epidermis as in the lesion. This suggests that early inflammatory changes have already occurred in normal 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)

Serum amyloid A: SAA was measured in 35 psoriasis patients and healthy humans. DNA microarray analysis in lesions of psoriasis patients showed that SAA levels were about 5 times higher than normal skin. The average SAA in psoriasis patients was 19.1 ug / ml, and the SAA after treatment was significantly reduced to an average of 6.9 ug / ml. There was a correlation between SAA and psoriasis severity score (PASI). In addition, amyloid A deposition, which is thought to be the result of prolonged chronic inflammation, was observed in the skin-stained section of the psoriatic lesion skin area. (J Dermatolog Treat. 2013; 24 (6): 477-80)
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.)


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.)


Regulatory Significance of the Adverse Outcome

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References

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  1. Kanagawa Psoriasis Treatment Study Group 2013.
  2. 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.
  3. 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.
  4. Kyowa Hakko Kirin Co., Ltd. Clinical pharmacology study, internal data