Elsevier

Clinical Immunology

Volume 146, Issue 2, February 2013, Pages 131-139
Clinical Immunology

Review
Targeting IL-17 in psoriasis: From cutaneous immunobiology to clinical application

https://doi.org/10.1016/j.clim.2012.12.004Get rights and content

Abstract

Psoriasis vulgaris is a chronic, immune-mediated inflammatory skin disease associated with complex genetic susceptibility. Although the hallmark of psoriasis is characterized by cutaneous inflammation and keratinocyte hyperproliferation, recent studies show that the pathologic features observed in psoriasis arises as a result of innate and adaptive immune activation in genetically prone individuals. Studies focused on the microenvironment in the skin of psoriasis lesions have revealed novel cellular and cytokine abnormalities of the immune system. One pathway important is the role of the TH17/IL-17 dysregulation. The recent development of biologics that target the IL-17 cytokine pathway has confirmed the importance of TH17 and IL-17 homeostasis in the skin and yielded potent therapies in the treatment of psoriasis, and potentially other autoimmune diseases.

Highlights

► There has been progress in dissecting the genetics and immunobiology of psoriasis. ► TH17 and IL-17 play an important role in the pathogenesis of psoriasis. ► Biologics that target the IL-17 axis are well tolerated and effective in treating psoriasis. ► Disrupting the TH17/IL-17 axis may be a strategy to treat autoimmune diseases.

Introduction

Psoriasis vulgaris is a chronic, immune-mediated inflammatory skin disease associated with complex genetic susceptibility [1]. The estimated prevalence of psoriasis in the United States is 3%, with approximately 17% of these patients having moderate-to-severe plaque psoriasis [2]. Up to 30% of psoriasis patients have psoriatic arthritis [3]. The hallmark of psoriasis is characterized by cutaneous inflammation and keratinocytes hyperproliferation, currently hypothesized to be the consequence of pathologic innate and adaptive immune activation in genetically prone individuals.

Recent studies to dissect the molecular basis of psoriasis have led to a better understanding of this complex disease. Although the primary feature of psoriasis is excessive keratinocyte hyperproliferation, an immune role was suggested by the identification of activated T cells in the dermis and epidermis, an improved response of psoriasis patients to anti-T cell therapies and the resolution of lesions in patients with psoriasis after bone marrow transplant [1], [4]. Further evidence emerged from the clinical efficacy of cyclosporine, a calcineurin inhibitor, which targets the transcription factor nuclear factor of activated T cell (NFAT), and is critical for T cell activation and function [5]. These observations highlighted the contribution of T cells in a disease of excessive epidermal hyperplasia.

Section snippets

Psoriasis genetics

From recent studies, it is clear that numerous components of the immune system are defective in psoriasis, belonging to both the innate and adaptive immune system. Thus, psoriasis is a complex disease characterized by a complex interplay between multiple risk genes, environmental factors and various cells involved in innate and adaptive immunity [1], [6]. Recently, accumulating evidence shows that psoriasis has biased immune alterations, affecting the TH17/IL-23 and NF-κB signaling pathways as

Immune dysfunction in psoriasis

Studies focused on the role of the microenvironment in the skin of psoriasis lesions have revealed additional cellular and cytokine abnormalities of the immune system [25]. The ability to distinguish subtypes of immune cells has identified different DC populations that mediate response to antigen, and lymphocyte subpopulations in the skin that play a role in psoriasis [26]. From these findings, insight into the molecular cellular mechanisms of psoriasis has emerged to reveal the disordered

Role of dendritic cells in psoriasis

DCs are professional antigen presenting cells that play an essential role in regulating the balance between immunity and immunological tolerance [60]. Recent studies have demonstrated that DCs play an important role in psoriasis and may be the primary cell type that drives TH17 differentiation in psoriasis through the production of IL-6 and IL23, which are required for differentiation to the TH17 subtype as well as the proliferation and stabilization of TH17 cells, respectively [1], [50], [61],

Therapeutic agents in psoriasis: targeting IL-17

The application of human monoclonal antibodies to specific targets has been a successful approach in treating autoimmune disease. Psoriasis has been an ideal disease to study the critical role of cytokine pathways that become dysregulated, since clinical responses can be monitored and quantitated visually with the disappearance of psoriasis lesions.

With the identification of various cytokines abnormally expressed in psoriasis, a challenge is to identify cytokines that are “driver” cytokines or

Conflict of interest statement

Henry Wong received honorarium from Amgen and grant as an investigator with Amgen, Janssen, Abbott Labs and Celgene.

Maria Ariza received grant support from the National Psoriasis Foundation.

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