Journal Article

TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis

French, Lars E., Belkhodja, Cyrine, Demaria, Olivier, Mylonas, Alessio, Vernez, Maxime, Gilliet, Michel, Lapointe, Anne-Karine, Di Domizio, Jeremy, Conrad, Curdin, Navarini, Alexander A.

2018

Overview

Although anti-tumor necrosis factor (TNF) agents are highly effective in the treatment of psoriasis, 2–5% of treated patients develop psoriasis-like skin lesions called paradoxical psoriasis. The pathogenesis of this side effect and its distinction from classical psoriasis remain unknown. Here we show that skin lesions from patients with paradoxical psoriasis are characterized by a selective overexpression of type I interferons, dermal accumulation of plasmacytoid dendritic cells (pDC), and reduced T-cell numbers, when compared to classical psoriasis. Anti-TNF treatment prolongs type I interferon production by pDCs through inhibition of their maturation. The resulting type I interferon overexpression is responsible for the skin phenotype of paradoxical psoriasis, which, unlike classical psoriasis, is independent of T cells. These findings indicate that paradoxical psoriasis represents an ongoing overactive innate inflammatory process, driven by pDC-derived type I interferon that does not lead to T-cell autoimmunity. The pathogenesis of paradoxical psoriasis in patients receiving anti-TNF treatments for classical psoriasis is unclear. Here, the authors show that anti-TNF drugs enhance the production of type I interferon by plasmacytoid dendritic cells, causing skin lesions that, unlike classical psoriasis, lack T- cell autoimmunity.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/21 / 13/31 / 13/51 / 14/1 / 14/19 / 14/63 / 38/77 / 631/250/249/2510 / 631/250/2504/133/1412 / 631/45/127/1212 / 631/45/127/1220 / 64/60 / Adalimumab - adverse effects / Adalimumab - immunology / Adalimumab - therapeutic use / Adolescent / Adult / Aged / Animals / Antibodies, Monoclonal - adverse effects / Antibodies, Monoclonal - immunology / Antibodies, Monoclonal - therapeutic use / Anticancer properties / Autoimmunity / Autoimmunity - drug effects / Autoimmunity - immunology / Cells, Cultured / Crohn Disease - drug therapy / Crohn Disease - immunology / Crohn Disease - metabolism / Cytokines - genetics / Cytokines - immunology / Cytokines - metabolism / Dendritic cells / Dendritic Cells - drug effects / Dendritic Cells - immunology / Dendritic Cells - metabolism / Female / Humanities and Social Sciences / Humans / Inflammation / Infliximab - adverse effects / Infliximab - immunology / Infliximab - therapeutic use / Interferon / Interferon Type I - genetics / Interferon Type I - immunology / Interferon Type I - metabolism / Lesions / Lymphocytes / Lymphocytes T / Male / Mice, Inbred BALB C / Middle Aged / multidisciplinary / Pathogenesis / Patients / Psoriasis / Psoriasis - chemically induced / Psoriasis - immunology / Science / Science (multidisciplinary) / Skin diseases / T-Lymphocytes - drug effects / T-Lymphocytes - immunology / T-Lymphocytes - metabolism / Tumor necrosis factor / Tumor Necrosis Factor-alpha - antagonists & inhibitors / Tumor Necrosis Factor-alpha - immunology / Tumor Necrosis Factor-alpha - metabolism / Tumor necrosis factor-TNF / Young Adult