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Commentary |

Psoriasis Bench to Bedside Genetics Meets Immunology

Rajan P. Nair, PhD; Jun Ding, MS; Kristina Callis Duffin, MD; Cynthia Helms; John J. Voorhees, MD; Gerald G. Krueger, MD; Anne M. Bowcock, PhD; Goncalo R. Abeçasis, PhD; James T. Elder, MD, PhD
Arch Dermatol. 2009;145(4):462-464. doi:10.1001/archdermatol.2009.73.
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More than 25 years of accumulating evidence strongly implicates the immune system in the pathogenesis of psoriasis, including both acquired immunity (T cells) and innate host defense (macrophages, antigen-presenting cells, and keratinocytes). Psoriasis also has a strong genetic component, but the identity of the genes involved has largely remained obscure. In a study recently published in Nature Genetics,1 these 2 themes of psoriasis—genetics and immunology—come together in a coherent and clinically relevant way.

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Model of psoriasis integrating genetics and immunology. The majority of dermal T cells are CD4+ (purple circles). Of these, most are TH1, and approximately 5% express interleukin (IL)-17 (TH17, yellow halo). Most of the T cells in the epidermis are CD8+ (green circles), and about 5% of these express IL-17 (Tc17, yellow halo). HLA-Cw6 may be involved in the activation of CD8+ T cells by dendritic cells (DC, blue), and activated CD8+ T cells may recognize keratinocyte (KC) antigens presented in the context of HLA-Cw6. Some of these T cells are likely to be Tc17 cells. IL23A and IL12B encode the subunits of IL-23. IL23R encodes a subunit of the receptor for IL-23. IL4 and IL13 may participate in tipping the balance of CD4+ T cells toward TH2. TH1 cells stimulate the production of IL-23 by DC. In turn, IL-23 stimulates the production of IL-17 (and other cytokines such as IL-22) by TH17 cells. These cytokines stimulate KC proliferation (mitotic figures) and upregulate KC innate immune defense mechanisms, including defensin, psoriasin, and other proteins that are highly expressed in psoriasis lesions (etc). Macrophages (MΦ, orange) express tumor necrosis factor (TNF) receptors and toll-like receptors (TLRs), which signal to NF-κB in the nucleus. The proteins encoded by TNFAIP3 and TNIP1 bind to each other and block this signaling. Similar signaling pathways may also be active in other types of skin cells. IFN-γ indicates interferon gamma. Genetic regions implicated by this study are italicized and outlined in purple.

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