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Journal ArticleDOI

Psoriasis pathogenesis and the development of novel targeted immune therapies

01 Sep 2017-The Journal of Allergy and Clinical Immunology (J Allergy Clin Immunol)-Vol. 140, Iss: 3, pp 645-653
TL;DR: Clinical trial data for mAbs against IL‐17 signaling and newer IL‐23p19 antagonists underscore the central role of these cytokines as predominant drivers of psoriatic disease.
Abstract: Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell–mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a "feed forward" inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management.
Citations
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Journal ArticleDOI
TL;DR: Recently, the Food and Drug Administration approved multiple highly effective psoriasis therapies that disrupt IL-17 and IL-23 signaling in the skin, thus leading to a major paradigm shift in the way that psoriatic disease is managed.
Abstract: Psoriasis vulgaris is a common, heterogeneous, chronic inflammatory skin disease characterized by thickened, red, scaly plaques and systemic inflammation Psoriasis is also associated with multiple comorbid conditions, such as joint destruction, cardiovascular disease, stroke, hypertension, metabolic syndrome, and chronic kidney disease The discovery of IL-17-producing T cells in a mouse model of autoimmunity transformed our understanding of inflammation driven by T lymphocytes and associations with human inflammatory diseases, such as psoriasis Under the regulation of IL-23, T cells that produce high levels of IL-17 create a self-amplifying, feed-forward inflammatory response in keratinocytes that drives the development of thickened skin lesions infiltrated with a mixture of inflammatory cell populations Recently, the Food and Drug Administration approved multiple highly effective psoriasis therapies that disrupt IL-17 (secukinumab, ixekizumab, and brodalumab) and IL-23 (guselkumab and tildrakizumab) signaling in the skin, thus leading to a major paradigm shift in the way that psoriatic disease is managed

347 citations


Cites background from "Psoriasis pathogenesis and the deve..."

  • ...The effects of IL-17 on epidermal keratinocytes produce a feed-forward inflammatory response by activating C/EBPb and d, STAT1, and NF-kB, which amplify the primary signals driving the development of mature psoriatic plaques (24)....

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Journal ArticleDOI
TL;DR: The current knowledge around the cytokines belonging to the IL-17 family in relation to skin inflammation in general and psoriasis in particular is summarized, possible clinical implications are discussed, and a comprehensive understanding of the different roles played by theIL-17 cytokines are discussed.
Abstract: Psoriasis is a frequent chronic inflammatory skin disease, nowadays considered a major global health problem Several new drugs, targeting the IL-23/IL-17A pathway, have been recently licensed or are in clinical development These therapies represent a major improvement of the way in which psoriasis is managed, since they show an unprecedented efficacy on skin symptoms of psoriasis This has been made possible, thanks to an increasingly more accurate pathogenic view of psoriasis Today, the belief that Th17 cells mediate psoriasis is moving to the concept of psoriasis as an IL-17A-driven disease New questions arise at the horizon, given that IL-17A is part of a newly described family of cytokines, which has five distinct homologous: IL-17B, IL-17C, IL-17D, IL-17E, also known as IL-25 and IL-17F IL-17 family cytokines elicit similar effects in target cells, but simultaneously trigger different and sometimes opposite functions in a tissue-specific manner This is complicated by the fact that IL-17 cytokines show a high capacity of synergisms with other inflammatory stimuli In this review, we will summarize the current knowledge around the cytokines belonging to the IL-17 family in relation to skin inflammation in general and psoriasis in particular, and discuss possible clinical implications A comprehensive understanding of the different roles played by the IL-17 cytokines is crucial to appreciate current and developing therapies and to allow an effective pathogenesis- and mechanisms-driven drug design

269 citations


Cites background from "Psoriasis pathogenesis and the deve..."

  • ...This might explain why targeting specifically IL-23 through blockade of the p19 subunits represents a promising therapeutic option, even in a scenario dominated by anti-IL-17A treatments (44)....

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Journal ArticleDOI
TL;DR: The current review emphasizes the aberrant interplay of immune cells and skin-resident keratinocytes in establishing and sustaining inflammatory and immune responses in psoriasis.
Abstract: Psoriasis is a chronic inflammatory skin disease resulting from genetic, epigenetic, environmental, and lifestyle factors. To date, several immunopathogenic mechanisms of psoriasis have been elucidated, and, in the current model, the cross talk between autoreactive T cells and resident keratinocytes generates inflammatory and immune circuits responsible for the initiation, progression, and persistence of the disease. Several autoantigens derived from keratinocytes (i.e., LL37 cathelecidin/nucleic acid complexes, newly generated lipid antigens) have been identified, which may trigger initial activation of T cells, particularly IL-17-producing T cells, T helper (Th)1 and Th22 cells. Hence, lymphokines released in skin lesions are pivotal for keratinocyte activation and production of inflammatory molecules, which in turn lead to amplification of the local immune responses. Intrinsic genetic alterations of keratinocytes in the activation of signal transduction pathways dependent on T-cell-derived cytokines are also fundamental. The current review emphasizes the aberrant interplay of immune cells and skin-resident keratinocytes in establishing and sustaining inflammatory and immune responses in psoriasis.

240 citations

Journal ArticleDOI
TL;DR: To evaluate the efficacy and safety of ustekinumab in 3 randomized, placebo‐controlled studies in patients with axial spondyloarthritis, patients had nonradiographic axial SpA.
Abstract: Author(s): Deodhar, Atul; Gensler, Lianne S; Sieper, Joachim; Clark, Michael; Calderon, Cesar; Wang, Yuhua; Zhou, Yiying; Leu, Jocelyn H; Campbell, Kim; Sweet, Kristen; Harrison, Diane D; Hsia, Elizabeth C; van der Heijde, Desiree | Abstract: ObjectiveTo evaluate the efficacy and safety of ustekinumab in 3 randomized, placebo-controlled studies in patients with axial spondyloarthritis (SpA). Studies 1 and 2 included patients with radiographic axial SpA (anti-tumor necrosis factor [anti-TNF]-naive patients and patients with inadequate response or intolerance to anti-TNF, respectively); study 3 patients had nonradiographic axial SpA.MethodsIn all 3 studies, patients were randomly assigned (1:1:1) to receive subcutaneous ustekinumab at 45 mg or 90 mg or placebo up to 24 weeks, after which placebo-treated patients were rerandomized to receive ustekinumab at 45 mg or 90 mg. The primary end point in studies 1 and 2 was the proportion of patients who met the Assessment of SpondyloArthritis international Society criteria for 40% improvement in disease activity (achieved an ASAS40 response). The primary end point in study 3 was the proportion of patients who achieved an ASAS20 response. Other disease activity and safety measures were also evaluated. A week 24 analysis of study 1 was preplanned to determine continuation of studies 2 and 3.ResultsFor study 1, the primary and major secondary end points were not met, and the study was discontinued. As a result, studies 2 and 3 were prematurely discontinued before they were fully enrolled. For all 3 studies, neither ustekinumab dose group demonstrated clinically meaningful improvement over placebo on key efficacy end points. The proportion of patients experiencing adverse events in the ustekinumab groups was consistent with that in previous studies.ConclusionIn these 3 placebo-controlled trials, efficacy of ustekinumab in the treatment of axial SpA was not demonstrated. The safety profile was consistent with that of studies in other indications.

213 citations

Journal ArticleDOI
TL;DR: The central role of the IL-23/IL-17 axis is put into perspective within the crosstalk between components of the innate and the adaptive immune system to better understand the complex immune regulation in psoriasis.
Abstract: Research into the pathophysiology of psoriasis has shed light onto many fascinating immunological interactions and underlying genetic constellations. Most prominent among these is the crosstalk between components of the innate and the adaptive immune system and the crucial role of interleukins (IL)-23 and -17 within this network. While it is clear that IL-23 drives and maintains the differentiation of Th17 lymphocytes, many aspects of the regulation of IL-23 and IL-17 are not quite as straightforward and have been unraveled only recently. For example, we know now that Th17 cells are not the only source of IL-17 but that cells of the innate immune system also produce considerable amounts of this central effector cytokine. In addition, there is IL-23-independent production of IL-17. Besides other innate immune cells, neutrophilic granulocytes prominently contribute to IL-17-related immune regulations in psoriasis, and it appears that they employ several mechanisms including the formation of neutrophil extracellular traps (NETs). Here, we strive to put the central role of the IL-23/IL-17 axis into perspective within the crosstalk between components of the innate and the adaptive immune system. Our aim is to better understand the complex immune regulation in psoriasis, a disorder that has become a model disease for chronic inflammation.

149 citations


Cites background from "Psoriasis pathogenesis and the deve..."

  • ...Perhaps equally important, such therapies have taught us a lot about disease mechanisms (1, 2)....

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  • ...Clin Exp Immunol (2014) 176(2):266–74....

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  • ...J Invest Dermatol (2014) 134(2):415–22....

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References
More filters
Journal ArticleDOI
24 Jan 2002-Nature
TL;DR: As the need for new antibiotics becomes more pressing, could the design of anti-infective drugs based on the design principles these molecules teach us?
Abstract: Multicellular organisms live, by and large, harmoniously with microbes. The cornea of the eye of an animal is almost always free of signs of infection. The insect flourishes without lymphocytes or antibodies. A plant seed germinates successfully in the midst of soil microbes. How is this accomplished? Both animals and plants possess potent, broad-spectrum antimicrobial peptides, which they use to fend off a wide range of microbes, including bacteria, fungi, viruses and protozoa. What sorts of molecules are they? How are they employed by animals in their defence? As our need for new antibiotics becomes more pressing, could we design anti-infective drugs based on the design principles these molecules teach us?

7,657 citations

Journal ArticleDOI
TL;DR: The investigation of the differentiation, effector function, and regulation of Th17 cells has opened up a new framework for understanding T cell differentiation and now appreciate the importance of Th 17 cells in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune disease.
Abstract: CD4+ T cells, upon activation and expansion, develop into different T helper cell subsets with different cytokine profiles and distinct effector functions. Until recently, T cells were divided into Th1 or Th2 cells, depending on the cytokines they produce. A third subset of IL-17-producing effector T helper cells, called Th17 cells, has now been discovered and characterized. Here, we summarize the current information on the differentiation and effector functions of the Th17 lineage. Th17 cells produce IL-17, IL-17F, and IL-22, thereby inducing a massive tissue reaction owing to the broad distribution of the IL-17 and IL-22 receptors. Th17 cells also secrete IL-21 to communicate with the cells of the immune system. The differentiation factors (TGF-β plus IL-6 or IL-21), the growth and stabilization factor (IL-23), and the transcription factors (STAT3, RORγt, and RORα) involved in the development of Th17 cells have just been identified. The participation of TGF-β in the differentiation of Th17 cells places ...

4,548 citations

Journal ArticleDOI
TL;DR: Anti-TNF strategies have three variants: a humanized chimeric anti–TNF- α monoclonal antibody, a fully human monocolonal anti-T NF- α antibody, and a human p75 TNF-receptor Fc fusion protein.

2,084 citations

Journal ArticleDOI
08 Feb 2007-Nature
TL;DR: The results suggest that TH17 cells, through the production of both IL-22 and IL-17, might have essential functions in host defence and in the pathogenesis of autoimmune diseases such as psoriasis.
Abstract: Psoriasis is a chronic inflammatory skin disease characterized by hyperplasia of the epidermis (acanthosis), infiltration of leukocytes into both the dermis and epidermis, and dilation and growth of blood vessels. The underlying cause of the epidermal acanthosis in psoriasis is still largely unknown. Recently, interleukin (IL)-23, a cytokine involved in the development of IL-17-producing T helper cells (T(H)17 cells), was found to have a potential function in the pathogenesis of psoriasis. Here we show that IL-22 is preferentially produced by T(H)17 cells and mediates the acanthosis induced by IL-23. We found that IL-23 or IL-6 can directly induce the production of IL-22 from both murine and human naive T cells. However, the production of IL-22 and IL-17 from T(H)17 cells is differentially regulated. Transforming growth factor-beta, although crucial for IL-17 production, actually inhibits IL-22 production. Furthermore, IL-22 mediates IL-23-induced acanthosis and dermal inflammation through the activation of Stat3 (signal transduction and activators of transcription 3) in vivo. Our results suggest that T(H)17 cells, through the production of both IL-22 and IL-17, might have essential functions in host defence and in the pathogenesis of autoimmune diseases such as psoriasis. IL-22, as an effector cytokine produced by T cells, mediates the crosstalk between the immune system and epithelial cells.

1,825 citations


"Psoriasis pathogenesis and the deve..." refers background in this paper

  • ...IL-17 also acts synergistically with TNF to potentiate IL-17–induced transcription of several proinflammatory genes (eg, TNF, IL-1b, IL-6, and IL-8),47-50 which activate mDCs and promote the differentiation of T17 cells in the skin and draining lymph nodes.32,51 Epidermal hyperplasia, a hallmark of psoriatic plaques, is associated with STAT3 activation and indirectly regulated by J ALLERGY CLIN IMMUNOL SEPTEMBER 2017 648 HAWKES, CHAN, AND KRUEGER IL-17 through induction of IL-19 and/or IL-36 by keratinocytes.46 The increased proliferation of epidermal keratinocytes is likely further potentiated by IL-22 and possibly IL-20 because both of these cytokines are also activators of STAT3....

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  • ...The increased proliferation of epidermal keratinocytes is likely further potentiated by IL-22 and possibly IL-20 because both of these cytokines are also activators of STAT3.(52,53) This marked thickening of the rapidly proliferating epidermis is accompanied by retention of the keratinocyte nucleus (parakeratosis), as well as upregulation of IL-17–induced transcription factors (eg, C/EBPb or C/EBPd) and keratinocyte-derived gene products, such as S100A7/8/9, hBD2, lipocalin-2, and CCL20....

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Journal ArticleDOI
04 Oct 2007-Nature
TL;DR: The data uncover a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggest that this pathway may drive autoimmunity in psoriasis.
Abstract: Plasmacytoid dendritic cells (pDCs) sense viral and microbial DNA through endosomal Toll-like receptors to produce type 1 interferons. pDCs do not normally respond to self-DNA, but this restriction seems to break down in human autoimmune disease by an as yet poorly understood mechanism. Here we identify the antimicrobial peptide LL37 (also known as CAMP) as the key factor that mediates pDC activation in psoriasis, a common autoimmune disease of the skin. LL37 converts inert self-DNA into a potent trigger of interferon production by binding the DNA to form aggregated and condensed structures that are delivered to and retained within early endocytic compartments in pDCs to trigger Toll-like receptor 9. Thus, our data uncover a fundamental role of an endogenous antimicrobial peptide in breaking innate tolerance to self-DNA and suggest that this pathway may drive autoimmunity in psoriasis.

1,628 citations


"Psoriasis pathogenesis and the deve..." refers background or result in this paper

  • ...Psoriasis autoantigens In a recent study of 56 patients, Lande et al(26) found that peripheral blood in 75% of patients with moderate-to-severe psoriasis contained autoreactive CD4(1) or CD8(1) T cells against LL-37/ cathelicidin, a cationic antimicrobial peptide (AMP) produced by keratinocytes and other immune cells (eg, neutrophils) in response to bacterial/viral infections(27,28) or skin trauma.(29) The cytokine profile of these autoreactive T cells revealed increased levels of skin-homing receptors (eg, cutaneous lymphocyte antigen, CCR6, and CCR10) and a strong IFN-g and IL-17 phenotype consistent with previous studies examining the T-cell...

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  • ...Importantly, the authors also showed that LL-37 expression is upregulated in psoriatic plaques, correlates with disease activity, and results in direct activation of plasmacytoid dendritic cells (pDCs) and myeloid dendritic cells (mDCs) by forming a complex with nucleic acids (DNA and RNA) released after skin trauma.(29,31) These multimeric LL-37–nucleic acid complexes are protected from enzymatic degradation and enter dendritic cells (DCs) by way of specific Toll-like receptors....

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