IL-17 and Other New Agents
John Y. M. Koo, Ethan C. Levin, Argentina Leon, Jashin J. Wu, Alice B. Gottlieb in Moderate to Severe Psoriasis, 2014
Psoriasis was once thought to be a disease primarily mediated by the Th1 axis [1]. In 2005, Th17 cells were recognized as a distinct subtype of helper T cells (see Chapter 13) and were linked to autoimmune inflammation in murine models [2,3]. Th17 cells are defined by their ability to secrete interleukin-17 (IL-17) cytokines. These proinflammatory cytokines have increased expression in psoriatic skin and are now recognized as playing a critical role in the pathogenesis of psoriasis (Figure 16.1) [4–13]. IL-17 cytokines as well as their cell surface receptors represent promising therapeutic targets [10]. Other proinflammatory cytokines secreted by Th17 cells thought to be key players in the pathogenesis of psoriasis include tumor necrosis factor-α (TNF-α) and IL-22 (for more information on TNF-α, see Chapters 11, 12, and 14). In the skin, IL-22 primarily targets epithelial cells leading to epidermal hyperplasia [14]. Stimulation of keratinocytes with IL-22 induces proliferation and inhibits terminal differentiation. In addition, expression of antimicrobial proteins (e.g., defensins) is increased. Recently, a new subset of cells was described known as Th22 cells, which also secrete IL-22 but lack the ability to secrete IL-17 [15]. This section will focus on the role of IL-17 in the pathogenesis of psoriasis and will summarize the clinical trials data for medications that target the IL-17 inflammatory pathway.
Bayesian Methods for Evaluating Drug Safety with Real-World Evidence
Harry Yang, Binbing Yu in Real-World Evidence in Drug Development and Evaluation, 2021
Psoriasis is a chronic autoimmune disease in which the growth cycle of skin cells is accelerated. Genetic and environmental factors induce immune responses mediated by several cytokines and chemokines, including interleukin-17 (IL-17) [27, 28]. IL-17 is a cytokine that controls cells and activates inflammation. For healthy individuals without psoriasis, these molecules stimulate the body's immune system into action only when there is a cut or a scrape, sending cells to the surface to fight infection and heal a wound. Psoriasis patients have 30 times more IL-17 than healthy people. Research has shown that stopping IL-17, or reducing it, may help clear psoriasis.
Helper T-Lymphocytes in Cardiovascular Diseases
Shyam S. Bansal in Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
The interleukin-17 (IL-17) family of cytokines and their ubiquitous receptors play a major role in host defense against pathogens. The IL-17 family (six known IL-17 family members: IL-17A–F) is characterized by a group of proteins with a highly conserved C-terminus domain comprising a cysteine-knot fold structure26, and among the IL-17 family members, IL-17A is the most widely studied. T-helper 17 (Th17) cells are known for their expression of pro-inflammatory cytokine interleukin-17 (IL-17) under the control of transcription factor RORγt, and they regulate the functioning of stromal cells in many tissues27. IL-17A, IL-17F, and IL-22 are the signature cytokines released from Th17 cells, and by inducing anti-microbial peptides from epithelial cells, and also by recruiting neutrophils during inflammation, they act as essential regulators of the mucosal host defense against extracellular bacteria and fungi28. These vital effects of IL-17 on stromal cells result in not only the production of other inflammatory cytokines but also the recruitment of leukocytes, especially neutrophils, thereby orchestrating a link between the innate and the adaptive immune systems. Th17 cells also play a critical role in the pathogenesis of several autoimmune and chronic tissue inflammatory diseases and subsequent organ failure29. The critical role of IL-17 in regulating pro-inflammatory networks could also be gleaned from the fact that, in addition to Th17 cells, several other immune cells such as dendritic cells, macrophages, natural killer cells, natural killer T-cells, and γδT-cells have also been shown to secrete IL-17 during activation30.
Anti-IL17 treatment in childhood chronic rheumatic diseases
Published in Expert Opinion on Biological Therapy, 2023
Valerio Maniscalco, Ilaria Maccora, Flavio Girodo, Marta Tomaselli, Gaia Priolo, Edoardo Marrani, Maria Vincenza Mastrolia, Ilaria Pagnini, Gabriele Simonini
Interleukin-17 (IL-17) is a widely studied group of cytokines that plays a key role in the pathogenesis of several inflammatory chronic diseases, in adults as well as children. The first description reported IL-17 in 1993 in murine T cells and it was initially named cytotoxic T lymphocyte-associated antigen 8 (CTLA8) [1]. Six IL-17 isoforms have been currently described, from IL-17A to IL-17F [2]. IL-17 is mainly produced by lymphocyte T helper 17 (Th17), along with other cells of the innate and adaptive immune responses, including macrophages, dendritic cells, natural killer cells, γδ-T cells and CD8+ cells [3]. IL-17 production is a keynote step to protect against extracellular pathogens, such as fungi and bacteria and it acts by upregulating the expression of numerous inflammatory cytokines (e.g. IL-6, tumor necrosis factor [TNF]-α), chemokines, and inflammatory factors (e.g. acute-phase proteins and complement) [3,4].
CNR2 rs2229579 and COMT Val158Met variants, but not CNR2 rs2501432, IL-17 rs763780 and UCP2 rs659366, contribute to susceptibility to substance use disorder in the Turkish population
Published in Psychiatry and Clinical Psychopharmacology, 2019
Selin Kurnaz, Ahmet Bulent Yazici, Ayse Feyda Nursal, Pinar Cetinay Aydin, Ayca Ongel Atar, Nazan Aydin, Zeliha Kincir, Sacide Pehlivan
Catechol-O-methyltransferase (COMT) is an enzyme found all over the mammalian central nervous system which breaks down the catecholamine neurotransmitters dopamine, epinephrine, and norepinephrine. A common G-to-A transition in exon 4 of the COMT gene, causing a valine (val)-to-methionine (met) substitution at the amino acid position 108 or 158 (depending on the splice variant), results in a four-fold reduction in enzyme activity in met homozygotes, whereas heterozygotes manifest intermediate activity [3]. The endocannabinoid system plays a role in susceptibility to substance abuse. There are two well-defined cannabinoid receptors (CNRs), CNR1/CB1 and CNR2/CB2, that mediate endocannabinoid signalling [4]. CNR2 has been classically defined as the peripheral cannabinoid receptor because CNR2 is expressed principally in some peripheral and immune cells [5]. Uncoupling protein 2 (UCP2) is a member of an anion-carrier protein family found in the mitochondrial inner membrane. In the central nervous system, mammalian UCP2 mRNA and protein expression occurs at highest levels in regions that could be described as high-risk for stress [6]. The Interleukin 17 (IL-17 or IL-17A) is a fundamental pro-inflammatory cytokine that is primarily released from T cells and is now believed to be the defining cytokine of a recently discovered new subset of T-helper cells, Th17 [7]. New studies have reported that cells of the central nervous system also express IL-17.
Ixekizumab and herpes zoster in an erythrodermic patient
Published in Baylor University Medical Center Proceedings, 2020
Corley C. Pruneda, Brett A. Austin, Daniel T. Wallis, Brent R. Paulger, Michelle B. Tarbox
Ixekizumab is an IL-17A antagonist approved by the US Food and Drug Administration for the treatment of moderate to severe plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. It is also indicated for active psoriatic arthritis and was recently approved for active ankylosing spondylitis. Interleukin-17 is a pro-inflammatory cytokine that plays an important role in host defense against bacterial and fungal infections. It works by inducing granulocyte-colony stimulating factor production and producing chemokines that attract neutrophils to sites of infection.1 Absence of the gene encoding IL-17 has been associated with chronic mucocutaneous candidiasis.2 It has also been implicated as a key mediator of the inflammation in psoriasis. Adverse reactions reported in patients taking ixekizumab include injection site reactions, upper respiratory tract infections, nausea, and tinea infections.3 To the authors’ knowledge, herpes zoster has not been reported in the literature in a patient treated with an IL-17 antagonist. Here we describe a case of herpes zoster in an erythrodermic patient treated with ixekizumab.
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