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

ABSTRACT: 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.

SUBMITTER: Conrad C

PROVIDER: S-EPMC5750213 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Conrad Curdin C Di Domizio Jeremy J Mylonas Alessio A Belkhodja Cyrine C Demaria Olivier O Navarini Alexander A AA Lapointe Anne-Karine AK French Lars E LE Vernez Maxime M Gilliet Michel M

Nature communications 20180102 1

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 redu ...[more]

PMID: 29295985

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Project description:Type I interferons (IFNs), mostly IFNα and IFNβ, and the type I IFN Signature are important in the pathogenesis of Systemic Lupus Erythematosus (SLE), an autoimmune chronic condition linked to inflammation. Both IFNα and IFNβ trigger a signaling cascade that, through the activation of JAK1, TYK2, STAT1 and STAT2, initiates gene transcription of IFN stimulated genes (ISGs). Noteworthy, other STAT family members and IFN Responsive Factors (IRFs) can also contribute to the activation of the IFN response. Aberrant type I IFN signaling, therefore, can exacerbate SLE by deregulated homeostasis leading to unnecessary persistence of the biological effects of type I IFNs. The etiopathogenesis of SLE is partially known and considered multifactorial. Family-based and genome wide association studies (GWAS) have identified genetic and transcriptional abnormalities in key molecules directly involved in the type I IFN signaling pathway, namely TYK2, STAT1 and STAT4, and IRF5. Gain-of-function mutations that heighten IFNα/β production, which in turn maintains type I IFN signaling, are found in other pathologies like the interferonopathies. However, the distinctive characteristics have yet to be determined. Signaling molecules activated in response to type I IFNs are upregulated in immune cell subsets and affected tissues of SLE patients. Moreover, Type I IFNs induce chromatin remodeling leading to a state permissive to transcription, and SLE patients have increased global and gene-specific epigenetic modifications, such as hypomethylation of DNA and histone acetylation. Epigenome wide association studies (EWAS) highlight important differences between SLE patients and healthy controls in Interferon Stimulated Genes (ISGs). The combination of environmental and genetic factors may stimulate type I IFN signaling transiently and produce long-lasting detrimental effects through epigenetic alterations. Substantial evidence for the pathogenic role of type I IFNs in SLE advocates the clinical use of neutralizing anti-type I IFN receptor antibodies as a therapeutic strategy, with clinical studies already showing promising results. Current and future clinical trials will determine whether drugs targeting molecules of the type I IFN signaling pathway, like non-selective JAK inhibitors or specific TYK2 inhibitors, may benefit people living with lupus.

Dataset Information

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

Publications

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

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