Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|Skin disease by stimulation of TLR7/8||KeyEvent|
Key Event Description
Psoriasis has been known to play a major role in the pathogenesis of T cell dysfunction, particularly overactivation of the Th17 pathway. Th17 cells are a subset of CD4 positive T helper cells newly found in 2005 as a cell population different from Th1 and Th2 (Lisa C. et al. 2007).
Serum IL-17 levels in psoriasis patients are significantly higher than in healthy individuals, and the neutralizing antibody Brodalumab against the IL-17A receptor has been shown to be effective in treating psoriasis (Gilliet et al. 2004). Furthermore, because the antibody preparations against IL-17 (Ixéquizumab [John K. et al. 2002]), Sequinumab (Szeimies et al. 2004)) are used for the treatment of psoriasis, the Th17 pathway for pathogenesis is considered to play an important role.
Psoriatic 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 dermal T cells Less up-regulation.（Cheuk et al. 2013）
IL-22, produced mainly by lesional epidermal CD4 T cells, is associated with the activation of keratinocytes and the formation of epidermal thickening, a prominent morphological feature of psoriasis. The lesional epidermal 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 the recruitment and activation of leukocytes to the skin.(Cheuk et al. 2013)
How It Is Measured or Detected
Flow cytometric analysis of psoriatic skin biopsy showed increased frequency of IL-17 + and IL-22 + CD4 + T cells, and IL-17 secretion was significantly increased. CD4 + cells making IL-17 or IL-22 expressed IL-23R, and the frequency of IL-17 +, CCR6 + and CCR4 + T cells increased. The frequency of IL-17 + and IL-22 + CD4 + T cells was increased compared with normal skin, and the proportion of IL-22 positive IL-17 + cells was high. There was also an increase in IL-22 producing cells (Th-22 cells) that do not produce IL-17 or IFNγ. (Benham et al. 2013)
Domain of Applicability
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）
- 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.
- 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.
- Rolf-Markus Szeimies, Marie-Jeanne P. Gerritsen, Girish Gupta,Jean Paul Ortonne, Stefano Serresi, Jens Bichel, James H. Lee, Terry L. Fox, Agustı́n Alomar. Imiquimod 5% cream for the treatment of actinic keratosis: results from a phase III, randomized, double-blind, vehicle-controlled, clinical trial with histology. J. Am. Acad. Dermatol. 2004, 51, 547-555.
- Stanley Cheak, Maria Wiken, Lennart Blomqvist, Susanne Nylen, Toomas Talme, Mona Stahle, and Liv Eidsmo. Epidermal Th22 and Tc17 Cells Form a Localized Disease Memory in Clinically Healed Psoriasis. J Immunol. 2014, Apr 1; 192(7): 3111-3120.
- 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.
- Norimasa Tamehiro, Kyoko Nishida, Yu Sugita, Kunihiro Hayakawa, Hiroyo Oda, Takeshi Nitta, Miwa Nakano, Akiko Nishioka, Reiko Yanobu-Takanashi, Motohito Goto, Tadashi Okamura, Reiko Adachi, Kazunari Kondo, Akimichi Morita, and Harumi Suzuki. Ras homolog gene family H(RhoH) deficiency induces psoriasis-like chronic dermatitis by promoting TH17 cell polarization. Jourmal of Allergy and Clinical Immunology 2019, May 5; 143, 1878-1891.